Cancers

47 pages, 9681 KiB

Open AccessEditor’s ChoiceReview

Targeting Autophagy for Cancer Treatment and Tumor Chemosensitization

by Marta Pérez-Hernández, Alain Arias, David Martínez-García, Ricardo Pérez-Tomás, Roberto Quesada and Vanessa Soto-Cerrato

Cancers 2019, 11(10), 1599; https://doi.org/10.3390/cancers11101599 - 19 Oct 2019

Cited by 103 | Viewed by 6905

Abstract

Autophagy is a tightly regulated catabolic process that facilitates nutrient recycling from damaged organelles and other cellular components through lysosomal degradation. Deregulation of this process has been associated with the development of several pathophysiological processes, such as cancer and neurodegenerative diseases. In cancer, [...] Read more.

Autophagy is a tightly regulated catabolic process that facilitates nutrient recycling from damaged organelles and other cellular components through lysosomal degradation. Deregulation of this process has been associated with the development of several pathophysiological processes, such as cancer and neurodegenerative diseases. In cancer, autophagy has opposing roles, being either cytoprotective or cytotoxic. Thus, deciphering the role of autophagy in each tumor context is crucial. Moreover, autophagy has been shown to contribute to chemoresistance in some patients. In this regard, autophagy modulation has recently emerged as a promising therapeutic strategy for the treatment and chemosensitization of tumors, and has already demonstrated positive clinical results in patients. In this review, the dual role of autophagy during carcinogenesis is discussed and current therapeutic strategies aimed at targeting autophagy for the treatment of cancer, both under preclinical and clinical development, are presented. The use of autophagy modulators in combination therapies, in order to overcome drug resistance during cancer treatment, is also discussed as well as the potential challenges and limitations for the use of these novel therapeutic strategies in the clinic. Full article

(This article belongs to the Special Issue The Role of Autophagy in Cancer Progression and Drug Resistance)

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21 pages, 1419 KiB

Open AccessEditor’s ChoiceReview

Acute Promyelocytic Leukemia: Update on the Mechanisms of Leukemogenesis, Resistance and on Innovative Treatment Strategies

by N. I. Noguera, G. Catalano, C. Banella, M. Divona, I. Faraoni, T. Ottone, W. Arcese and M. T. Voso

Cancers 2019, 11(10), 1591; https://doi.org/10.3390/cancers11101591 - 18 Oct 2019

Cited by 74 | Viewed by 9045

Abstract

This review highlights new findings that have deepened our understanding of the mechanisms of leukemogenesis, therapy and resistance in acute promyelocytic leukemia (APL). Promyelocytic leukemia-retinoic acid receptor α (PML-RARa) sets the cellular landscape of acute promyelocytic leukemia (APL) by repressing the transcription of [...] Read more.

This review highlights new findings that have deepened our understanding of the mechanisms of leukemogenesis, therapy and resistance in acute promyelocytic leukemia (APL). Promyelocytic leukemia-retinoic acid receptor α (PML-RARa) sets the cellular landscape of acute promyelocytic leukemia (APL) by repressing the transcription of RARa target genes and disrupting PML-NBs. The RAR receptors control the homeostasis of tissue growth, modeling and regeneration, and PML-NBs are involved in self-renewal of normal and cancer stem cells, DNA damage response, senescence and stress response. The additional somatic mutations in APL mainly involve FLT3, WT1, NRAS, KRAS, ARID1B and ARID1A genes. The treatment outcomes in patients with newly diagnosed APL improved dramatically since the advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). ATRA activates the transcription of blocked genes and degrades PML-RARα, while ATO degrades PML-RARa by promoting apoptosis and has a pro-oxidant effect. The resistance to ATRA and ATO may derive from the mutations in the RARa ligand binding domain (LBD) and in the PML-B2 domain of PML-RARa, but such mutations cannot explain the majority of resistances experienced in the clinic, globally accounting for 5–10% of cases. Several studies are ongoing to unravel clonal evolution and resistance, suggesting the therapeutic potential of new retinoid molecules and combinatorial treatments of ATRA or ATO with different drugs acting through alternative mechanisms of action, which may lead to synergistic effects on growth control or the induction of apoptosis in APL cells. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia)

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26 pages, 1099 KiB

Open AccessEditor’s ChoiceReview

Breast Cancer Stem Cells as Drivers of Tumor Chemoresistance, Dormancy and Relapse: New Challenges and Therapeutic Opportunities

by Maria Laura De Angelis, Federica Francescangeli and Ann Zeuner

Cancers 2019, 11(10), 1569; https://doi.org/10.3390/cancers11101569 - 15 Oct 2019

Cited by 112 | Viewed by 7908

Abstract

Breast cancer is the most frequent cancer among women worldwide. Therapeutic strategies to prevent or treat metastatic disease are still inadequate although great progress has been made in treating early-stage breast cancer. Cancer stem-like cells (CSCs) that are endowed with high plasticity and [...] Read more.

Breast cancer is the most frequent cancer among women worldwide. Therapeutic strategies to prevent or treat metastatic disease are still inadequate although great progress has been made in treating early-stage breast cancer. Cancer stem-like cells (CSCs) that are endowed with high plasticity and self-renewal properties have been shown to play a key role in breast cancer development, progression, and metastasis. A subpopulation of CSCs that combines tumor-initiating capacity and a dormant/quiescent/slow cycling status is present throughout the clinical history of breast cancer patients. Dormant/quiescent/slow cycling CSCs are a key component of tumor heterogeneity and they are responsible for chemoresistance, tumor migration, and metastatic dormancy, defined as the ability of CSCs to survive in target organs and generate metastasis up to two decades after diagnosis. Understanding the strategies that are used by CSCs to resist conventional and targeted therapies, to interact with their niche, to escape immune surveillance, and finally to awaken from dormancy is of key importance to prevent and treat metastatic cancer. This review summarizes the current understanding of mechanisms involved in CSCs chemoresistance, dissemination, and metastasis in breast cancer, with a particular focus on dormant cells. Finally, we discuss how advancements in the detection, molecular understanding, and targeting of dormant CSCs will likely open new therapeutic avenues for breast cancer treatment. Full article

(This article belongs to the Special Issue Breast Cancer Stem Cells: Therapy Resistance and Novel Therapeutic Targets)

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13 pages, 1298 KiB

Open AccessEditor’s ChoiceArticle

Comprehensive Metabolomic Search for Biomarkers to Differentiate Early Stage Hepatocellular Carcinoma from Cirrhosis

by Da Jung Kim, Eun Ju Cho, Kyung-Sang Yu, In-Jin Jang, Jung-Hwan Yoon, Taesung Park and Joo-Youn Cho

Cancers 2019, 11(10), 1497; https://doi.org/10.3390/cancers11101497 - 06 Oct 2019

Cited by 54 | Viewed by 4666

Abstract

The established biomarker for hepatocellular carcinoma (HCC), serum α-fetoprotein (AFP), has suboptimal performance in early disease stages. This study aimed to develop a metabolite panel to differentiate early-stage HCC from cirrhosis. Cross-sectional metabolomic analyses of serum samples were performed for 53 and 47 [...] Read more.

The established biomarker for hepatocellular carcinoma (HCC), serum α-fetoprotein (AFP), has suboptimal performance in early disease stages. This study aimed to develop a metabolite panel to differentiate early-stage HCC from cirrhosis. Cross-sectional metabolomic analyses of serum samples were performed for 53 and 47 patients with early HCC and cirrhosis, respectively, and 50 matched healthy controls. Results were validated in 82 and 80 patients with early HCC and cirrhosis, respectively. To retain a broad spectrum of metabolites, technically distinct analyses (global metabolomic profiling using gas chromatography time-of-flight mass spectrometry and targeted analyses using liquid chromatography with tandem mass spectrometry) were employed. Multivariate analyses classified distinct metabolites; logistic regression was employed to construct a prediction model for HCC diagnosis. Five metabolites (methionine, proline, ornithine, pimelylcarnitine, and octanoylcarnitine) were selected in a panel. The panel distinguished HCC from cirrhosis and normal controls, with an area under the receiver operating curve (AUC) of 0.82; this was significantly better than that of AFP (AUC: 0.75). During validation, the panel demonstrated significantly better predictability (AUC: 0.94) than did AFP (AUC: 0.78). Defects in ammonia recycling, the urea cycle, and amino acid metabolism, demonstrated on enrichment pathway analysis, may reliably distinguish HCC from cirrhosis. Compared with AFP alone, the metabolite panel substantially improved early-stage HCC detection. Full article

(This article belongs to the Special Issue Human Hepatocellular Carcinoma (HCC))

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20 pages, 4485 KiB

Open AccessEditor’s ChoiceArticle

STAT3 Activity Promotes Programmed-Death Ligand 1 Expression and Suppresses Immune Responses in Breast Cancer

by Ioannis Zerdes, Majken Wallerius, Emmanouil G. Sifakis, Tatjana Wallmann, Stina Betts, Margarita Bartish, Nikolaos Tsesmetzis, Nicholas P. Tobin, Christos Coucoravas, Jonas Bergh, George Z. Rassidakis, Charlotte Rolny and Theodoros Foukakis

Cancers 2019, 11(10), 1479; https://doi.org/10.3390/cancers11101479 - 01 Oct 2019

Cited by 59 | Viewed by 6188

Abstract

Signal transducer and activator of transcription 3 (STAT3) is an oncogene and multifaceted transcription factor involved in multiple cellular functions. Its role in modifying anti-tumor immunity has been recently recognized. In this study, the biologic effects of STAT3 on immune checkpoint expression and [...] Read more.

Signal transducer and activator of transcription 3 (STAT3) is an oncogene and multifaceted transcription factor involved in multiple cellular functions. Its role in modifying anti-tumor immunity has been recently recognized. In this study, the biologic effects of STAT3 on immune checkpoint expression and anti-tumor responses were investigated in breast cancer (BC). A transcriptional signature of phosphorylated STAT3 was positively correlated with PD-L1 expression in two independent cohorts of early BC. Pharmacologic inhibition and gene silencing of STAT3 led to decreased Programmed Death Ligand 1 (PD-L1) expression levels in vitro, and resulted as well in reduction of tumor growth and decreased metastatic dissemination in a mammary carcinoma mouse model. The hampering of tumor progression was correlated to an anti-tumoral macrophage phenotype and accumulation of natural-killer cells, but also in reduced accrual of cytotoxic lymphocytes. In human BC, pro-tumoral macrophages correlated to PD-L1 expression, proliferation status and higher grade of malignancy, indicating a subset of patients with immunosuppressive properties. In conclusion, this study provides evidence for STAT3-mediated regulation of PD-L1 and modulation of immune microenvironment in BC. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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38 pages, 1835 KiB

Open AccessEditor’s ChoiceReview

Current Perspectives in Cancer Immunotherapy

by Theodoulakis Christofi, Stavroula Baritaki, Luca Falzone, Massimo Libra and Apostolos Zaravinos

Cancers 2019, 11(10), 1472; https://doi.org/10.3390/cancers11101472 - 30 Sep 2019

Cited by 140 | Viewed by 15277

Abstract

Different immunotherapeutic approaches have proved to be of significant clinical value to many patients with different types of advanced cancer. However, we need more precise immunotherapies and predictive biomarkers to increase the successful response rates. The advent of next generation sequencing technologies and [...] Read more.

