Cancers

17 pages, 2439 KiB

Open AccessFeature PaperArticle

A Novel Inhibitor of STAT5 Signaling Overcomes Chemotherapy Resistance in Myeloid Leukemia Cells

by Marie Brachet-Botineau, Margaux Deynoux, Nicolas Vallet, Marion Polomski, Ludovic Juen, Olivier Hérault, Frédéric Mazurier, Marie-Claude Viaud-Massuard, Gildas Prié and Fabrice Gouilleux

Cancers 2019, 11(12), 2043; https://doi.org/10.3390/cancers11122043 - 17 Dec 2019

Cited by 15 | Viewed by 3674

Abstract

Signal transducers and activators of transcription 5A and 5B (STAT5A and STAT5B) are crucial downstream effectors of tyrosine kinase oncogenes (TKO) such as BCR-ABL in chronic myeloid leukemia (CML) and FLT3-ITD in acute myeloid leukemia (AML). Both proteins have been shown to promote [...] Read more.

Signal transducers and activators of transcription 5A and 5B (STAT5A and STAT5B) are crucial downstream effectors of tyrosine kinase oncogenes (TKO) such as BCR-ABL in chronic myeloid leukemia (CML) and FLT3-ITD in acute myeloid leukemia (AML). Both proteins have been shown to promote the resistance of CML cells to tyrosine kinase inhibitors (TKI) such as imatinib mesylate (IM). We recently synthesized and discovered a new inhibitor (17f) with promising antileukemic activity. 17f selectively inhibits STAT5 signaling in CML and AML cells by interfering with the phosphorylation and transcriptional activity of these proteins. In this study, the effects of 17f were evaluated on CML and AML cell lines that respectively acquired resistance to IM and cytarabine (Ara-C), a conventional therapeutic agent used in AML treatment. We showed that 17f strongly inhibits the growth and survival of resistant CML and AML cells when associated with IM or Ara-C. We also obtained evidence that 17f inhibits STAT5B but not STAT5A protein expression in resistant CML and AML cells. Furthermore, we demonstrated that 17f also targets oncogenic STAT5B N642H mutant in transformed hematopoietic cells. Full article

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

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17 pages, 4499 KiB

Open AccessArticle

The Benzimidazole-Based Anthelmintic Parbendazole: A Repurposed Drug Candidate That Synergizes with Gemcitabine in Pancreatic Cancer

by Rosalba Florio, Serena Veschi, Viviana di Giacomo, Sara Pagotto, Simone Carradori, Fabio Verginelli, Roberto Cirilli, Adriano Casulli, Antonino Grassadonia, Nicola Tinari, Amelia Cataldi, Rosa Amoroso, Alessandro Cama and Laura De Lellis

Cancers 2019, 11(12), 2042; https://doi.org/10.3390/cancers11122042 - 17 Dec 2019

Cited by 40 | Viewed by 13060

Abstract

Pancreatic cancer (PC) is one of the most lethal, chemoresistant malignancies and it is of paramount importance to find more effective therapeutic agents. Repurposing of non-anticancer drugs may expand the repertoire of effective molecules. Studies on repurposing of benzimidazole-based anthelmintics in PC and [...] Read more.

Pancreatic cancer (PC) is one of the most lethal, chemoresistant malignancies and it is of paramount importance to find more effective therapeutic agents. Repurposing of non-anticancer drugs may expand the repertoire of effective molecules. Studies on repurposing of benzimidazole-based anthelmintics in PC and on their interaction with agents approved for PC therapy are lacking. We analyzed the effects of four Food and Drug Administration (FDA)-approved benzimidazoles on AsPC-1 and Capan-2 pancreatic cancer cell line viability. Notably, parbendazole was the most potent benzimidazole affecting PC cell viability, with half maximal inhibitory concentration (IC₅₀) values in the nanomolar range. The drug markedly inhibited proliferation, clonogenicity and migration of PC cell lines through mechanisms involving alteration of microtubule organization and formation of irregular mitotic spindles. Moreover, parbendazole interfered with cell cycle progression promoting G2/M arrest, followed by the emergence of enlarged, polyploid cells. These abnormalities, suggesting a mitotic catastrophe, culminated in PC cell apoptosis, are also associated with DNA damage in PC cell lines. Remarkably, combinations of parbendazole with gemcitabine, a drug employed as first-line treatment in PC, synergistically decreased PC cell viability. In conclusion, this is the first study providing evidence that parbendazole as a single agent, or in combination with gemcitabine, is a repurposing candidate in the currently dismal PC therapy. Full article

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21 pages, 6482 KiB

Open AccessReview

A Review of Key Biological and Molecular Events Underpinning Transformation of Melanocytes to Primary and Metastatic Melanoma

by Louise A. Jackett and Richard A. Scolyer

Cancers 2019, 11(12), 2041; https://doi.org/10.3390/cancers11122041 - 17 Dec 2019

Cited by 17 | Viewed by 4142

Abstract

Melanoma is a major public health concern that is responsible for significant morbidity and mortality, particularly in countries such as New Zealand and Australia where it is the commonest cause of cancer death in young adults. Until recently, there were no effective drug [...] Read more.

Melanoma is a major public health concern that is responsible for significant morbidity and mortality, particularly in countries such as New Zealand and Australia where it is the commonest cause of cancer death in young adults. Until recently, there were no effective drug therapies for patients with advanced melanoma however significant advances in our understanding of the biological and molecular basis of melanoma in recent decades have led to the development of revolutionary treatments, including targeted molecular therapy and immunotherapy. This review summarizes our current understanding of the key events in the pathway of melanomagenesis and discusses the role of genomic analysis as a potential tool for improved diagnostic evaluation, prognostication and treatment strategies. Ultimately, it is hoped that a continued deeper understanding of the mechanisms of melanomagenesis will lead to the development of even more effective treatments that continue to provide better outcomes for patients with melanoma. Full article

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22 pages, 11627 KiB

Open AccessArticle

Magnetic Silica-Coated Iron Oxide Nanochains as Photothermal Agents, Disrupting the Extracellular Matrix, and Eradicating Cancer Cells

by Jelena Kolosnjaj-Tabi, Slavko Kralj, Elena Griseti, Sebastjan Nemec, Claire Wilhelm, Anouchka Plan Sangnier, Elisabeth Bellard, Isabelle Fourquaux, Muriel Golzio and Marie-Pierre Rols

Cancers 2019, 11(12), 2040; https://doi.org/10.3390/cancers11122040 - 17 Dec 2019

Cited by 25 | Viewed by 3775

Abstract

Cancerous cells and the tumor microenvironment are among key elements involved in cancer development, progression, and resistance to treatment. In order to tackle the cells and the extracellular matrix, we herein propose the use of a class of silica-coated iron oxide nanochains, which [...] Read more.

Cancerous cells and the tumor microenvironment are among key elements involved in cancer development, progression, and resistance to treatment. In order to tackle the cells and the extracellular matrix, we herein propose the use of a class of silica-coated iron oxide nanochains, which have superior magnetic responsiveness and can act as efficient photothermal agents. When internalized by different cancer cell lines and normal (non-cancerous) cells, the nanochains are not toxic, as assessed on 2D and 3D cell culture models. Yet, upon irradiation with near infrared light, the nanochains become efficient cytotoxic photothermal agents. Besides, not only do they generate hyperthermia, which effectively eradicates tumor cells in vitro, but they also locally melt the collagen matrix, as we evidence in real-time, using engineered cell sheets with self-secreted extracellular matrix. By simultaneously acting as physical (magnetic and photothermal) effectors and chemical delivery systems, the nanochain-based platforms offer original multimodal possibilities for prospective cancer treatment, affecting both the cells and the extracellular matrix. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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Graphical abstract

18 pages, 4749 KiB

Open AccessArticle

Simultaneous Multi-Organ Metastases from Chemo-Resistant Triple-Negative Breast Cancer Are Prevented by Interfering with WNT-Signaling

by Iram Fatima, Ikbale El-Ayachi, Hilaire C. Playa, Jackelyn A. Alva-Ornelas, Aysha B. Khalid, William L. Kuenzinger, Peter Wend, Jackelyn C. Pence, Lauren Brakefield, Raisa I. Krutilina, Daniel L. Johnson, Ruth M. O’Regan, Victoria Seewaldt, Tiffany N. Seagroves, Susan A. Krum and Gustavo A. Miranda-Carboni

Cancers 2019, 11(12), 2039; https://doi.org/10.3390/cancers11122039 - 17 Dec 2019

Cited by 23 | Viewed by 3840

Abstract

Triple-negative breast cancers (TNBCs), which lack specific targeted therapy options, evolve into highly chemo-resistant tumors that metastasize to multiple organs simultaneously. We have previously shown that TNBCs maintain an activated WNT10B-driven network that drives metastasis. Pharmacologic inhibition by ICG-001 decreases β-catenin-mediated proliferation of [...] Read more.

Triple-negative breast cancers (TNBCs), which lack specific targeted therapy options, evolve into highly chemo-resistant tumors that metastasize to multiple organs simultaneously. We have previously shown that TNBCs maintain an activated WNT10B-driven network that drives metastasis. Pharmacologic inhibition by ICG-001 decreases β-catenin-mediated proliferation of multiple TNBC cell lines and TNBC patient-derived xenograft (PDX)-derived cell lines. In vitro, ICG-001 was effective in combination with the conventional cytotoxic chemotherapeutics, cisplatin and doxorubicin, to decrease the proliferation of MDA-MB-231 cells. In contrast, in TNBC PDX-derived cells doxorubicin plus ICG-001 was synergistic, while pairing with cisplatin was not as effective. Mechanistically, cytotoxicity induced by doxorubicin, but not cisplatin, with ICG-001 was associated with increased cleavage of PARP-1 in the PDX cells only. In vivo, MDA-MB-231 and TNBC PDX orthotopic primary tumors initiated de novo simultaneous multi-organ metastases, including bone metastases. WNT monotherapy blocked multi-organ metastases as measured by luciferase imaging and histology. The loss of expression of the WNT10B/β-catenin direct targets HMGA2, EZH2, AXIN2, MYC, PCNA, CCND1, transcriptionally active β-catenin, SNAIL and vimentin both in vitro and in vivo in the primary tumors mechanistically explains loss of multi-organ metastases. WNT monotherapy induced VEGFA expression in both tumor model systems, whereas increased CD31 was observed only in the MDA-MB-231 tumors. Moreover, WNT-inhibition sensitized the anticancer response of the TNBC PDX model to doxorubicin, preventing simultaneous metastases to the liver and ovaries, as well as to bone. Our data demonstrate that WNT-inhibition sensitizes TNBC to anthracyclines and treats multi-organ metastases of TNBC. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer)

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18 pages, 3203 KiB

Open AccessArticle

GSTO1*CC Genotype (rs4925) Predicts Shorter Survival in Clear Cell Renal Cell Carcinoma Male Patients

by Tanja Radic, Vesna Coric, Zoran Bukumiric, Marija Pljesa-Ercegovac, Tatjana Djukic, Natasa Avramovic, Marija Matic, Smiljana Mihailovic, Dejan Dragicevic, Zoran Dzamic, Tatjana Simic and Ana Savic-Radojevic

Cancers 2019, 11(12), 2038; https://doi.org/10.3390/cancers11122038 - 17 Dec 2019

Cited by 8 | Viewed by 3169

Abstract

Omega class glutathione transferases, GSTO1-1 and GSTO2-2, exhibit different activities involved in regulation of inflammation, apoptosis and redox homeostasis. We investigated the the prognostic significance of GSTO1 (rs4925) and GSTO2 (rs156697 and rs2297235) polymorphisms in clear cell renal cell carcinoma (ccRCC) patients. GSTO1-1 [...] Read more.