Different immunotherapeutic approaches have proved to be of significant clinical value to many patients with different types of advanced cancer. However, we need more precise immunotherapies and predictive biomarkers to increase the successful response rates. The advent of next generation sequencing technologies and their applications in immuno-oncology has helped us tremendously towards this aim. We are now moving towards the realization of personalized medicine, thus, significantly increasing our expectations for a more successful management of the disease. Here, we discuss the current immunotherapeutic approaches against cancer, including immune checkpoint blockade with an emphasis on anti-PD-L1 and anti-CTLA-4 monoclonal antibodies. We also analyze a growing list of other co-inhibitory and co-stimulatory markers and emphasize the mechanism of action of the principal pathway for each of these, as well as on drugs that either have been FDA-approved or are under clinical investigation. We further discuss recent advances in other immunotherapies, including cytokine therapy, adoptive cell transfer therapy and therapeutic vaccines. We finally discuss the modulation of gut microbiota composition and response to immunotherapy, as well as how tumor-intrinsic factors and immunological processes influence the mutational and epigenetic landscape of progressing tumors and response to immunotherapy but also how immunotherapeutic intervention influences the landscape of cancer neoepitopes and tumor immunoediting. Full article

(This article belongs to the Special Issue New Insights into Cancer Vaccines and Immunotherapy)

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11 pages, 1749 KiB

Open AccessEditor’s ChoiceArticle

Increased Plasmatic Levels of PSA-Expressing Exosomes Distinguish Prostate Cancer Patients from Benign Prostatic Hyperplasia: A Prospective Study

by Mariantonia Logozzi, Daniela F. Angelini, Alessandro Giuliani, Davide Mizzoni, Rossella Di Raimo, Martina Maggi, Alessandro Gentilucci, Vittorio Marzio, Stefano Salciccia, Giovanna Borsellino, Luca Battistini, Alessandro Sciarra and Stefano Fais

Cancers 2019, 11(10), 1449; https://doi.org/10.3390/cancers11101449 - 27 Sep 2019

Cited by 67 | Viewed by 7394

Abstract

Prostate Specific Antigen (PSA) fails to discriminate between benign prostatic hyperplasia (BPH) and Prostate Cancer (PCa), resulting in large numbers of unnecessary biopsies and missed cancer diagnoses. Nanovesicles called exosomes are directly detectable in patient plasma and here we explore the potential use [...] Read more.

Prostate Specific Antigen (PSA) fails to discriminate between benign prostatic hyperplasia (BPH) and Prostate Cancer (PCa), resulting in large numbers of unnecessary biopsies and missed cancer diagnoses. Nanovesicles called exosomes are directly detectable in patient plasma and here we explore the potential use of plasmatic exosomes expressing PSA (Exo-PSA) in distinguishing healthy individuals, BPH, and PCa. Exosomes were obtained from plasma samples of 80 PCa, 80 BPH, and 80 healthy donors (CTR). Nanoparticle Tracking Analysis (NTA), immunocapture-based ELISA (IC-ELISA), and nanoscale flow-cytometry (NSFC), were exploited to detect and characterize plasmatic exosomes. Statistical analysis showed that plasmatic exosomes expressing both CD81 and PSA were significantly higher in PCa as compared to both BPH and CTR, reaching 100% specificity and sensitivity in distinguishing PCa patients from healthy individuals. IC-ELISA, NSFC, and Exo-PSA consensus score (EXOMIX) showed 98% to 100% specificity and sensitivity for BPH-PCa discrimination. This study outperforms the conventional PSA test with a minimally invasive widely exploitable approach. Full article

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15 pages, 1085 KiB

Open AccessEditor’s ChoiceReview

Tumour Microenvironment and Immune Evasion in EGFR Addicted NSCLC: Hurdles and Possibilities

by Antonio Santaniello, Fabiana Napolitano, Alberto Servetto, Pietro De Placido, Nicola Silvestris, Cataldo Bianco, Luigi Formisano and Roberto Bianco

Cancers 2019, 11(10), 1419; https://doi.org/10.3390/cancers11101419 - 24 Sep 2019

Cited by 48 | Viewed by 6308

Abstract

In the last few years, the treatment strategy in Non-Small Cell Lung Cancer (NSCLC) patients has been heavily modified by the introduction of the immune-checkpoint inhibitors. Anti-programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) therapy has improved both progression-free and the overall [...] Read more.

In the last few years, the treatment strategy in Non-Small Cell Lung Cancer (NSCLC) patients has been heavily modified by the introduction of the immune-checkpoint inhibitors. Anti-programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) therapy has improved both progression-free and the overall survival in almost all subgroups of patients, with or without PDL1 expression, with different degrees of responses. However, there are patients that are not benefitting from this treatment. A defined group of immune-checkpoint inhibitors non-responder tumours carry EGFR (epidermal growth factor receptor) mutations: nowadays, anti-PD-1/PD-L1 clinical trials often do not involve this type of patient and the use of immune-checkpoint inhibitors are under evaluation in this setting. Our review aims to elucidate the mechanisms underlying this resistance: we focused on evaluating the role of the tumour microenvironment, including infiltrating cells, cytokines, secreted factors, and angiogenesis, and its interaction with the tumour tissue. Finally, we analysed the possible role of immunotherapy in EGFR mutated tumours. Full article

(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)

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13 pages, 5407 KiB

Open AccessEditor’s ChoiceArticle

CD8+ and Regulatory T cells Differentiate Tumor Immune Phenotypes and Predict Survival in Locally Advanced Head and Neck Cancer

by Alessia Echarti, Markus Hecht, Maike Büttner-Herold, Marlen Haderlein, Arndt Hartmann, Rainer Fietkau and Luitpold Distel

Cancers 2019, 11(9), 1398; https://doi.org/10.3390/cancers11091398 - 19 Sep 2019

Cited by 59 | Viewed by 4089

Abstract

Background: The tumor immune status “inflamed”, “immune excluded”, and “desert” might serve as a predictive parameter. We studied these three cancer immune phenotypes while using a simple immunohistochemical algorithm. Methods: Pre-treatment tissue samples of 280 patients with locally advanced HNSCC treated with radiochemotherapy [...] Read more.

Background: The tumor immune status “inflamed”, “immune excluded”, and “desert” might serve as a predictive parameter. We studied these three cancer immune phenotypes while using a simple immunohistochemical algorithm. Methods: Pre-treatment tissue samples of 280 patients with locally advanced HNSCC treated with radiochemotherapy were analyzed. A double staining of CD8+ cytotoxic T cells (CTL) and FoxP3+ (Treg) was performed and the cell density was evaluated in the intraepithelial and stromal compartment of the tumor. Results: The classification of tumors as “immune desert” when stromal CTL were ≤ 50 cells/mm², “inflamed” when intraepithelial CTL were > 500 cells/mm², and as “excluded” when neither of these definitions met these cut off values allowed the best discrimination regarding overall survival. These groups had median OS periods of 37, 61, and 85 months, respectively. In “immune desert” and “immune excluded” tumors high Treg tended to worsen OS, but in “inflamed” tumors high Treg clearly improved OS. Conclusions: We propose that, in locally advanced HNSCC, the tumor immune state “inflamed”, “immune excluded”, and “immune desert” can be defined by intraepithelial and stromal CTL. Tregs can further subdivide these groups. The opposing effects of Tregs in the different groups might be the reason for the inconsistency of Tregs prognostic values published earlier. Full article

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23 pages, 1979 KiB

Open AccessEditor’s ChoiceReview

Hyperglycemia Associated Metabolic and Molecular Alterations in Cancer Risk, Progression, Treatment, and Mortality

by Pranay Ramteke, Ankita Deb, Varsha Shepal and Manoj Kumar Bhat

Cancers 2019, 11(9), 1402; https://doi.org/10.3390/cancers11091402 - 19 Sep 2019

Cited by 74 | Viewed by 12938

Abstract

Cancer and diabetes are amongst the leading causes of deaths worldwide. There is an alarming rise in cancer incidences and mortality, with approximately 18.1 million new cases and 9.6 million deaths in 2018. A major contributory but neglected factor for risk of neoplastic [...] Read more.

Cancer and diabetes are amongst the leading causes of deaths worldwide. There is an alarming rise in cancer incidences and mortality, with approximately 18.1 million new cases and 9.6 million deaths in 2018. A major contributory but neglected factor for risk of neoplastic transformation is hyperglycemia. Epidemiologically too, lifestyle patterns resulting in high blood glucose level, with or without the role of insulin, are more often correlated with cancer risk, progression, and mortality. The two conditions recurrently exist in comorbidity, and their interplay has rendered treatment regimens more challenging by restricting the choice of drugs, affecting surgical consequences, and having associated fatal complications. Limited comprehensive literature is available on their correlation, and a lack of clarity in understanding in such comorbid conditions contributes to higher mortality rates. Hence, a critical analysis of the elements responsible for enhanced mortality due to hyperglycemia-cancer concomitance is warranted. Given the lifestyle changes in the human population, increasing metabolic disorders, and glucose addiction of cancer cells, hyperglycemia related complications in cancer underline the necessity for further in-depth investigations. This review, therefore, attempts to shed light upon hyperglycemia associated factors in the risk, progression, mortality, and treatment of cancer to highlight important mechanisms and potential therapeutic targets. Full article

(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)

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20 pages, 363 KiB

Open AccessEditor’s ChoiceReview

Current Treatment Options for Metastatic Hormone-Sensitive Prostate Cancer

by Carlo Cattrini, Elena Castro, Rebeca Lozano, Elisa Zanardi, Alessandra Rubagotti, Francesco Boccardo and David Olmos

Cancers 2019, 11(9), 1355; https://doi.org/10.3390/cancers11091355 - 12 Sep 2019

Cited by 53 | Viewed by 9238

Abstract

The possible treatments options for metastatic hormone-sensitive prostate cancer (mHSPC) have dramatically increased during the last years. The old backbone, which androgen-deprivation therapy (ADT) is the exclusive approach for hormone-naïve patients, has been disrupted. Despite the fact that several high-quality, randomized, controlled phase [...] Read more.

The possible treatments options for metastatic hormone-sensitive prostate cancer (mHSPC) have dramatically increased during the last years. The old backbone, which androgen-deprivation therapy (ADT) is the exclusive approach for hormone-naïve patients, has been disrupted. Despite the fact that several high-quality, randomized, controlled phase 3 trials have been conducted in this setting, no direct comparison is currently available among the different strategies. Inadequate power, absence of preplanning and small sample size frequently affect the subgroup analyses according to disease volume or patient’s risk. The choice between ADT alone and ADT combined with docetaxel, abiraterone acetate, enzalutamide, apalutamide or radiotherapy to the primary tumor remains challenging. Factors that are related to the tumor, patient or drug side effects, currently guide these clinical decisions. This comprehensive review aims to indirectly compare the phase 3 trials in the mHSPC setting, in order to extrapolate data useful for treatment selection, providing also perspectives on future biomarkers. Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

36 pages, 2366 KiB

Open AccessEditor’s ChoiceReview

Triple-Negative Breast Cancer: Current Understanding and Future Therapeutic Breakthrough Targeting Cancer Stemness

by Kha-Liang Lee, Yung-Che Kuo, Yuan-Soon Ho and Yen-Hua Huang

Cancers 2019, 11(9), 1334; https://doi.org/10.3390/cancers11091334 - 09 Sep 2019

Cited by 150 | Viewed by 17967

Abstract

Triple-negative breast cancer (TNBC) is cancer that tested as negative for estrogen receptors (ER), progesterone receptors (PR), and excess human epidermal growth factor receptor 2 (HER2) protein which accounts for 15%–20% of all breast cancer cases. TNBC is considered to be a poorer [...] Read more.

Triple-negative breast cancer (TNBC) is cancer that tested as negative for estrogen receptors (ER), progesterone receptors (PR), and excess human epidermal growth factor receptor 2 (HER2) protein which accounts for 15%–20% of all breast cancer cases. TNBC is considered to be a poorer prognosis than other types of breast cancer, mainly because it involves more aggressive phenotypes that are similar to stem cell–like cancer cells (cancer stem cell, CSC). Thus, targeted treatment of TNBC remains a major challenge in clinical practice. This review article surveys the latest evidence concerning the role of genomic alteration in current TNBC treatment responses, current clinical trials and potential targeting sites, CSC and drug resistance, and potential strategies targeting CSCs in TNBC. Furthermore, the role of insulin-like growth factor 1 receptor (IGF-1R) and nicotinic acetylcholine receptors (nAChR) in stemness expression, chemoresistance, and metastasis in TNBC and their relevance to potential treatments are also discussed and highlighted. Full article

(This article belongs to the Special Issue Breast Cancer Stem Cells: Therapy Resistance and Novel Therapeutic Targets)

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24 pages, 447 KiB

Open AccessEditor’s ChoiceReview

STAT3, a Master Regulator of Anti-Tumor Immune Response

by Cédric Rébé and François Ghiringhelli

Cancers 2019, 11(9), 1280; https://doi.org/10.3390/cancers11091280 - 30 Aug 2019

Cited by 69 | Viewed by 6990

Abstract

Immune cells in the tumor microenvironment regulate cancer growth. Thus cancer progression is dependent on the activation or repression of transcription programs involved in the proliferation/activation of lymphoid and myeloid cells. One of the main transcription factors involved in many of these pathways [...] Read more.

Immune cells in the tumor microenvironment regulate cancer growth. Thus cancer progression is dependent on the activation or repression of transcription programs involved in the proliferation/activation of lymphoid and myeloid cells. One of the main transcription factors involved in many of these pathways is the signal transducer and activator of transcription 3 (STAT3). In this review we will focus on the role of STAT3 and its regulation, e.g., by phosphorylation or acetylation in immune cells and how it might impact immune cell function and tumor progression. Moreover, we will review the ability of STAT3 to regulate checkpoint inhibitors. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

20 pages, 606 KiB

Open AccessEditor’s ChoiceReview

The PI3K/AKT/mTOR and CDK4/6 Pathways in Endocrine Resistant HR+/HER2− Metastatic Breast Cancer: Biological Mechanisms and New Treatments

by Daniele Presti and Erica Quaquarini

Cancers 2019, 11(9), 1242; https://doi.org/10.3390/cancers11091242 - 24 Aug 2019

Cited by 75 | Viewed by 12791

Abstract

Endocrine-based treatments are the normal standard-of-care in women with hormone receptor-positive/Human Epidermal growth factor Receptor 2-negative metastatic breast cancer. Despite the well-known efficacy of these drugs as first-line therapies, about 50% of women develop endocrine resistance and disease progression. The treatment of these [...] Read more.

Endocrine-based treatments are the normal standard-of-care in women with hormone receptor-positive/Human Epidermal growth factor Receptor 2-negative metastatic breast cancer. Despite the well-known efficacy of these drugs as first-line therapies, about 50% of women develop endocrine resistance and disease progression. The treatment of these patients has represented one of the most important research fields in the last few years, with several multicenter phase II/III trials published or still ongoing. Novel therapies, such as cyclin-dependent kinase (CDK)4/6 and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) inhibitors, have significantly changed the prognosis of patients progressing to a previous endocrine treatment, allowing a great benefit in terms of progression-free survival and, in some cases, of overall survival. However, identifying response predictors is essential for the rational use of these drugs to avoid unnecessary toxicity and costs, and to ensure the optimal therapeutic sequence is used. In this review, we analyze the PI3K/AKT/mTOR and CDK4/6 pathways and their roles in endocrine resistant metastatic breast cancer. We then focus on the new treatments developed and the roles of these drugs in overcoming endocrine resistance, describing the latest clinical trials that led to the approval of the drugs in clinical practice. Full article

(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)

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17 pages, 2558 KiB

Open AccessEditor’s ChoiceReview

Targeting Heat Shock Protein 27 in Cancer: A Druggable Target for Cancer Treatment?

by Seul-Ki Choi, Heejin Kam, Kye-Young Kim, Suk In Park and Yun-Sil Lee

Cancers 2019, 11(8), 1195; https://doi.org/10.3390/cancers11081195 - 16 Aug 2019

Cited by 77 | Viewed by 8252

Abstract

Heat shock protein 27 (HSP27), induced by heat shock, environmental, and pathophysiological stressors, is a multi-functional protein that acts as a protein chaperone and an antioxidant. HSP27 plays a significant role in the inhibition of apoptosis and actin cytoskeletal remodeling. HSP27 is upregulated [...] Read more.

Heat shock protein 27 (HSP27), induced by heat shock, environmental, and pathophysiological stressors, is a multi-functional protein that acts as a protein chaperone and an antioxidant. HSP27 plays a significant role in the inhibition of apoptosis and actin cytoskeletal remodeling. HSP27 is upregulated in many cancers and is associated with a poor prognosis, as well as treatment resistance, whereby cells are protected from therapeutic agents that normally induce apoptosis. This review highlights the most recent findings and role of HSP27 in cancer, as well as the strategies for using HSP27 inhibitors for therapeutic purposes. Full article

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20 pages, 845 KiB

Open AccessEditor’s ChoiceReview

Reactive Oxygen Species in the Tumor Microenvironment: An Overview

by Frank Weinberg, Nithya Ramnath and Deepak Nagrath

Cancers 2019, 11(8), 1191; https://doi.org/10.3390/cancers11081191 - 16 Aug 2019

Cited by 277 | Viewed by 17140

Abstract

Reactive oxygen species (ROS) are important signaling molecules in cancer. The level of ROS will determine physiological effects. While high levels of ROS can cause damage to tissues and cell death, low levels of ROS can have a proliferative effect. ROS are produced [...] Read more.

Reactive oxygen species (ROS) are important signaling molecules in cancer. The level of ROS will determine physiological effects. While high levels of ROS can cause damage to tissues and cell death, low levels of ROS can have a proliferative effect. ROS are produced by tumor cells but also cellular components that make up the tumor microenvironment (TME). In this review, we discuss the mechanisms by which ROS can affect the TME with particular emphasis on tumor-infiltrating leukocytes. Greater insight into ROS biology in this setting may allow for therapeutic manipulation of ROS levels in order to remodel the tumor microenvironment and increase anti-tumor activity. Full article

(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)

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23 pages, 2667 KiB

Open AccessEditor’s ChoiceReview

The Tumor Microenvironment in Colorectal Cancer Therapy

by Leire Pedrosa, Francis Esposito, Timothy M. Thomson and Joan Maurel

Cancers 2019, 11(8), 1172; https://doi.org/10.3390/cancers11081172 - 14 Aug 2019

Cited by 50 | Viewed by 6841

Abstract

The current standard-of-care for metastatic colorectal cancer (mCRC) includes chemotherapy and anti-angiogenic or anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, even though the addition of anti-angiogenic agents to backbone chemotherapy provides little benefit for overall survival. Since the approval of anti-angiogenic monoclonal antibodies [...] Read more.

The current standard-of-care for metastatic colorectal cancer (mCRC) includes chemotherapy and anti-angiogenic or anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, even though the addition of anti-angiogenic agents to backbone chemotherapy provides little benefit for overall survival. Since the approval of anti-angiogenic monoclonal antibodies bevacizumab and aflibercept, for the management of mCRC over a decade ago, extensive efforts have been devoted to discovering predictive factors of the anti-angiogenic response, unsuccessfully. Recent evidence has suggested a potential correlation between angiogenesis and immune phenotypes associated with colorectal cancer. Here, we review evidence of interactions between tumor angiogenesis, the immune microenvironment, and metabolic reprogramming. More specifically, we will highlight such interactions as inferred from our novel immune-metabolic (IM) signature, which groups mCRC into three distinct clusters, namely inflamed-stromal-dependent (IM Cluster 1), inflamed-non stromal-dependent (IM Cluster 2), and non-inflamed or cold (IM Cluster 3), and discuss the merits of the IM classification as a guide to new immune-metabolic combinatorial therapeutic strategies in mCRC. Full article

(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)

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52 pages, 799 KiB

Open AccessEditor’s ChoiceReview

Noncoding RNAs in Extracellular Fluids as Cancer Biomarkers: The New Frontier of Liquid Biopsies

by Barbara Pardini, Alexandru Anton Sabo, Giovanni Birolo and George Adrian Calin

Cancers 2019, 11(8), 1170; https://doi.org/10.3390/cancers11081170 - 14 Aug 2019

Cited by 135 | Viewed by 8873

Abstract

The last two decades of cancer research have been devoted in two directions: (1) understanding the mechanism of carcinogenesis for an effective treatment, and (2) improving cancer prevention and screening for early detection of the disease. This last aspect has been developed, especially [...] Read more.

The last two decades of cancer research have been devoted in two directions: (1) understanding the mechanism of carcinogenesis for an effective treatment, and (2) improving cancer prevention and screening for early detection of the disease. This last aspect has been developed, especially for certain types of cancers, thanks also to the introduction of new concepts such as liquid biopsies and precision medicine. In this context, there is a growing interest in the application of alternative and noninvasive methodologies to search for cancer biomarkers. The new frontiers of the research lead to a search for RNA molecules circulating in body fluids. Searching for biomarkers in extracellular body fluids represents a better option for patients because they are easier to access, less painful, and potentially more economical. Moreover, the possibility for these types of samples to be taken repeatedly, allows a better monitoring of the disease progression or treatment efficacy for a better intervention and dynamic treatment of the patient, which is the fundamental basis of personalized medicine. RNA molecules, freely circulating in body fluids or packed in microvesicles, have all the characteristics of the ideal biomarkers owing to their high stability under storage and handling conditions and being able to be sampled several times for monitoring. Moreover, as demonstrated for many cancers, their plasma/serum levels mirror those in the primary tumor. There are a large variety of RNA species noncoding for proteins that could be used as cancer biomarkers in liquid biopsies. Among them, the most studied are microRNAs, but recently the attention of the researcher has been also directed towards Piwi-interacting RNAs, circular RNAs, and other small noncoding RNAs. Another class of RNA species, the long noncoding RNAs, is larger than microRNAs and represents a very versatile and promising group of molecules which, apart from their use as biomarkers, have also a possible therapeutic role. In this review, we will give an overview of the most common noncoding RNA species detectable in extracellular fluids and will provide an update concerning the situation of the research on these molecules as cancer biomarkers. Full article

(This article belongs to the Special Issue Liquid Biopsy for Cancer)

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20 pages, 1349 KiB

Open AccessEditor’s ChoiceReview

Cancer Metabolism and the Evasion of Apoptotic Cell Death

by Aditi Sharma, Lawrence H. Boise and Mala Shanmugam

Cancers 2019, 11(8), 1144; https://doi.org/10.3390/cancers11081144 - 09 Aug 2019

Cited by 93 | Viewed by 8929

Abstract

Cellular growth and proliferation depend upon the acquisition and synthesis of specific metabolites. These metabolites fuel the bioenergy, biosynthesis, and redox potential required for duplication of cellular biomass. Multicellular organisms maintain tissue homeostasis by balancing signals promoting proliferation and removal of cells via [...] Read more.

Cellular growth and proliferation depend upon the acquisition and synthesis of specific metabolites. These metabolites fuel the bioenergy, biosynthesis, and redox potential required for duplication of cellular biomass. Multicellular organisms maintain tissue homeostasis by balancing signals promoting proliferation and removal of cells via apoptosis. While apoptosis is in itself an energy dependent process activated by intrinsic and extrinsic signals, whether specific nutrient acquisition (elevated or suppressed) and their metabolism regulates apoptosis is less well investigated. Normal cellular metabolism is regulated by lineage specific intrinsic features and microenvironment driven extrinsic features. In the context of cancer, genetic abnormalities, unconventional microenvironments and/or therapy engage constitutive pro-survival signaling to re-program and rewire metabolism to maintain survival, growth, and proliferation. It thus becomes particularly relevant to understand whether altered nutrient acquisition and metabolism in cancer can also contribute to the evasion of apoptosis and consequently therapy resistance. Our review attempts to dissect a causal relationship between two cancer hallmarks, i.e., deregulated cellular energetics and the evasion of programmed cell death with primary focus on the intrinsic pathway of apoptosis. Full article

(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)

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18 pages, 1581 KiB

Open AccessEditor’s ChoiceReview

Cancer Cell Lines Are Useful Model Systems for Medical Research

by Peppino Mirabelli, Luigi Coppola and Marco Salvatore

Cancers 2019, 11(8), 1098; https://doi.org/10.3390/cancers11081098 - 01 Aug 2019

Cited by 174 | Viewed by 13211

Abstract

Cell lines are in vitro model systems that are widely used in different fields of medical research, especially basic cancer research and drug discovery. Their usefulness is primarily linked to their ability to provide an indefinite source of biological material for experimental purposes. [...] Read more.