Omega class glutathione transferases, GSTO1-1 and GSTO2-2, exhibit different activities involved in regulation of inflammation, apoptosis and redox homeostasis. We investigated the the prognostic significance of GSTO1 (rs4925) and GSTO2 (rs156697 and rs2297235) polymorphisms in clear cell renal cell carcinoma (ccRCC) patients. GSTO1-1 and GSTO2-2 expression and phosphorylation status of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/ /mammalian target of rapamycin (mTOR) and Raf/MEK/extracellular signal-regulated kinase (ERK) signaling pathways in non-tumor and tumor ccRCC tissue, as well as possible association of GSTO1-1 with signaling molecules were also assessed. GSTO genotyping was performed by quantitative PCR in 228 ccRCC patients, while expression and immunoprecipitation were analyzed by Western blot in 30 tissue specimens. Shorter survival in male carriers of GSTO1*C/C wild-type genotype compared to the carriers of at least one variant allele was demonstrated (p = 0.049). GSTO1*C/C genotype independently predicted higher risk of overall mortality among male ccRCC patients (p = 0.037). Increased expression of GSTO1-1 and GSTO2-2 was demonstrated in tumor compared to corresponding non-tumor tissue (p = 0.002, p = 0.007, respectively), while GSTO1 expression was correlated with interleukin-1β (IL-1β)/pro-interleukin-1β (pro-IL-1β) ratio (r = 0.260, p = 0.350). Interaction of GSTO1 with downstream effectors of investigated pathways was shown in ccRCC tumor tissue. This study demonstrated significant prognostic role of GSTO1 polymorphism in ccRCC. Up-regulated GSTO1-1 and GSTO2-2 in tumor tissue might contribute to aberrant ccRCC redox homeostasis. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

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18 pages, 958 KiB

Open AccessReview

Pain Management in Patients with Multiple Myeloma: An Update

by Flaminia Coluzzi, Roman Rolke and Sebastiano Mercadante

Cancers 2019, 11(12), 2037; https://doi.org/10.3390/cancers11122037 - 17 Dec 2019

Cited by 36 | Viewed by 7035

Abstract

Most patients with multiple myeloma (MM) suffer from chronic pain at every stage of the natural disease process. This review focuses on the most common causes of chronic pain in MM patients: (1) pain from myeloma bone disease (MBD); (2) chemotherapy-induced peripheral neuropathy [...] Read more.

Most patients with multiple myeloma (MM) suffer from chronic pain at every stage of the natural disease process. This review focuses on the most common causes of chronic pain in MM patients: (1) pain from myeloma bone disease (MBD); (2) chemotherapy-induced peripheral neuropathy as a possible consequence of proteasome inhibitor therapy (i.e., bortezomib-induced); (3) post-herpetic neuralgia as a possible complication of varicella zoster virus reactivation because of post-transplantation immunodepression; and (4) pain in cancer survivors, with increasing numbers due to the success of antiblastic treatments, which have significantly improved overall survival and quality of life. In this review, non-pain specialists will find an overview including a detailed description of physiopathological mechanisms underlying central sensitization and pain chronification in bone pain, the rationale for the correct use of analgesics and invasive techniques in different pain syndromes, and the most recent recommendations published on these topics. The ultimate target of this review was to underlie that different types of pain can be observed in MM patients, and highlight that only after an accurate pain assessment, clinical examination, and pain classification, can pain be safely and effectively addressed by selecting the right analgesic option for the right patient. Full article

(This article belongs to the Special Issue Latest Development in Multiple Myeloma)

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13 pages, 3061 KiB

Open AccessArticle

Pathways, Processes, and Candidate Drugs Associated with a Hoxa Cluster-Dependency Model of Leukemia

by Laura M. Kettyle, Charles-Étienne Lebert-Ghali, Ivan V. Grishagin, Glenda J. Dickson, Paul G. O’Reilly, David A. Simpson, Janet J. Bijl, Ken I. Mills, Guy Sauvageau and Alexander Thompson

Cancers 2019, 11(12), 2036; https://doi.org/10.3390/cancers11122036 - 17 Dec 2019

Cited by 4 | Viewed by 2731

Abstract

High expression of the HOXA cluster correlates with poor clinical outcome in acute myeloid leukemias, particularly those harboring rearrangements of the mixed-lineage-leukemia gene (MLLr). Whilst decreased HOXA expression acts as a readout for candidate experimental therapies, the necessity of the HOXA [...] Read more.