Cell lines are in vitro model systems that are widely used in different fields of medical research, especially basic cancer research and drug discovery. Their usefulness is primarily linked to their ability to provide an indefinite source of biological material for experimental purposes. Under the right conditions and with appropriate controls, authenticated cancer cell lines retain most of the genetic properties of the cancer of origin. During the last few years, comparing genomic data of most cancer cell lines has corroborated this statement and those that were observed studying the tumoral tissue equivalents included in the The Cancer Genome Atlas (TCGA) database. We are at the disposal of comprehensive open access cell line datasets describing their molecular and cellular alterations at an unprecedented level of accuracy. This aspect, in association with the possibility of setting up accurate culture conditions that mimic the in vivo microenvironment (e.g., three-dimensional (3D) coculture), has strengthened the importance of cancer cell lines for continuing to sustain medical research fields. However, it is important to consider that the appropriate use of cell lines needs to follow established guidelines for guaranteed data reproducibility and quality, and to prevent the occurrence of detrimental events (i.e., those that are linked to cross-contamination and mycoplasma contamination). Full article

(This article belongs to the Collection Targeting Solid Tumors)

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30 pages, 1880 KiB

Open AccessEditor’s ChoiceReview

Targeting Cancer Stem Cells in Triple-Negative Breast Cancer

by So-Yeon Park, Jang-Hyun Choi and Jeong-Seok Nam

Cancers 2019, 11(7), 965; https://doi.org/10.3390/cancers11070965 - 09 Jul 2019

Cited by 113 | Viewed by 12177

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that lacks targeted therapy options, and patients diagnosed with TNBC have poorer outcomes than patients with other breast cancer subtypes. Emerging evidence suggests that breast cancer stem cells (BCSCs), which have [...] Read more.

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that lacks targeted therapy options, and patients diagnosed with TNBC have poorer outcomes than patients with other breast cancer subtypes. Emerging evidence suggests that breast cancer stem cells (BCSCs), which have tumor-initiating potential and possess self-renewal capacity, may be responsible for this poor outcome by promoting therapy resistance, metastasis, and recurrence. TNBC cells have been consistently reported to display cancer stem cell (CSC) signatures at functional, molecular, and transcriptional levels. In recent decades, CSC-targeting strategies have shown therapeutic effects on TNBC in multiple preclinical studies, and some of these strategies are currently being evaluated in clinical trials. Therefore, understanding CSC biology in TNBC has the potential to guide the discovery of novel therapeutic agents in the future. In this review, we focus on the self-renewal signaling pathways (SRSPs) that are aberrantly activated in TNBC cells and discuss the specific signaling components that are involved in the tumor-initiating potential of TNBC cells. Additionally, we describe the molecular mechanisms shared by both TNBC cells and CSCs, including metabolic plasticity, which enables TNBC cells to switch between metabolic pathways according to substrate availability to meet the energetic and biosynthetic demands for rapid growth and survival under harsh conditions. We highlight CSCs as potential key regulators driving the aggressiveness of TNBC. Thus, the manipulation of CSCs in TNBC can be a targeted therapeutic strategy for TNBC in the future. Full article

(This article belongs to the Special Issue Breast Cancer Stem Cells: Therapy Resistance and Novel Therapeutic Targets)

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24 pages, 2084 KiB

Open AccessEditor’s ChoiceReview

Metabolic Regulation of Redox Balance in Cancer

by Vinee Purohit, Diane M. Simeone and Costas A. Lyssiotis

Cancers 2019, 11(7), 955; https://doi.org/10.3390/cancers11070955 - 08 Jul 2019

Cited by 75 | Viewed by 8838

Abstract

Reactive oxygen species (ROS) are chemically active free radicals produced by partial reduction of oxygen that can activate discrete signaling pathways or disrupt redox homeostasis depending on their concentration. ROS interacts with biomolecules, including DNA, and can cause mutations that can transform normal [...] Read more.

Reactive oxygen species (ROS) are chemically active free radicals produced by partial reduction of oxygen that can activate discrete signaling pathways or disrupt redox homeostasis depending on their concentration. ROS interacts with biomolecules, including DNA, and can cause mutations that can transform normal cells into cancer cells. Furthermore, certain cancer-causing mutations trigger alterations in cellular metabolism that can increase ROS production, resulting in genomic instability, additional DNA mutations, and tumor evolution. To prevent excess ROS-mediated toxicity, cancer-causing mutations concurrently activate pathways that manage this oxidative burden. Hence, an understanding of the metabolic pathways that regulate ROS levels is imperative for devising therapies that target tumor cells. In this review, we summarize the dual role of metabolism as a generator and inhibitor of ROS in cancer and discuss current strategies to target the ROS axis. Full article

(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)

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20 pages, 2730 KiB

Open AccessEditor’s ChoiceArticle

Mir526b and Mir655 Promote Tumour Associated Angiogenesis and Lymphangiogenesis in Breast Cancer

by Stephanie Hunter, Braydon Nault, Kingsley Chukwunonso Ugwuagbo, Sujit Maiti and Mousumi Majumder

Cancers 2019, 11(7), 938; https://doi.org/10.3390/cancers11070938 - 04 Jul 2019

Cited by 55 | Viewed by 6920

Abstract

MicroRNAs (miRNAs) are small endogenously produced RNAs, which regulate growth and development, and oncogenic miRNA regulate tumor growth and metastasis. Tumour-associated angiogenesis and lymphangiogenesis are processes involving the release of growth factors from tumour cells into the microenvioronemnt to communicate with endothelial cells [...] Read more.

MicroRNAs (miRNAs) are small endogenously produced RNAs, which regulate growth and development, and oncogenic miRNA regulate tumor growth and metastasis. Tumour-associated angiogenesis and lymphangiogenesis are processes involving the release of growth factors from tumour cells into the microenvioronemnt to communicate with endothelial cells to induce vascular propagation. Here, we examined the roles of cyclo-oxygenase (COX)-2 induced miR526b and miR655 in tumour-associated angiogenesis and lymphangiogenesis. Ectopic overexpression of miR526b and miR655 in poorly metastatic estrogen receptor (ER) positive MCF7 breast cancer cells resulted in upregulation of angiogenesis and lymphangiogenesis markers vascular endothelial growth factor A (VEGFA); VEGFC; VEGFD; COX-2; lymphatic vessel endothelial hyaluronan receptor-1 (LYVE1); and receptors VEGFR1, VEGFR2, and EP4. Further, miRNA-high cell free conditioned media promoted migration and tube formation by human umbilical vein endothelial cells (HUVECs), and upregulated VEGFR1, VEGFR2, and EP4 expression, showing paracrine stimulation of miRNA in the tumor microenvironment. The miRNA-induced migration and tube formation phenotypes were abrogated with EP4 antagonist or PI3K/Akt inhibitor treatments, confirming the involvement of the EP4 and PI3K/Akt pathway. Tumour supressor gene PTEN was found to be downregulated in miRNA high cells, confirming that it is a target of both miRNAs. PTEN inhibits hypoxia-inducible factor-1 (HIF1α) and the PI3K/Akt pathway, and loss of regulation of these pathways through PTEN results in upregulation of VEGF expression. Moreover, in breast tumors, angiogenesis marker VEGFA and lymphangiogenesis marker VEGFD expression was found to be significantly higher compared with non-adjacent control, and expression of miR526b and miR655 was positively correlated with VEGFA, VEGFC, VEGFD, CD31, and LYVE1 expression in breast tumour samples. These findings further strengthen the role of miRNAs as breast cancer biomarkers and EP4 as a potential therapeutic target to abrogate miRNA-induced angiogenesis and lymphangiogenesis in breast cancer. Full article

(This article belongs to the Special Issue Role of miRNAs in Cancer—Analysis of Their Targetome)

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Graphical abstract

19 pages, 8384 KiB

Open AccessEditor’s ChoiceArticle

Gene Expression Comparison between the Lymph Node-Positive and -Negative Reveals a Peculiar Immune Microenvironment Signature and a Theranostic Role for WNT Targeting in Pancreatic Ductal Adenocarcinoma: A Pilot Study

by Antonella Argentiero, Simona De Summa, Roberta Di Fonte, Rosa Maria Iacobazzi, Letizia Porcelli, Matteo Da Vià, Oronzo Brunetti, Amalia Azzariti, Nicola Silvestris and Antonio Giovanni Solimando

Cancers 2019, 11(7), 942; https://doi.org/10.3390/cancers11070942 - 04 Jul 2019

Cited by 66 | Viewed by 4590

Abstract

Over the past several years there has been much debate with regards to the prognostic and clinical significance of pancreatic ductal adenocarcinoma (PDAC) with lymph nodes metastasis. The PDAC gene expression knowledge and the biologic alterations underlying the lymph node involvement convey a [...] Read more.

Over the past several years there has been much debate with regards to the prognostic and clinical significance of pancreatic ductal adenocarcinoma (PDAC) with lymph nodes metastasis. The PDAC gene expression knowledge and the biologic alterations underlying the lymph node involvement convey a clinical implication in dealing with the theranostic window. To this end, we provide an original bioinformatic dissection of the gene expression differences of PDAC according to the nodal involvement from a large public available dataset. Comprehensive transcriptomic analysis from 143 RNA-seq patient’s derived samples indicated that WNT increased activation and a peculiar immune microenvironment identify subjects with nodal involvement. In frame of this thinking, we validated the WNT pathway role in increasing the likelihood of lymphatic dissemination in vitro. Moreover, we demonstrated for the first time in a PDAC model the potential therapeutic window that XAV-939—a specific WNT pathway inhibitor—has in re-educating a tumor-permissive immune system. Finally, we outline the potential implication on bystander molecular drivers exerted by WNT molecular inhibition, providing a picture of the proteomic oncogenic landscape changes elicited by XAV-939 on PDAC cells and their clinical implication. Our findings hold the promise to identify novel immune-based therapeutic strategies targeting WNT to enhance PDAC cytotoxicity and restore anti-PDAC immunity in node-positive disease. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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15 pages, 1218 KiB

Open AccessEditor’s ChoiceReview

DNAM-1 and the TIGIT/PVRIG/TACTILE Axis: Novel Immune Checkpoints for Natural Killer Cell-Based Cancer Immunotherapy

by Beatriz Sanchez-Correa, Isabel Valhondo, Fakhri Hassouneh, Nelson Lopez-Sejas, Alejandra Pera, Juan M. Bergua, Maria Jose Arcos, Helena Bañas, Ignacio Casas-Avilés, Esther Durán, Corona Alonso, Rafael Solana and Raquel Tarazona

Cancers 2019, 11(6), 877; https://doi.org/10.3390/cancers11060877 - 23 Jun 2019

Cited by 147 | Viewed by 13612

Abstract

Natural killer (NK) cells are lymphocytes of the innate immune response characterized by their role in the destruction of tumor cells. Activation of NK cells depend on a fine balance between activating and inhibitory signals mediated by different receptors. In recent years, a [...] Read more.

Natural killer (NK) cells are lymphocytes of the innate immune response characterized by their role in the destruction of tumor cells. Activation of NK cells depend on a fine balance between activating and inhibitory signals mediated by different receptors. In recent years, a family of paired receptors that interact with ligands of the Nectin/Nectin-like (Necl) family has attracted great interest. Two of these ligands, Necl-5 (usually termed CD155 or PVR) and Nectin-2 (CD112), frequently expressed on different types of tumor cells, are recognized by a group of receptors expressed on T and NK cells that exert opposite functions after interacting with their ligands. These receptors include DNAM-1 (CD226), TIGIT, TACTILE (CD96) and the recently described PVRIG. Whereas activation through DNAM-1 after recognition of CD155 or CD112 enhances NK cell-mediated cytotoxicity against a wide range of tumor cells, TIGIT recognition of these ligands exerts an inhibitory effect on NK cells by diminishing IFN-γ production, as well as NK cell-mediated cytotoxicity. PVRIG has also been identified as an inhibitory receptor that recognizes CD112 but not CD155. However, little is known about the role of TACTILE as modulator of immune responses in humans. TACTILE control of tumor growth and metastases has been reported in murine models, and it has been suggested that it negatively regulates the anti-tumor functions mediated by DNAM-1. In NK cells from patients with solid cancer and leukemia, it has been observed a decreased expression of DNAM-1 that may shift the balance in favor to the inhibitory receptors TIGIT or PVRIG, further contributing to the diminished NK cell-mediated cytotoxic capacity observed in these patients. Analysis of DNAM-1, TIGIT, TACTILE and PVRIG on human NK cells from solid cancer or leukemia patients will clarify the role of these receptors in cancer surveillance. Overall, it can be speculated that in cancer patients the TIGIT/PVRIG pathways are upregulated and represent novel targets for checkpoint blockade immunotherapy. Full article

(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)

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20 pages, 999 KiB

Open AccessEditor’s ChoiceReview

Cancer Stem Cells and Radioresistance: DNA Repair and Beyond

by Alexander Schulz, Felix Meyer, Anna Dubrovska and Kerstin Borgmann

Cancers 2019, 11(6), 862; https://doi.org/10.3390/cancers11060862 - 21 Jun 2019

Cited by 188 | Viewed by 10828

Abstract

The current preclinical and clinical findings demonstrate that, in addition to the conventional clinical and pathological indicators that have a prognostic value in radiation oncology, the number of cancer stem cells (CSCs) and their inherent radioresistance are important parameters for local control after [...] Read more.

The current preclinical and clinical findings demonstrate that, in addition to the conventional clinical and pathological indicators that have a prognostic value in radiation oncology, the number of cancer stem cells (CSCs) and their inherent radioresistance are important parameters for local control after radiotherapy. In this review, we discuss the molecular mechanisms of CSC radioresistance attributable to DNA repair mechanisms and the development of CSC-targeted therapies for tumor radiosensitization. We also discuss the current challenges in preclinical and translational CSC research including the high inter- and intratumoral heterogeneity, plasticity of CSCs, and microenvironment-stimulated tumor cell reprogramming. Full article

(This article belongs to the Special Issue Tumor Radioresistance)

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16 pages, 3023 KiB

Open AccessEditor’s ChoiceArticle

Determination of PD-L1 Expression in Circulating Tumor Cells of NSCLC Patients and Correlation with Response to PD-1/PD-L1 Inhibitors

by Melanie Janning, Franca Kobus, Anna Babayan, Harriet Wikman, Janna-Lisa Velthaus, Sonja Bergmann, Stefanie Schatz, Markus Falk, Lars-Arne Berger, Lisa-Marie Böttcher, Sarina Päsler, Tobias M. Gorges, Linda O’Flaherty, Claudia Hille, Simon A. Joosse, Ronald Simon, Markus Tiemann, Carsten Bokemeyer, Martin Reck, Sabine Riethdorf, Klaus Pantel and Sonja Loges Show full author list Hide full author list

Cancers 2019, 11(6), 835; https://doi.org/10.3390/cancers11060835 - 17 Jun 2019

Cited by 105 | Viewed by 8942

Abstract

Circulating tumor cells (CTCs) hold great potential to answer key questions of how non-small cell lung cancer (NSCLC) evolves and develops resistance upon anti-PD-1/PD-L1 treatment. Currently, their clinical utility in NSCLC is compromised by a low detection rate with the established, Food and [...] Read more.

Circulating tumor cells (CTCs) hold great potential to answer key questions of how non-small cell lung cancer (NSCLC) evolves and develops resistance upon anti-PD-1/PD-L1 treatment. Currently, their clinical utility in NSCLC is compromised by a low detection rate with the established, Food and Drug Administration (FDA)-approved, EpCAM-based CellSearch^® System. We tested an epitope-independent method (Parsortix^TM system) and utilized it to assess PD-L1 expression of CTCs from NSCLC patients. We prospectively collected 127 samples, 97 of which were analyzed with the epitope-independent system in comparison to the CellSearch system. CTCs were determined by immunocytochemistry as intact, nucleated, CD45⁻, pankeratins (K)⁺ cells. PD-L1 status of CTCs was evaluated from 89 samples. With the epitope-independent system, ≥1 CTC per blood sample was detected in 59 samples (61%) compared to 31 samples (32%) with the EpCAM-based system. Upon PD-L1 staining, 47% of patients harbored only PD-L1⁺CTCs, 47% had PD-L1⁺ and PD-L1⁻CTCs, and only 7% displayed exclusively PD-L1⁻CTCs. The percentage of PD-L1⁺CTCs did not correlate with the percentage of PD-L1⁺ in biopsies determined by immunohistochemistry (p = 0.179). Upon disease progression, all patients showed an increase in PD-L1⁺CTCs, while no change or a decrease in PD-L1⁺CTCs was observed in responding patients (n = 11; p = 0.001). Our data show a considerable heterogeneity in the PD-L1 status of CTCs from NSCLC patients. An increase of PD-L1⁺CTCs holds potential to predict resistance to PD-1/PD-L1 inhibitors. Full article

(This article belongs to the Special Issue Liquid Biopsy for Cancer)

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22 pages, 987 KiB

Open AccessEditor’s ChoiceReview

The Role of Epithelial-to-Mesenchymal Plasticity in Ovarian Cancer Progression and Therapy Resistance

by Nele Loret, Hannelore Denys, Philippe Tummers and Geert Berx

Cancers 2019, 11(6), 838; https://doi.org/10.3390/cancers11060838 - 17 Jun 2019

Cited by 161 | Viewed by 8797

Abstract

Ovarian cancer is the most lethal of all gynecologic malignancies and the eighth leading cause of cancer-related deaths among women worldwide. The main reasons for this poor prognosis are late diagnosis; when the disease is already in an advanced stage, and the frequent [...] Read more.

Ovarian cancer is the most lethal of all gynecologic malignancies and the eighth leading cause of cancer-related deaths among women worldwide. The main reasons for this poor prognosis are late diagnosis; when the disease is already in an advanced stage, and the frequent development of resistance to current chemotherapeutic regimens. Growing evidence demonstrates that apart from its role in ovarian cancer progression, epithelial-to-mesenchymal transition (EMT) can promote chemotherapy resistance. In this review, we will highlight the contribution of EMT to the distinct steps of ovarian cancer progression. In addition, we will review the different types of ovarian cancer resistance to therapy with particular attention to EMT-mediated mechanisms such as cell fate transitions, enhancement of cancer cell survival, and upregulation of genes related to drug resistance. Preclinical studies of anti-EMT therapies have yielded promising results. However, before anti-EMT therapies can be effectively implemented in clinical trials, more research is needed to elucidate the mechanisms leading to EMT-induced therapy resistance. Full article

(This article belongs to the Special Issue Locoregional Treatment and Gene Targeted Therapies for Cancer Metastasis)

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20 pages, 2860 KiB

Open AccessEditor’s ChoiceArticle

Taxol-Loaded MSC-Derived Exosomes Provide a Therapeutic Vehicle to Target Metastatic Breast Cancer and Other Carcinoma Cells

by Catharina Melzer, Vanessa Rehn, Yuanyuan Yang, Heike Bähre, Juliane von der Ohe and Ralf Hass

Cancers 2019, 11(6), 798; https://doi.org/10.3390/cancers11060798 - 09 Jun 2019

Cited by 171 | Viewed by 10165

Abstract

MSC-derived exosomes display, among others, an efficient biocompatibility and a reduced intrinsic immunogenicity, representing a valuable vehicle for drug delivery in a tumor-therapeutic approach. Following treatment of several human mesenchymal stroma/stem-like cell (MSC) populations with sub-lethal concentrations of taxol for 24 h, exosomes [...] Read more.

MSC-derived exosomes display, among others, an efficient biocompatibility and a reduced intrinsic immunogenicity, representing a valuable vehicle for drug delivery in a tumor-therapeutic approach. Following treatment of several human mesenchymal stroma/stem-like cell (MSC) populations with sub-lethal concentrations of taxol for 24 h, exosomes were isolated and applied to different human cancer populations including A549 lung cancer, SK-OV-3 ovarian cancer, and MDA-hyb1 breast cancer cells. While MSC control exosomes revealed little if any growth inhibition on the tumor cells, exposure to taxol-loaded MSC-derived exosomes was associated with 80–90% cytotoxicity. A similar application of taxol-loaded exosomes from HuVEC displayed much fewer effects. Quantification by LC-MS/MS analysis demonstrated a 7.6-fold reduced taxol concentration in MSC exosomes when compared to equivalent cytotoxic in vitro effects achieved with taxol substances, indicating a specific and more efficient tumor-targeting property. Consequently, MSC-derived taxol exosomes were tested in vivo. Highly metastatic MDA-hyb1 breast tumors were induced in NODscid mice, and systemic intravenous application of MSC-derived taxol exosomes revealed a more than 60% reduction of subcutaneous primary tumors. Moreover, the amount of distant organ metastases observed at least in lung, liver, spleen, and kidney was reduced by 50% with MSC taxol exosomes, similar to the effects observed with taxol, although the concentration of taxol in exosomes was about 1000-fold reduced. Together, these findings in different cancer cell populations and in vivo provide promising future perspectives for drug-loaded MSC-derived exosomes in efficiently targeting primary tumors and metastases by reducing side effects. Full article

(This article belongs to the Special Issue Breast Cancer Stem Cells: Therapy Resistance and Novel Therapeutic Targets)

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16 pages, 732 KiB

Open AccessEditor’s ChoiceReview

The Pleiotropic Effects of Glutamine Metabolism in Cancer

by Alex J. Bott, Sara Maimouni and Wei-Xing Zong

Cancers 2019, 11(6), 770; https://doi.org/10.3390/cancers11060770 - 04 Jun 2019

Cited by 88 | Viewed by 8686

Abstract

Metabolic programs are known to be altered in cancers arising from various tissues. Malignant transformation can alter signaling pathways related to metabolism and increase the demand for both energy and biomass for the proliferating cancerous cells. This scenario is further complexed by the [...] Read more.

Metabolic programs are known to be altered in cancers arising from various tissues. Malignant transformation can alter signaling pathways related to metabolism and increase the demand for both energy and biomass for the proliferating cancerous cells. This scenario is further complexed by the crosstalk between transformed cells and the microenvironment. One of the most common metabolic alterations, which occurs in many tissues and in the context of multiple oncogenic drivers, is the increased demand for the amino acid glutamine. Many studies have attributed this increased demand for glutamine to the carbon backbone and its role in the tricarboxylic acid (TCA) cycle anaplerosis. However, an increasing number of studies are now emphasizing the importance of glutamine functioning as a proteogenic building block, a nitrogen donor and carrier, an exchanger for import of other amino acids, and a signaling molecule. Herein, we highlight the recent literature on glutamine’s versatile role in cancer, with a focus on nitrogen metabolism, and therapeutic implications of glutamine metabolism in cancer. Full article

(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)

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17 pages, 446 KiB

Open AccessEditor’s ChoiceReview

Integrins, CAFs and Mechanical Forces in the Progression of Cancer

by Imjoo Jang and Karen A. Beningo

Cancers 2019, 11(5), 721; https://doi.org/10.3390/cancers11050721 - 24 May 2019

Cited by 106 | Viewed by 11270

Abstract

Cells respond to both chemical and mechanical cues present within their microenvironment. Various mechanical signals are detected by and transmitted to the cells through mechanoreceptors. These receptors often contact with the extracellular matrix (ECM), where the external signals are converted into a physiological [...] Read more.

Cells respond to both chemical and mechanical cues present within their microenvironment. Various mechanical signals are detected by and transmitted to the cells through mechanoreceptors. These receptors often contact with the extracellular matrix (ECM), where the external signals are converted into a physiological response. Integrins are well-defined mechanoreceptors that physically connect the actomyosin cytoskeleton to the surrounding matrix and transduce signals. Families of α and β subunits can form a variety of heterodimers that have been implicated in cancer progression and differ among types of cancer. These heterodimers serve as the nexus of communication between the cells and the tumor microenvironment (TME). The TME is dynamic and composed of stromal cells, ECM and associated soluble factors. The most abundant stromal cells within the TME are cancer-associated fibroblasts (CAFs). Accumulating studies implicate CAFs in cancer development and metastasis through their remodeling of the ECM and release of large amounts of ECM proteins and soluble factors. Considering that the communication between cancer cells and CAFs, in large part, takes place through the ECM, the involvement of integrins in the crosstalk is significant. This review discusses the role of integrins, as the primary cell-ECM mechanoreceptors, in cancer progression, highlighting integrin-mediated mechanical communication between cancer cells and CAFs. Full article

(This article belongs to the Special Issue The Role of Integrins in Cancer)

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19 pages, 1091 KiB

Open AccessEditor’s ChoiceReview

The Non-Essential Amino Acid Cysteine Becomes Essential for Tumor Proliferation and Survival

by Joseph A. Combs and Gina M. DeNicola

Cancers 2019, 11(5), 678; https://doi.org/10.3390/cancers11050678 - 16 May 2019

Cited by 154 | Viewed by 10836

Abstract

The non-essential amino acid cysteine is used within cells for multiple processes that rely on the chemistry of its thiol group. Under physiological conditions, many non-transformed tissues rely on glutathione, circulating cysteine, and the de novo cysteine synthesis (transsulfuration) pathway as sources of [...] Read more.