High expression of the HOXA cluster correlates with poor clinical outcome in acute myeloid leukemias, particularly those harboring rearrangements of the mixed-lineage-leukemia gene (MLLr). Whilst decreased HOXA expression acts as a readout for candidate experimental therapies, the necessity of the HOXA cluster for leukemia maintenance has not been fully explored. Primary leukemias were generated in hematopoietic stem/progenitor cells from Cre responsive transgenic mice for conditional deletion of the Hoxa locus. Hoxa deletion resulted in reduced proliferation and colony formation in which surviving leukemic cells retained at least one copy of the Hoxa cluster, indicating dependency. Comparative transcriptome analysis of Hoxa wild type and deleted leukemic cells identified a unique gene signature associated with key pathways including transcriptional mis-regulation in cancer, the Fanconi anemia pathway and cell cycle progression. Further bioinformatics analysis of the gene signature identified a number of candidate FDA-approved drugs for potential repurposing in high HOXA expressing cancers including MLLr leukemias. Together these findings support dependency for an MLLr leukemia on Hoxa expression and identified candidate drugs for further therapeutic evaluation. Full article

(This article belongs to the Special Issue HOX Genes in Cancer)

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Graphical abstract

16 pages, 1066 KiB

Open AccessReview

Companion Animals as Models for Inhibition of STAT3 and STAT5

by Matthias Kieslinger, Alexander Swoboda, Nina Kramer, Barbara Pratscher, Birgitt Wolfesberger and Iwan A. Burgener

Cancers 2019, 11(12), 2035; https://doi.org/10.3390/cancers11122035 - 17 Dec 2019

Cited by 3 | Viewed by 4435

Abstract

The use of transgenic mouse models has revolutionized the study of many human diseases. However, murine models are limited in their representation of spontaneously arising tumors and often lack key clinical signs and pathological changes. Thus, a closer representation of complex human diseases [...] Read more.

The use of transgenic mouse models has revolutionized the study of many human diseases. However, murine models are limited in their representation of spontaneously arising tumors and often lack key clinical signs and pathological changes. Thus, a closer representation of complex human diseases is of high therapeutic relevance. Given the high failure rate of drugs at the clinical trial phase (i.e., around 90%), there is a critical need for additional clinically relevant animal models. Companion animals like cats and dogs display chronic inflammatory or neoplastic diseases that closely resemble the human counterpart. Cat and dog patients can also be treated with clinically approved inhibitors or, if ethics and drug safety studies allow, pilot studies can be conducted using, e.g., inhibitors of the evolutionary conserved JAK-STAT pathway. The incidence by which different types of cancers occur in companion animals as well as mechanisms of disease are unique between humans and companion animals, where one can learn from each other. Taking advantage of this situation, existing inhibitors of known oncogenic STAT3/5 or JAK kinase signaling pathways can be studied in the context of rare human diseases, benefitting both, the development of drugs for human use and their application in veterinary medicine. Full article

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

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18 pages, 2218 KiB

Open AccessArticle

Nanosecond Pulsed Electric Fields Induce Endoplasmic Reticulum Stress Accompanied by Immunogenic Cell Death in Murine Models of Lymphoma and Colorectal Cancer

by Alessandra Rossi, Olga N. Pakhomova, Peter A. Mollica, Maura Casciola, Uma Mangalanathan, Andrei G. Pakhomov and Claudia Muratori

Cancers 2019, 11(12), 2034; https://doi.org/10.3390/cancers11122034 - 17 Dec 2019

Cited by 36 | Viewed by 4767

Abstract

Depending on the initiating stimulus, cancer cell death can be immunogenic or non-immunogenic. Inducers of immunogenic cell death (ICD) rely on endoplasmic reticulum (ER) stress for the trafficking of danger signals such as calreticulin (CRT) and ATP. We found that nanosecond pulsed electric [...] Read more.

Depending on the initiating stimulus, cancer cell death can be immunogenic or non-immunogenic. Inducers of immunogenic cell death (ICD) rely on endoplasmic reticulum (ER) stress for the trafficking of danger signals such as calreticulin (CRT) and ATP. We found that nanosecond pulsed electric fields (nsPEF), an emerging new modality for tumor ablation, cause the activation of the ER-resident stress sensor PERK in both CT-26 colon carcinoma and EL-4 lymphoma cells. PERK activation correlates with sustained CRT exposure on the cell plasma membrane and apoptosis induction in both nsPEF-treated cell lines. Our results show that, in CT-26 cells, the activity of caspase-3/7 was increased fourteen-fold as compared with four-fold in EL-4 cells. Moreover, while nsPEF treatments induced the release of the ICD hallmark HMGB1 in both cell lines, extracellular ATP was detected only in CT-26. Finally, in vaccination assays, CT-26 cells treated with nsPEF or doxorubicin equally impaired the growth of tumors at challenge sites eliciting a protective anticancer immune response in 78% and 80% of the animals, respectively. As compared to CT-26, both nsPEF- and mitoxantrone-treated EL-4 cells had a less pronounced effect and protected 50% and 20% of the animals, respectively. These results support our conclusion that nsPEF induce ER stress, accompanied by bona fide ICD. Full article

(This article belongs to the Special Issue Electric Field Based Therapies in Cancer Treatment: a Selection of Studies Presented at the 3rd World Congress on Electroporation)

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11 pages, 992 KiB

Open AccessArticle

Clinicopathologic and Imaging Features of Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations

by Subba R. Digumarthy, Dexter P. Mendoza, Eric W. Zhang, Jochen K. Lennerz and Rebecca S. Heist

Cancers 2019, 11(12), 2033; https://doi.org/10.3390/cancers11122033 - 17 Dec 2019

Cited by 24 | Viewed by 3273

Abstract

MET exon 14 (METex14) skipping mutations are an emerging potentially targetable oncogenic driver mutation in non-small-cell lung cancer (NSCLC). The imaging features and patterns of metastasis of NSCLC with primary METex14 skipping mutations (METex14-mutated NSCLC) are not well [...] Read more.

MET exon 14 (METex14) skipping mutations are an emerging potentially targetable oncogenic driver mutation in non-small-cell lung cancer (NSCLC). The imaging features and patterns of metastasis of NSCLC with primary METex14 skipping mutations (METex14-mutated NSCLC) are not well described. Our goal was to determine the clinicopathologic and imaging features that may suggest the presence of METex14 skipping mutations in NSCLC. This IRB-approved retrospective study included NSCLC patients with primary METex14 skipping mutations and pre-treatment imaging data between January 2013 and December 2018. The clinicopathologic characteristics were extracted from electronic medical records. The imaging features of the primary tumor and metastases were analyzed by two thoracic radiologists. In total, 84 patients with METex14-mutated NSCLC (mean age = 71.4 ± 10 years; F = 52, 61.9%, M = 32, 38.1%; smokers = 47, 56.0%, nonsmokers = 37, 44.0%) were included in the study. Most tumors were adenocarcinoma (72; 85.7%) and presented as masses (53/84; 63.1%) that were peripheral in location (62/84; 73.8%). More than one in five cancers were multifocal (19/84; 22.6%). Most patients with metastatic disease had only extrathoracic metastases (23/34; 67.6%). Fewer patients had both extrathoracic and intrathoracic metastases (10/34; 29.4%), and one patient had only intrathoracic metastases (1/34, 2.9%). The most common metastatic sites were the bones (14/34; 41.2%), the brain (7/34; 20.6%), and the adrenal glands (7/34; 20.6%). Four of the 34 patients (11.8%) had metastases only at a single site. METex14-mutated NSCLC has distinct clinicopathologic and radiologic features. Full article

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20 pages, 5801 KiB

Open AccessArticle

Gigantol Targets Cancer Stem Cells and Destabilizes Tumors via the Suppression of the PI3K/AKT and JAK/STAT Pathways in Ectopic Lung Cancer Xenografts

by Nattanan Losuwannarak, Arnatchai Maiuthed, Nakarin Kitkumthorn, Asada Leelahavanichkul, Sittiruk Roytrakul and Pithi Chanvorachote

Cancers 2019, 11(12), 2032; https://doi.org/10.3390/cancers11122032 - 17 Dec 2019

Cited by 34 | Viewed by 4198

Abstract

Lung cancer has long been recognized as an important world heath concern due to its high incidence and death rate. The failure of treatment strategies, as well as the regrowth of the disease driven by cancer stem cells (CSCs) residing in the tumor, [...] Read more.

Lung cancer has long been recognized as an important world heath concern due to its high incidence and death rate. The failure of treatment strategies, as well as the regrowth of the disease driven by cancer stem cells (CSCs) residing in the tumor, lead to the urgent need for a novel CSC-targeting therapy. Here, we utilized proteome alteration analysis and ectopic tumor xenografts to gain insight on how gigantol, a bibenzyl compound from orchid species, could attenuate CSCs and reduce tumor integrity. The proteomics revealed that gigantol affected several functional proteins influencing the properties of CSCs, especially cell proliferation and survival. Importantly, the PI3K/AKT/mTOR and JAK/STAT related pathways were found to be suppressed by gigantol, while the JNK signal was enhanced. The in vivo nude mice model confirmed that pretreatment of the cells with gigantol prior to a tumor becoming established could decrease the cell division and tumor maintenance. The results indicated that gigantol decreased the relative tumor weight with dramatically reduced tumor cell proliferation, as indicated by Ki-67 labeling. Although gigantol only slightly altered the epithelial-to-mesenchymal and angiogenesis statuses, the gigantol-treated group showed a dramatic loss of tumor integrity as compared with the well-grown tumor mass of the untreated control. This study reveals the effects of gigantol on tumor initiation, growth, and maintain in the scope that the cells at the first step of tumor initiation have lesser CSC property than the control untreated cells. This study reveals novel insights into the anti-tumor mechanisms of gigantol focused on CSC targeting and destabilizing tumor integrity via suppression of the PI3K/AKT/mTOR and JAK/STAT pathways. This data supports the potential of gigantol to be further developed as a drug for lung cancer. 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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18 pages, 3256 KiB

Open AccessArticle

Aberrant DNA Methylation Predicts Melanoma-Specific Survival in Patients with Acral Melanoma

by Dinesh Pradhan, George Jour, Denái Milton, Varshini Vasudevaraja, Michael T. Tetzlaff, Priyadharsini Nagarajan, Jonathan L. Curry, Doina Ivan, Lihong Long, Yingwen Ding, Ravesanker Ezhilarasan, Erik P. Sulman, Adi Diab, Wen-Jen Hwu, Victor G. Prieto, Carlos Antonio Torres-Cabala and Phyu P. Aung

Cancers 2019, 11(12), 2031; https://doi.org/10.3390/cancers11122031 - 16 Dec 2019

Cited by 13 | Viewed by 3425

Abstract

Acral melanoma (AM) is a rare, aggressive type of cutaneous melanoma (CM) with a distinct genetic profile. We aimed to identify a methylome signature distinguishing primary acral lentiginous melanoma (PALM) from primary non-lentiginous AM (NALM), metastatic ALM (MALM), primary non-acral CM (PCM), and [...] Read more.