The non-essential amino acid cysteine is used within cells for multiple processes that rely on the chemistry of its thiol group. Under physiological conditions, many non-transformed tissues rely on glutathione, circulating cysteine, and the de novo cysteine synthesis (transsulfuration) pathway as sources of intracellular cysteine to support cellular processes. In contrast, many cancers require exogeneous cystine for proliferation and viability. Herein, we review how the cystine transporter, xCT, and exogenous cystine fuel cancer cell proliferation and the mechanisms that regulate xCT expression and activity. Further, we discuss the potential contribution of additional sources of cysteine to the cysteine pool and what is known about the essentiality of these processes in cancer cells. Finally, we discuss whether cyst(e)ine dependency and associated metabolic alterations represent therapeutically targetable metabolic vulnerabilities. Full article

(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)

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17 pages, 1108 KiB

Open AccessEditor’s ChoiceReview

The Diverse Functions of Non-Essential Amino Acids in Cancer

by Bo-Hyun Choi and Jonathan L. Coloff

Cancers 2019, 11(5), 675; https://doi.org/10.3390/cancers11050675 - 15 May 2019

Cited by 122 | Viewed by 15266

Abstract

Far beyond simply being 11 of the 20 amino acids needed for protein synthesis, non-essential amino acids play numerous important roles in tumor metabolism. These diverse functions include providing precursors for the biosynthesis of macromolecules, controlling redox status and antioxidant systems, and serving [...] Read more.

Far beyond simply being 11 of the 20 amino acids needed for protein synthesis, non-essential amino acids play numerous important roles in tumor metabolism. These diverse functions include providing precursors for the biosynthesis of macromolecules, controlling redox status and antioxidant systems, and serving as substrates for post-translational and epigenetic modifications. This functional diversity has sparked great interest in targeting non-essential amino acid metabolism for cancer therapy and has motivated the development of several therapies that are either already used in the clinic or are currently in clinical trials. In this review, we will discuss the important roles that each of the 11 non-essential amino acids play in cancer, how their metabolic pathways are linked, and how researchers are working to overcome the unique challenges of targeting non-essential amino acid metabolism for cancer therapy. Full article

(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)

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17 pages, 4148 KiB

Open AccessEditor’s ChoiceArticle

CAR T-Cells Targeting the Integrin αvβ6 and Co-Expressing the Chemokine Receptor CXCR2 Demonstrate Enhanced Homing and Efficacy against Several Solid Malignancies

by Lynsey M. Whilding, Leena Halim, Benjamin Draper, Ana C. Parente-Pereira, Tomasz Zabinski, David Marc Davies and John Maher

Cancers 2019, 11(5), 674; https://doi.org/10.3390/cancers11050674 - 14 May 2019

Cited by 128 | Viewed by 9003

Abstract

Despite the unprecedented clinical success of chimeric antigen receptors (CAR) T-cells against haematological malignancy, solid tumors impose a far greater challenge to success. Largely, this stems from an inadequate capacity of CAR T-cells that can traffic and maintain function within a hostile microenvironment. [...] Read more.

Despite the unprecedented clinical success of chimeric antigen receptors (CAR) T-cells against haematological malignancy, solid tumors impose a far greater challenge to success. Largely, this stems from an inadequate capacity of CAR T-cells that can traffic and maintain function within a hostile microenvironment. To enhance tumor-directed T-cell trafficking, we have engineered CAR T-cells to acquire heightened responsiveness to interleukin (IL)-8. Circulating IL-8 levels correlate with disease burden and prognosis in multiple solid tumors in which it exerts diverse pathological functions including angiogenesis, support of cancer stem cell survival, and recruitment of immunosuppressive myeloid cells. To harness tumor-derived IL-8 for therapeutic benefit, we have co-expressed either of its cognate receptors (CXCR1 or CXCR2) in CAR T-cells that target the tumor-associated αvβ6 integrin. We demonstrate here that CXCR2-expressing CAR T-cells migrate more efficiently towards IL-8 and towards tumor conditioned media that contains this cytokine. As a result, these CAR T-cells elicit superior anti-tumor activity against established αvβ6-expressing ovarian or pancreatic tumor xenografts, with a more favorable toxicity profile. These data support the further engineering of CAR T-cells to acquire responsiveness to cancer-derived chemokines in order to improve their therapeutic activity against solid tumors. Full article

(This article belongs to the Special Issue The Role of Integrins in Cancer)

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26 pages, 1660 KiB

Open AccessEditor’s ChoiceReview

Breast Cancer Tumor Stroma: Cellular Components, Phenotypic Heterogeneity, Intercellular Communication, Prognostic Implications and Therapeutic Opportunities

by Noemi Eiro, Luis O. Gonzalez, María Fraile, Sandra Cid, Jose Schneider and Francisco J. Vizoso

Cancers 2019, 11(5), 664; https://doi.org/10.3390/cancers11050664 - 13 May 2019

Cited by 71 | Viewed by 7185

Abstract

Although the mechanisms underlying the genesis and progression of breast cancer are better understood than ever, it is still the most frequent malignant tumor in women and one of the leading causes of cancer death. Therefore, we need to establish new approaches that [...] Read more.

Although the mechanisms underlying the genesis and progression of breast cancer are better understood than ever, it is still the most frequent malignant tumor in women and one of the leading causes of cancer death. Therefore, we need to establish new approaches that lead us to better understand the prognosis of this heterogeneous systemic disease and to propose new therapeutic strategies. Cancer is not only a malignant transformation of the epithelial cells merely based on their autonomous or acquired proliferative capacity. Today, data support the concept of cancer as an ecosystem based on a cellular sociology, with diverse components and complex interactions between them. Among the different cell types that make up the stroma, which have a relevant role in the dynamics of tumor/stromal cell interactions, the main ones are cancer associated fibroblasts, endothelial cells, immune cells and mesenchymal stromal cells. Several factors expressed by the stroma of breast carcinomas are associated with the development of metastasis, such as matrix metalloproteases, their tissular inhibitors or some of their regulators like integrins, cytokines or toll-like receptors. Based on the expression of these factors, two types of breast cancer stroma can be proposed with significantly different influence on the prognosis of patients. In addition, there is evidence about the existence of bi-directional signals between cancer cells and tumor stroma cells with prognostic implications, suggesting new therapeutic strategies in breast cancer. Full article

(This article belongs to the Special Issue The Role of Integrins in Cancer)

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13 pages, 2966 KiB

Open AccessEditor’s ChoiceReview

Active Targeting Strategies Using Biological Ligands for Nanoparticle Drug Delivery Systems

by Jihye Yoo, Changhee Park, Gawon Yi, Donghyun Lee and Heebeom Koo

Cancers 2019, 11(5), 640; https://doi.org/10.3390/cancers11050640 - 08 May 2019

Cited by 432 | Viewed by 16949

Abstract

Targeting nanoparticle (NP) carriers to sites of disease is critical for their successful use as drug delivery systems. Along with optimization of physicochemical properties, researchers have focused on surface modification of NPs with biological ligands. Such ligands can bind specific receptors on the [...] Read more.

Targeting nanoparticle (NP) carriers to sites of disease is critical for their successful use as drug delivery systems. Along with optimization of physicochemical properties, researchers have focused on surface modification of NPs with biological ligands. Such ligands can bind specific receptors on the surface of target cells. Furthermore, biological ligands can facilitate uptake of modified NPs, which is referred to as ‘active targeting’ of NPs. In this review, we discuss recent applications of biological ligands including proteins, polysaccharides, aptamers, peptides, and small molecules for NP-mediated drug delivery. We prioritized studies that have demonstrated targeting in animals over in vitro studies. We expect that this review will assist biomedical researchers working with NPs for drug delivery and imaging. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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25 pages, 1935 KiB

Open AccessEditor’s ChoiceReview

Emerging Roles of the Endoplasmic Reticulum Associated Unfolded Protein Response in Cancer Cell Migration and Invasion

by Celia Maria Limia, Chloé Sauzay, Hery Urra, Claudio Hetz, Eric Chevet and Tony Avril

Cancers 2019, 11(5), 631; https://doi.org/10.3390/cancers11050631 - 06 May 2019

Cited by 62 | Viewed by 8142

Abstract

Endoplasmic reticulum (ER) proteostasis is often altered in tumor cells due to intrinsic (oncogene expression, aneuploidy) and extrinsic (environmental) challenges. ER stress triggers the activation of an adaptive response named the Unfolded Protein Response (UPR), leading to protein translation repression, and to the [...] Read more.

Endoplasmic reticulum (ER) proteostasis is often altered in tumor cells due to intrinsic (oncogene expression, aneuploidy) and extrinsic (environmental) challenges. ER stress triggers the activation of an adaptive response named the Unfolded Protein Response (UPR), leading to protein translation repression, and to the improvement of ER protein folding and clearance capacity. The UPR is emerging as a key player in malignant transformation and tumor growth, impacting on most hallmarks of cancer. As such, the UPR can influence cancer cells’ migration and invasion properties. In this review, we overview the involvement of the UPR in cancer progression. We discuss its cross-talks with the cell migration and invasion machinery. Specific aspects will be covered including extracellular matrix (ECM) remodeling, modification of cell adhesion, chemo-attraction, epithelial-mesenchymal transition (EMT), modulation of signaling pathways associated with cell mobility, and cytoskeleton remodeling. The therapeutic potential of targeting the UPR to treat cancer will also be considered with specific emphasis in the impact on metastasis and tissue invasion. Full article

(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)

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23 pages, 1325 KiB

Open AccessEditor’s ChoiceReview

Focus on Formononetin: Anticancer Potential and Molecular Targets

by Samantha Kah Ling Ong, Muthu K. Shanmugam, Lu Fan, Sarah E. Fraser, Frank Arfuso, Kwang Seok Ahn, Gautam Sethi and Anupam Bishayee

Cancers 2019, 11(5), 611; https://doi.org/10.3390/cancers11050611 - 01 May 2019

Cited by 111 | Viewed by 9016

Abstract

Formononetin, an isoflavone, is extracted from various medicinal plants and herbs, including the red clover (Trifolium pratense) and Chinese medicinal plant Astragalus membranaceus. Formononetin’s antioxidant and neuroprotective effects underscore its therapeutic use against Alzheimer’s disease. Formononetin has been under intense investigation for [...] Read more.

Formononetin, an isoflavone, is extracted from various medicinal plants and herbs, including the red clover (Trifolium pratense) and Chinese medicinal plant Astragalus membranaceus. Formononetin’s antioxidant and neuroprotective effects underscore its therapeutic use against Alzheimer’s disease. Formononetin has been under intense investigation for the past decade as strong evidence on promoting apoptosis and against proliferation suggests for its use as an anticancer agent against diverse cancers. These anticancer properties are observed in multiple cancer cell models, including breast, colorectal, and prostate cancer. Formononetin also attenuates metastasis and tumor growth in various in vivo studies. The beneficial effects exuded by formononetin can be attributed to its antiproliferative and cell cycle arrest inducing properties. Formononetin regulates various transcription factors and growth-factor-mediated oncogenic pathways, consequently alleviating the possible causes of chronic inflammation that are linked to cancer survival of neoplastic cells and their resistance against chemotherapy. As such, this review summarizes and critically analyzes current evidence on the potential of formononetin for therapy of various malignancies with special emphasis on molecular targets. Full article

(This article belongs to the Special Issue Role of Natural Bioactive Compounds in the Rise and Fall of Cancers)

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20 pages, 1254 KiB

Open AccessEditor’s ChoiceReview

Tumor-Associated Neutrophils in Cancer: Going Pro

by Lingyun Wu, Sugandha Saxena, Mohammad Awaji and Rakesh K. Singh

Cancers 2019, 11(4), 564; https://doi.org/10.3390/cancers11040564 - 19 Apr 2019

Cited by 226 | Viewed by 11049

Abstract

The progression of cancer is not only about the tumor cell itself, but also about other involved players including cancer cell recruited immune cells, their released pro-inflammatory factors, and the extracellular matrix. These players constitute the tumor microenvironment and play vital roles in [...] Read more.