Acral melanoma (AM) is a rare, aggressive type of cutaneous melanoma (CM) with a distinct genetic profile. We aimed to identify a methylome signature distinguishing primary acral lentiginous melanoma (PALM) from primary non-lentiginous AM (NALM), metastatic ALM (MALM), primary non-acral CM (PCM), and acral nevus (AN). A total of 22 PALM, nine NALM, 10 MALM, nine PCM, and three AN were subjected to genome-wide methylation analysis using the Illumina Infinium Methylation EPIC array interrogating 866,562 CpG sites. A prominent finding was that the methylation profiles of PALM and NALM were distinct. Four of the genes most differentially methylated between PALM and NALM or MALM were HHEX, DIPK2A, NELFB, and TEF. However, when primary AMs (PALM + NALM) were compared with MALM, IFITM1 and SIK3 were the most differentially methylated, highlighting their pivotal role in the metastatic potential of AMs. Patients with NALM had significantly worse disease-specific survival (DSS) than patients with PALM. Aberrant methylation was significantly associated with aggressive clinicopathologic parameters and worse DSS. Our study emphasizes the importance of distinguishing the two epigenetically distinct subtypes of AM. We also identified novel epigenetic prognostic biomarkers that may serve to risk-stratify patients with AM and may be leveraged for the development of targeted therapies. Full article

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16 pages, 710 KiB

Open AccessProject Report

Standardization of Somatic Variant Classifications in Solid and Haematological Tumours by a Two-Level Approach of Biological and Clinical Classes: An Initiative of the Belgian ComPerMed Expert Panel

by Guy Froyen, Marie Le Mercier, Els Lierman, Karl Vandepoele, Friedel Nollet, Elke Boone, Joni Van der Meulen, Koen Jacobs, Suzan Lambin, Sara Vander Borght, Els Van Valckenborgh, Aline Antoniou and Aline Hébrant

Cancers 2019, 11(12), 2030; https://doi.org/10.3390/cancers11122030 - 16 Dec 2019

Cited by 24 | Viewed by 6159

Abstract

In most diagnostic laboratories, targeted next-generation sequencing (NGS) is currently the default assay for the detection of somatic variants in solid as well as haematological tumours. Independent of the method, the final outcome is a list of variants that differ from the human [...] Read more.

In most diagnostic laboratories, targeted next-generation sequencing (NGS) is currently the default assay for the detection of somatic variants in solid as well as haematological tumours. Independent of the method, the final outcome is a list of variants that differ from the human genome reference sequence of which some may relate to the establishment of the tumour in the patient. A critical point towards a uniform patient management is the assignment of the biological contribution of each variant to the malignancy and its subsequent clinical impact in a specific malignancy. These so-called biological and clinical classifications of somatic variants are currently not standardized and are vastly dependent on the subjective analysis of each laboratory. This subjectivity can thus result in a different classification and subsequent clinical interpretation of the same variant. Therefore, the ComPerMed panel of Belgian experts in cancer diagnostics set up a working group with the goal to harmonize the biological classification and clinical interpretation of somatic variants detected by NGS. This effort resulted in the establishment of a uniform, two-level classification workflow system that should enable high consistency in diagnosis, prognosis, treatment and follow-up of cancer patients. Variants are first classified into a tumour-independent biological five class system and subsequently in a four tier ACMG clinical classification. Here, we describe the ComPerMed workflow in detail including examples for each step of the pipeline. Moreover, this workflow can be implemented in variant classification software tools enabling automatic reporting of NGS data, independent of panel, method or analysis software. Full article

(This article belongs to the Collection Targeting Solid Tumors)

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13 pages, 1472 KiB

Open AccessArticle

Expression of GP88 (Progranulin) Protein Is an Independent Prognostic Factor in Prostate Cancer Patients

by Amer Abdulrahman, Markus Eckstein, Rudolf Jung, Juan Guzman, Katrin Weigelt, Ginette Serrero, Binbin Yue, Carol Geppert, Robert Stöhr, Arndt Hartmann, Bernd Wullich, Sven Wach, Helge Taubert and Verena Lieb

Cancers 2019, 11(12), 2029; https://doi.org/10.3390/cancers11122029 - 16 Dec 2019

Cited by 9 | Viewed by 2278

Abstract

Prostate cancer, the second most common cancer, is still a major cause of morbidity and mortality among men worldwide. The expression of the survival and proliferation factor progranulin (GP88) has not yet been comprehensively studied in PCa tumors. The aim of this study [...] Read more.

Prostate cancer, the second most common cancer, is still a major cause of morbidity and mortality among men worldwide. The expression of the survival and proliferation factor progranulin (GP88) has not yet been comprehensively studied in PCa tumors. The aim of this study was to characterize GP88 protein expression in PCa by immunohistochemistry and to correlate the findings to the clinico-pathological data and prognosis. Immunohistochemical staining for GP88 was performed by TMA with samples from 442 PCa patients using an immunoreactive score (IRS). Altogether, 233 cases (52.7%) with negative GP88 staining (IRS < 2) and 209 cases (47.3%) with positive GP88 staining (IRS ≥ 2) were analyzed. A significant positive correlation was found for the GP88 IRS with the PSA value at prostatectomy and the cytoplasmic cytokeratin 20 IRS, whereas it was negatively associated with follow-up times. The association of GP88 staining with prognosis was further studied by survival analyses (Kaplan–Meier, univariate and multivariate Cox’s regression analysis). Increased GP88 protein expression appeared as an independent prognostic factor for overall, disease-specific and relapse-free survival in all PCa patients. Interestingly, in the subgroup of younger PCa patients (≤65 years), GP88 positivity was associated with a 3.8-fold (p = 0.004), a 6.0-fold (p = 0.008) and a 3.7-fold (p = 0.003) increased risk for death, disease-specific death and occurrence of a relapse, respectively. In the PCa subgroup with negative CK20 staining, GP88 positivity was associated with a 1.8-fold (p = 0.018) and a 2.8-fold increased risk for death and disease-specific death (p = 0.028). Altogether, GP88 protein positivity appears to be an independent prognostic factor for PCa patients. Full article

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

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20 pages, 3331 KiB

Open AccessArticle

Mutant IDH1 Differently Affects Redox State and Metabolism in Glial Cells of Normal and Tumor Origin

by Julia Biedermann, Matthias Preussler, Marina Conde, Mirko Peitzsch, Susan Richter, Ralf Wiedemuth, Khalil Abou-El-Ardat, Alexander Krüger, Matthias Meinhardt, Gabriele Schackert, William P. Leenders, Christel Herold-Mende, Simone P. Niclou, Rolf Bjerkvig, Graeme Eisenhofer, Achim Temme, Michael Seifert, Leoni A. Kunz-Schughart, Evelin Schröck and Barbara Klink

Cancers 2019, 11(12), 2028; https://doi.org/10.3390/cancers11122028 - 16 Dec 2019

Cited by 20 | Viewed by 5549

Abstract

IDH1^R132H (isocitrate dehydrogenase 1) mutations play a key role in the development of low-grade gliomas. IDH1^wt converts isocitrate to α-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP⁺), whereas IDH1^R132H uses α-ketoglutarate and NADPH to generate the oncometabolite 2-hydroxyglutarate [...] Read more.

IDH1^R132H (isocitrate dehydrogenase 1) mutations play a key role in the development of low-grade gliomas. IDH1^wt converts isocitrate to α-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP⁺), whereas IDH1^R132H uses α-ketoglutarate and NADPH to generate the oncometabolite 2-hydroxyglutarate (2-HG). While the effects of 2-HG have been the subject of intense research, the 2-HG independent effects of IDH1^R132H are still ambiguous. The present study demonstrates that IDH1^R132H expression but not 2-HG alone leads to significantly decreased tricarboxylic acid (TCA) cycle metabolites, reduced proliferation, and enhanced sensitivity to irradiation in both glioblastoma cells and astrocytes in vitro. Glioblastoma cells, but not astrocytes, showed decreased NADPH and NAD⁺ levels upon IDH1^R132H transduction. However, in astrocytes IDH1^R132H led to elevated expression of the NAD-synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT). These effects were not 2-HG mediated. This suggests that IDH1^R132H cells utilize NAD⁺ to restore NADP pools, which only astrocytes could compensate via induction of NAMPT. We found that the expression of NAMPT is lower in patient-derived IDH1-mutant glioma cells and xenografts compared to IDH1-wildtype models. The Cancer Genome Atlas (TCGA) data analysis confirmed lower NAMPT expression in IDH1-mutant versus IDH1-wildtype gliomas. We show that the IDH1 mutation directly affects the energy homeostasis and redox state in a cell-type dependent manner. Targeting the impairments in metabolism and redox state might open up new avenues for treating IDH1-mutant gliomas. Full article

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19 pages, 6009 KiB

Open AccessFeature PaperArticle

Inhibition of Histone Demethylases LSD1 and UTX Regulates ERα Signaling in Breast Cancer

by Rosaria Benedetti, Carmela Dell’Aversana, Tommaso De Marchi, Dante Rotili, Ning Qing Liu, Boris Novakovic, Serena Boccella, Salvatore Di Maro, Sandro Cosconati, Alfonso Baldi, Emma Niméus, Johan Schultz, Urban Höglund, Sabatino Maione, Chiara Papulino, Ugo Chianese, Francesco Iovino, Antonio Federico, Antonello Mai, Hendrik G. Stunnenberg, Angela Nebbioso and Lucia Altucci Show full author list Hide full author list

Cancers 2019, 11(12), 2027; https://doi.org/10.3390/cancers11122027 - 16 Dec 2019

Cited by 34 | Viewed by 5864

Abstract

In breast cancer, Lysine-specific demethylase-1 (LSD1) and other lysine demethylases (KDMs), such as Lysine-specific demethylase 6A also known as Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), are co-expressed and co-localize with estrogen receptors (ERs), suggesting the potential use of hybrid (epi)molecules to target [...] Read more.

In breast cancer, Lysine-specific demethylase-1 (LSD1) and other lysine demethylases (KDMs), such as Lysine-specific demethylase 6A also known as Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), are co-expressed and co-localize with estrogen receptors (ERs), suggesting the potential use of hybrid (epi)molecules to target histone methylation and therefore regulate/redirect hormone receptor signaling. Here, we report on the biological activity of a dual-KDM inhibitor (MC3324), obtained by coupling the chemical properties of tranylcypromine, a known LSD1 inhibitor, with the 2OG competitive moiety developed for JmjC inhibition. MC3324 displays unique features not exhibited by the single moieties and well-characterized mono-pharmacological inhibitors. Inhibiting LSD1 and UTX, MC3324 induces significant growth arrest and apoptosis in hormone-responsive breast cancer model accompanied by a robust increase in H3K4me2 and H3K27me3. MC3324 down-regulates ERα in breast cancer at both transcriptional and non-transcriptional levels, mimicking the action of a selective endocrine receptor disruptor. MC3324 alters the histone methylation of ERα-regulated promoters, thereby affecting the transcription of genes involved in cell surveillance, hormone response, and death. MC3324 reduces cell proliferation in ex vivo breast cancers, as well as in breast models with acquired resistance to endocrine therapies. Similarly, MC3324 displays tumor-selective potential in vivo, in both xenograft mice and chicken embryo models, with no toxicity and good oral efficacy. This epigenetic multi-target approach is effective and may overcome potential mechanism(s) of resistance in breast cancer. Full article