The progression of cancer is not only about the tumor cell itself, but also about other involved players including cancer cell recruited immune cells, their released pro-inflammatory factors, and the extracellular matrix. These players constitute the tumor microenvironment and play vital roles in the cancer progression. Neutrophils—the most abundant white blood cells in the circulation system—constitute a significant part of the tumor microenvironment. Neutrophils play major roles linking inflammation and cancer and are actively involved in progression and metastasis. Additionally, recent data suggest that neutrophils could be considered one of the emerging targets for multiple cancer types. This review summarizes the most recent updates regarding neutrophil recruitments and functions in the tumor microenvironment as well as potential development of neutrophils-targeted putative therapeutic strategies. Full article

(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)

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20 pages, 1185 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy

by Elisabeth Peer, Suzana Tesanovic and Fritz Aberger

Cancers 2019, 11(4), 538; https://doi.org/10.3390/cancers11040538 - 15 Apr 2019

Cited by 67 | Viewed by 7561

Abstract

The Hedgehog/Glioma-associated oncogene homolog (HH/GLI) signaling pathway regulates self-renewal of rare and highly malignant cancer stem cells (CSC), which have been shown to account for the initiation and maintenance of tumor growth as well as for drug resistance, metastatic spread and relapse. Efficacious [...] Read more.

The Hedgehog/Glioma-associated oncogene homolog (HH/GLI) signaling pathway regulates self-renewal of rare and highly malignant cancer stem cells (CSC), which have been shown to account for the initiation and maintenance of tumor growth as well as for drug resistance, metastatic spread and relapse. Efficacious therapeutic approaches targeting CSC pathways, such as HH/GLI signaling in combination with chemo, radiation or immunotherapy are, therefore, of high medical need. Pharmacological inhibition of HH/GLI pathway activity represents a promising approach to eliminate malignant CSC. Clinically approved HH/GLI pathway inhibitors target the essential pathway effector Smoothened (SMO) with striking therapeutic efficacy in skin and brain cancer patients. However, multiple genetic and molecular mechanisms resulting in de novo and acquired resistance to SMO inhibitors pose major limitations to anti-HH/GLI therapies and, thus, the eradication of CSC. In this review, we summarize reasons for clinical failure of SMO inhibitors, including mechanisms caused by genetic alterations in HH pathway effectors or triggered by additional oncogenic signals activating GLI transcription factors in a noncanonical manner. We then discuss emerging novel and rationale-based approaches to overcome SMO-inhibitor resistance, focusing on pharmacological perturbations of enzymatic modifiers of GLI activity and on compounds either directly targeting oncogenic GLI factors or interfering with synergistic crosstalk signals known to boost the oncogenicity of HH/GLI signaling. Full article

(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)

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21 pages, 3175 KiB

Open AccessEditor’s ChoiceReview

Dendritic Cells and Cancer: From Biology to Therapeutic Intervention

by Ben Wylie, Christophe Macri, Justine D. Mintern and Jason Waithman

Cancers 2019, 11(4), 521; https://doi.org/10.3390/cancers11040521 - 11 Apr 2019

Cited by 95 | Viewed by 8579

Abstract

Inducing effective anti-tumor immunity has become a major therapeutic strategy against cancer. Dendritic cells (DC) are a heterogenous population of antigen presenting cells that infiltrate tumors. While DC play a critical role in the priming and maintenance of local immunity, their functions are [...] Read more.

Inducing effective anti-tumor immunity has become a major therapeutic strategy against cancer. Dendritic cells (DC) are a heterogenous population of antigen presenting cells that infiltrate tumors. While DC play a critical role in the priming and maintenance of local immunity, their functions are often diminished, or suppressed, by factors encountered in the tumor microenvironment. Furthermore, DC populations with immunosuppressive activities are also recruited to tumors, limiting T cell infiltration and promoting tumor growth. Anti-cancer therapies can impact the function of tumor-associated DC and/or alter their phenotype. Therefore, the design of effective anti-cancer therapies for clinical translation should consider how best to boost tumor-associated DC function to drive anti-tumor immunity. In this review, we discuss the different subsets of tumor-infiltrating DC and their role in anti-tumor immunity. Moreover, we describe strategies to enhance DC function within tumors and harness these cells for effective tumor immunotherapy. Full article

(This article belongs to the Special Issue Tumour Associated Dendritic Cells)

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15 pages, 1635 KiB

Open AccessEditor’s ChoiceArticle

Head and Body/Tail Pancreatic Carcinomas Are Not the Same Tumors

by David Jérémie Birnbaum, François Bertucci, Pascal Finetti, Daniel Birnbaum and Emilie Mamessier

Cancers 2019, 11(4), 497; https://doi.org/10.3390/cancers11040497 - 08 Apr 2019

Cited by 60 | Viewed by 8059

Abstract

The association between pancreatic ductal adenocarcinoma (PDAC) location (head vs. Body/Tail (B/T)) and clinical outcome remains controversial. We collected clinicopathological and gene expression data from 249 resected PDAC samples from public data sets, and we compared data between 208 head and 41 B/T [...] Read more.

The association between pancreatic ductal adenocarcinoma (PDAC) location (head vs. Body/Tail (B/T)) and clinical outcome remains controversial. We collected clinicopathological and gene expression data from 249 resected PDAC samples from public data sets, and we compared data between 208 head and 41 B/T samples. The 2-year overall survival (OS) was better for the head than for the B/T PDACs (44 vs. 27%, p = 0.043), especially when comparing tumors with similar TNM classification (T3/4N0M0: 67% vs. 17%, p = 0.002) or from the same molecular class (squamous subtype: 31% vs. 0%, p < 0.0001). Bailey’s molecular subtypes were differentially distributed within the two groups, with the immunogenic subtype being underrepresented in the “B/T” group (p = 0.005). Uni- and multivariate analyses indicated that PDAC anatomic location was an independent prognostic factor. Finally, the supervised analysis identified 334 genes differentially expressed. Genes upregulated in the “head” group suggested lymphocyte activation and pancreas exocrine functions. Genes upregulated in the “B/T” group were related to keratinocyte differentiation, in line with the enrichment for squamous phenotype. We identified a robust gene expression signature (GES) associated with B/T PDAC location, suggesting that head and B/T PDAC are different. This GES could serve as an indicator for differential therapeutic management based on PDAC location. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)

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29 pages, 1552 KiB

Open AccessEditor’s ChoiceReview

Natural Killer Cells as Key Players of Tumor Progression and Angiogenesis: Old and Novel Tools to Divert Their Pro-Tumor Activities into Potent Anti-Tumor Effects

by Barbara Bassani, Denisa Baci, Matteo Gallazzi, Alessandro Poggi, Antonino Bruno and Lorenzo Mortara

Cancers 2019, 11(4), 461; https://doi.org/10.3390/cancers11040461 - 01 Apr 2019

Cited by 112 | Viewed by 10330

Abstract

Immune cells, as a consequence of their plasticity, can acquire altered phenotype/functions within the tumor microenvironment (TME). Some of these aberrant functions include attenuation of targeting and killing of tumor cells, tolerogenic/immunosuppressive behavior and acquisition of pro-angiogenic activities. Natural killer (NK) cells are [...] Read more.

Immune cells, as a consequence of their plasticity, can acquire altered phenotype/functions within the tumor microenvironment (TME). Some of these aberrant functions include attenuation of targeting and killing of tumor cells, tolerogenic/immunosuppressive behavior and acquisition of pro-angiogenic activities. Natural killer (NK) cells are effector lymphocytes involved in tumor immunosurveillance. In solid malignancies, tumor-associated NK cells (TANK cells) in peripheral blood and tumor-infiltrating NK (TINK) cells show altered phenotypes and are characterized by either anergy or reduced cytotoxicity. Here, we aim at discussing how NK cells can support tumor progression and how induction of angiogenesis, due to TME stimuli, can be a relevant part on the NK cell-associated tumor supporting activities. We will review and discuss the contribution of the TME in shaping NK cell response favoring cancer progression. We will focus on TME-derived set of factors such as TGF-β, soluble HLA-G, prostaglandin E₂, adenosine, extracellular vesicles, and miRNAs, which can exhibit a dual function. On one hand, these factors can suppress NK cell-mediated activities but, on the other hand, they can induce a pro-angiogenic polarization in NK cells. Also, we will analyze the impact on cancer progression of the interaction of NK cells with several TME-associated cells, including macrophages, neutrophils, mast cells, cancer-associated fibroblasts, and endothelial cells. Then, we will discuss the most relevant therapeutic approaches aimed at potentiating/restoring NK cell activities against tumors. Finally, supported by the literature revision and our new findings on NK cell pro-angiogenic activities, we uphold NK cells to a key host cellular paradigm in controlling tumor progression and angiogenesis; thus, we should bear in mind NK cells like a TME-associated target for anti-tumor therapeutic approaches. Full article

(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)

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22 pages, 13350 KiB

Open AccessFeature PaperEditor’s ChoiceReview

PTEN as a Prognostic/Predictive Biomarker in Cancer: An Unfulfilled Promise?

by Chiara Bazzichetto, Fabiana Conciatori, Matteo Pallocca, Italia Falcone, Maurizio Fanciulli, Francesco Cognetti, Michele Milella and Ludovica Ciuffreda

Cancers 2019, 11(4), 435; https://doi.org/10.3390/cancers11040435 - 28 Mar 2019

Cited by 88 | Viewed by 7668

Abstract

Identifying putative biomarkers of clinical outcomes in cancer is crucial for successful enrichment, and for the selection of patients who are the most likely to benefit from a specific therapeutic approach. Indeed, current research in personalized cancer therapy focuses on the possibility of [...] Read more.

Identifying putative biomarkers of clinical outcomes in cancer is crucial for successful enrichment, and for the selection of patients who are the most likely to benefit from a specific therapeutic approach. Indeed, current research in personalized cancer therapy focuses on the possibility of identifying biomarkers that predict prognosis, sensitivity or resistance to therapies. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene that regulates several crucial cell functions such as proliferation, survival, genomic stability and cell motility through both enzymatic and non-enzymatic activities and phosphatidylinositol 3-kinase (PI3K)-dependent and -independent mechanisms. Despite its undisputed role as a tumor suppressor, assessment of PTEN status in sporadic human tumors has yet to provide clinically robust prognostic, predictive or therapeutic information. This is possibly due to the exceptionally complex regulation of PTEN function, which involves genetic, transcriptional, post-transcriptional and post-translational events. This review shows a brief summary of the regulation and function of PTEN and discusses its controversial aspects as a prognostic/predictive biomarker. Full article

(This article belongs to the Special Issue PTEN: A Multifaceted Tumor Suppressor)

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22 pages, 1286 KiB

Open AccessEditor’s ChoiceReview

The Contributions of Prostate Cancer Stem Cells in Prostate Cancer Initiation and Metastasis

by Wenjuan Mei, Xiaozeng Lin, Anil Kapoor, Yan Gu, Kuncheng Zhao and Damu Tang

Cancers 2019, 11(4), 434; https://doi.org/10.3390/cancers11040434 - 27 Mar 2019

Cited by 68 | Viewed by 6343

Abstract

Research in the last decade has clearly revealed a critical role of prostate cancer stem cells (PCSCs) in prostate cancer (PC). Prostate stem cells (PSCs) reside in both basal and luminal layers, and are the target cells of oncogenic transformation, suggesting a role [...] Read more.

Research in the last decade has clearly revealed a critical role of prostate cancer stem cells (PCSCs) in prostate cancer (PC). Prostate stem cells (PSCs) reside in both basal and luminal layers, and are the target cells of oncogenic transformation, suggesting a role of PCSCs in PC initiation. Mutations in PTEN, TP53, and RB1 commonly occur in PC, particularly in metastasis and castration-resistant PC. The loss of PTEN together with Ras activation induces partial epithelial–mesenchymal transition (EMT), which is a major mechanism that confers plasticity to cancer stem cells (CSCs) and PCSCs, which contributes to metastasis. While PTEN inactivation leads to PC, it is not sufficient for metastasis, the loss of PTEN concurrently with the inactivation of both TP53 and RB1 empower lineage plasticity in PC cells, which substantially promotes PC metastasis and the conversion to PC adenocarcinoma to neuroendocrine PC (NEPC), demonstrating the essential function of TP53 and RB1 in the suppression of PCSCs. TP53 and RB1 suppress lineage plasticity through the inhibition of SOX2 expression. In this review, we will discuss the current evidence supporting a major role of PCSCs in PC initiation and metastasis, as well as the underlying mechanisms regulating PCSCs. These discussions will be developed along with the cancer stem cell (CSC) knowledge in other cancer types. Full article

(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)

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18 pages, 3871 KiB

Open AccessEditor’s ChoiceArticle

The Flavonoid Metabolite 2,4,6-Trihydroxybenzoic Acid Is a CDK Inhibitor and an Anti-Proliferative Agent: A Potential Role in Cancer Prevention

by Ranjini Sankaranarayanan, Chaitanya K. Valiveti, D. Ramesh Kumar, Severine Van slambrouck, Siddharth S. Kesharwani, Teresa Seefeldt, Joy Scaria, Hemachand Tummala and G. Jayarama Bhat

Cancers 2019, 11(3), 427; https://doi.org/10.3390/cancers11030427 - 26 Mar 2019

Cited by 39 | Viewed by 14732

Abstract

Flavonoids have emerged as promising compounds capable of preventing colorectal cancer (CRC) due to their anti-oxidant and anti-inflammatory properties. It is hypothesized that the metabolites of flavonoids are primarily responsible for the observed anti-cancer effects owing to the unstable nature of the parent [...] Read more.

Flavonoids have emerged as promising compounds capable of preventing colorectal cancer (CRC) due to their anti-oxidant and anti-inflammatory properties. It is hypothesized that the metabolites of flavonoids are primarily responsible for the observed anti-cancer effects owing to the unstable nature of the parent compounds and their degradation by colonic microflora. In this study, we investigated the ability of one metabolite, 2,4,6-trihydroxybenzoic acid (2,4,6-THBA) to inhibit Cyclin Dependent Kinase (CDK) activity and cancer cell proliferation. Using in vitro kinase assays, we demonstrated that 2,4,6-THBA dose-dependently inhibited CDKs 1, 2 and 4 and in silico studies identified key amino acids involved in these interactions. Interestingly, no significant CDK inhibition was observed with the structurally related compounds 3,4,5-trihydroxybenzoic acid (3,4,5-THBA) and phloroglucinol, suggesting that orientation of the functional groups and specific amino acid interactions may play a role in inhibition. We showed that cellular uptake of 2,4,6-THBA required the expression of functional SLC5A8, a monocarboxylic acid transporter. Consistent with this, in cells expressing functional SLC5A8, 2,4,6-THBA induced CDK inhibitory proteins p21^Cip1 and p27^Kip1 and inhibited cell proliferation. These findings, for the first time, suggest that the flavonoid metabolite 2,4,6-THBA may mediate its effects through a CDK- and SLC5A8-dependent pathway contributing to the prevention of CRC. Full article

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17 pages, 1027 KiB

Open AccessEditor’s ChoiceReview

Acquired Resistance to Antibody-Drug Conjugates

by Denis M. Collins, Birgit Bossenmaier, Gwendlyn Kollmorgen and Gerhard Niederfellner

Cancers 2019, 11(3), 394; https://doi.org/10.3390/cancers11030394 - 20 Mar 2019

Cited by 82 | Viewed by 8622

Abstract

Antibody-drug conjugates (ADCs) combine the tumor selectivity of antibodies with the potency of cytotoxic small molecules thereby constituting antibody-mediated chemotherapy. As this inherently limits the adverse effects of the chemotherapeutic, such approaches are heavily pursued by pharma and biotech companies and have resulted [...] Read more.

Antibody-drug conjugates (ADCs) combine the tumor selectivity of antibodies with the potency of cytotoxic small molecules thereby constituting antibody-mediated chemotherapy. As this inherently limits the adverse effects of the chemotherapeutic, such approaches are heavily pursued by pharma and biotech companies and have resulted in four FDA (Food and Drug Administration)-approved ADCs. However, as with other cancer therapies, durable responses are limited by the fact that under cell stress exerted by these drugs, tumors can acquire mechanisms of escape. Resistance can develop against the antibody component of ADCs by down-regulation/mutation of the targeted cell surface antigen or against payload toxicity by up-regulation of drug efflux transporters. Unique resistance mechanisms specific for the mode of action of ADCs have also emerged, like altered internalization or cell surface recycling of the targeted tumor antigen, changes in the intracellular routing or processing of ADCs, and impaired release of the toxic payload into the cytosol. These evasive changes are tailored to the specific nature and interplay of the three ADC constituents: the antibody, the linker, and the payload. Hence, they do not necessarily endow broad resistance to ADC therapy. This review summarizes preclinical and clinical findings that shed light on the mechanisms of acquired resistance to ADC therapies. Full article

(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)

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24 pages, 18990 KiB

Open AccessEditor’s ChoiceReview

Contribution of Anoctamins to Cell Survival and Cell Death

by Karl Kunzelmann, Jiraporn Ousingsawat, Roberta Benedetto, Ines Cabrita and Rainer Schreiber

Cancers 2019, 11(3), 382; https://doi.org/10.3390/cancers11030382 - 19 Mar 2019

Cited by 58 | Viewed by 7812

Abstract

Before anoctamins (TMEM16 proteins) were identified as a family of Ca²⁺-activated chloride channels and phospholipid scramblases, the founding member anoctamin 1 (ANO1, TMEM16A) was known as DOG1, a marker protein for gastrointestinal stromal tumors (GIST). Meanwhile, ANO1 has been examined in [...] Read more.

Before anoctamins (TMEM16 proteins) were identified as a family of Ca²⁺-activated chloride channels and phospholipid scramblases, the founding member anoctamin 1 (ANO1, TMEM16A) was known as DOG1, a marker protein for gastrointestinal stromal tumors (GIST). Meanwhile, ANO1 has been examined in more detail, and the role of ANO1 in cell proliferation and the development of different types of malignomas is now well established. While ANO5, ANO7, and ANO9 may also be relevant for growth of cancers, evidence has been provided for a role of ANO6 (TMEM16F) in regulated cell death. The cellular mechanisms by which anoctamins control cell proliferation and cell death, respectively, are just emerging; however, the pronounced effects of anoctamins on intracellular Ca²⁺ levels are likely to play a significant role. Recent results suggest that some anoctamins control membrane exocytosis by setting Ca²⁺_i levels near the plasma membrane, and/or by controlling the intracellular Cl⁻ concentration. Exocytosis and increased membrane trafficking induced by ANO1 and ANO6 may enhance membrane expression of other chloride channels, such as CFTR and volume activated chloride channels (VRAC). Notably, ANO6-induced phospholipid scrambling with exposure of phosphatidylserine is pivotal for the sheddase function of disintegrin and metalloproteinase (ADAM). This may support cell death and tumorigenic activity of IL-6 by inducing IL-6 trans-signaling. The reported anticancer effects of the anthelminthic drug niclosamide are probably related to the potent inhibitory effect on ANO1, apart from inducing cell cycle arrest through the Let-7d/CDC34 axis. On the contrary, pronounced activation of ANO6 due to a large increase in intracellular calcium, activation of phospholipase A2 or lipid peroxidation, can lead to ferroptotic death of cancer cells. It therefore appears reasonable to search for both inhibitors and potent activators of TMEM16 in order to interfere with cancer growth and metastasis. Full article

(This article belongs to the Special Issue Ion Channels in Cancer)

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14 pages, 1230 KiB

Open AccessEditor’s ChoiceReview

Newer-Generation EGFR Inhibitors in Lung Cancer: How Are They Best Used?

by Tri Le and David E. Gerber

Cancers 2019, 11(3), 366; https://doi.org/10.3390/cancers11030366 - 15 Mar 2019

Cited by 48 | Viewed by 7648

Abstract

The FLAURA trial established osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), as a viable first-line therapy in non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations, namely exon 19 deletion and L858R. In this phase 3 randomized, controlled, [...] Read more.

The FLAURA trial established osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), as a viable first-line therapy in non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations, namely exon 19 deletion and L858R. In this phase 3 randomized, controlled, double-blind trial of treatment-naïve patients with EGFR mutant NSCLC, osimertinib was compared to standard-of-care EGFR TKIs (i.e., erlotinib or gefinitib) in the first-line setting. Osimertinib demonstrated improvement in median progression-free survival (18.9 months vs. 10.2 months; hazard ratio 0.46; 95% CI, 0.37 to 0.57; p < 0.001) and a more favorable toxicity profile due to its lower affinity for wild-type EGFR. Furthermore, similar to later-generation anaplastic lymphoma kinase (ALK) inhibitors, osimertinib has improved efficacy against brain metastases. Despite this impressive effect, the optimal sequencing of osimertinib, whether in the first line or as subsequent therapy after the failure of earlier-generation EGFR TKIs, is not clear. Because up-front use of later-generation TKIs may result in the inability to use earlier-generation TKIs, this treatment paradigm must be evaluated carefully. For EGFR mutant NSCLC, considerations include the incidence of T790M resistance mutations, quality of life, whether there is a potential role for earlier-generation TKIs after osimertinib failure, and overall survival. This review explores these issues for EGFR inhibitors and other molecularly targeted therapies. Full article

(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)

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27 pages, 11879 KiB

Open AccessEditor’s ChoiceArticle

The Small Molecule Ephrin Receptor Inhibitor, GLPG1790, Reduces Renewal Capabilities of Cancer Stem Cells, Showing Anti-Tumour Efficacy on Preclinical Glioblastoma Models

by Giovanni Luca Gravina, Andrea Mancini, Alessandro Colapietro, Simona Delle Monache, Roberta Sferra, Flora Vitale, Loredana Cristiano, Stefano Martellucci, Francesco Marampon, Vincenzo Mattei, Filip Beirinckx, Philippe Pujuguet, Laurent Saniere, Giocondo Lorenzon, Ellen van der Aar and Claudio Festuccia

Cancers 2019, 11(3), 359; https://doi.org/10.3390/cancers11030359 - 13 Mar 2019

Cited by 40 | Viewed by 5737

Abstract

Therapies against glioblastoma (GBM) show a high percentage of failure associated with the survival of glioma stem cells (GSCs) that repopulate treated tumours. Forced differentiation of GSCs is a promising new approach in cancer treatment. Erythropoietin-producing hepatocellular (Eph) receptors drive tumourigenicity and stemness [...] Read more.

Therapies against glioblastoma (GBM) show a high percentage of failure associated with the survival of glioma stem cells (GSCs) that repopulate treated tumours. Forced differentiation of GSCs is a promising new approach in cancer treatment. Erythropoietin-producing hepatocellular (Eph) receptors drive tumourigenicity and stemness in GBM. We tested GLPG1790, a first small molecule with inhibition activity versus inhibitor of various Eph receptor kinases, in preclinical GBM models using in vitro and in vivo assays. GLPG1790 rapidly and persistently inhibited Ephrin-A1-mediated phosphorylation of Tyr⁵⁸⁸ and Ser⁸⁹⁷, completely blocking EphA2 receptor signalling. Similarly, this compound blocks the ephrin B2-mediated EphA3 and EphB4 tyrosine phosphorylation. This resulted in anti-glioma effects. GLPG1790 down-modulated the expression of mesenchymal markers CD44, Sox2, nestin, octamer-binding transcription factor 3/4 (Oct3/4), Nanog, CD90, and CD105, and up-regulated that of glial fibrillary acidic protein (GFAP) and pro-neural/neuronal markers, βIII tubulin, and neurofilaments. GLPG1790 reduced tumour growth in vivo. These effects were larger compared to radiation therapy (RT; U251 and T98G xenografts) and smaller than those of temozolomide (TMZ; U251 and U87MG cell models). By contrast, GLPG1790 showed effects that were higher than Radiotherapy (RT) and similar to Temozolomide (TMZ) in orthotopic U87MG and CSCs-5 models in terms of disease-free survival (DFS) and overall survival (OS). Further experiments were necessary to study possible interactions with radio- and chemotherapy. GLPG1790 demonstrated anti-tumor effects regulating both the differentiative status of Glioma Initiating Cells (GICs) and the quality of tumor microenvironment, translating into efficacy in aggressive GBM mouse models. Significant common molecular targets to radio and chemo therapy supported the combination use of GLPG1790 in ameliorative antiglioma therapy. Full article

(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)

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