(This article belongs to the Collection Targeting Solid Tumors)

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41 pages, 5674 KiB

Open AccessReview

Liver Cancer: Current and Future Trends Using Biomaterials

by Sue Anne Chew, Stefania Moscato, Sachin George, Bahareh Azimi and Serena Danti

Cancers 2019, 11(12), 2026; https://doi.org/10.3390/cancers11122026 - 16 Dec 2019

Cited by 27 | Viewed by 6766

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common type of cancer diagnosed and the second leading cause of death worldwide. Despite advancement in current treatments for HCC, the prognosis for this cancer is still unfavorable. This comprehensive review article focuses on all the [...] Read more.

Hepatocellular carcinoma (HCC) is the fifth most common type of cancer diagnosed and the second leading cause of death worldwide. Despite advancement in current treatments for HCC, the prognosis for this cancer is still unfavorable. This comprehensive review article focuses on all the current technology that applies biomaterials to treat and study liver cancer, thus showing the versatility of biomaterials to be used as smart tools in this complex pathologic scenario. Specifically, after introducing the liver anatomy and pathology by focusing on the available treatments for HCC, this review summarizes the current biomaterial-based approaches for systemic delivery and implantable tools for locally administrating bioactive factors and provides a comprehensive discussion of the specific therapies and targeting agents to efficiently deliver those factors. This review also highlights the novel application of biomaterials to study HCC, which includes hydrogels and scaffolds to tissue engineer 3D in vitro models representative of the tumor environment. Such models will serve to better understand the tumor biology and investigate new therapies for HCC. Special focus is given to innovative approaches, e.g., combined delivery therapies, and to alternative approaches—e.g., cell capture—as promising future trends in the application of biomaterials to treat HCC. Full article

(This article belongs to the Special Issue Models of Experimental Liver Cancer)

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16 pages, 2698 KiB

Open AccessArticle

Discovering Rare Genes Contributing to Cancer Stemness and Invasive Potential by GBM Single-Cell Transcriptional Analysis

by Lin Pang, Jing Hu, Feng Li, Huating Yuan, Min Yan, Gaoming Liao, Liwen Xu, Bo Pang, Yanyan Ping, Yun Xiao and Xia Li

Cancers 2019, 11(12), 2025; https://doi.org/10.3390/cancers11122025 - 16 Dec 2019

Cited by 7 | Viewed by 3350

Abstract

Single-cell RNA sequencing presents the sophisticated delineation of cell transcriptomes in many cancer types and highlights the tumor heterogeneity at higher resolution, which provides a new chance to explore the molecular mechanism in a minority of cells. In this study, we utilized publicly [...] Read more.

Single-cell RNA sequencing presents the sophisticated delineation of cell transcriptomes in many cancer types and highlights the tumor heterogeneity at higher resolution, which provides a new chance to explore the molecular mechanism in a minority of cells. In this study, we utilized publicly available single-cell RNA-seq data to discover and comprehensively dissect rare genes existing in few glioblastoma (GBM) cells. Moreover, we designed a framework to systematically identify 51 rare protein-coding genes (PCGs) and 47 rare long non-coding RNAs (lncRNAs) in GBM. Patients with high expression levels of rare genes like CYB5R2 and TPPP3 had worse overall survival and disease-free survival, implying their potential implication in GBM progression and prognosis. We found that these rare genes tended to be specifically expressed in GBM cancer stem cells, which emphasized their ability to characterize stem-like cancer cells and implied their contribution to GBM growth. Furthermore, rare genes were enriched in a 17-cell subset, which was located in an individual branch of the pseudotime trajectory of cancer progression and exhibited high cell cycle activity and invasive potential. Our study captures the rare genes highly expressed in few cells, deepens our understanding of special states during GBM tumorigenesis and progression such as cancer stemness and invasion, and proposes potential targets for cancer therapy. Full article

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11 pages, 649 KiB

Open AccessReview

Chimeric Antigen Receptor T-Cell Therapy for Multiple Myeloma

by Naoki Hosen

Cancers 2019, 11(12), 2024; https://doi.org/10.3390/cancers11122024 - 15 Dec 2019

Cited by 12 | Viewed by 6162

Abstract

CD19 Chimeric antigen receptor (CAR) T cell therapy has been shown to be effective for B cell leukemia and lymphoma. Many researchers are now trying to develop CAR T cells for various types of cancer. For multiple myeloma (MM), B-cell maturation antigen (BCMA) [...] Read more.

CD19 Chimeric antigen receptor (CAR) T cell therapy has been shown to be effective for B cell leukemia and lymphoma. Many researchers are now trying to develop CAR T cells for various types of cancer. For multiple myeloma (MM), B-cell maturation antigen (BCMA) has been recently proved to be a promising target. However, cure of MM is still difficult, and several other targets, for example immunoglobulin kappa chain, SLAM Family Member 7 (SLAMF7), or G-protein coupled receptor family C group 5 member D (GPRC5D), are being tested as targets for CAR T cells. We also reported that the activated integrin β7 can serve as a specific target for CAR T cells against MM, and are preparing a clinical trial. In this review, we summarized current status of CAR T cell therapy for MM and discussed about the future perspectives. Full article

(This article belongs to the Special Issue Latest Development in Multiple Myeloma)

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20 pages, 4224 KiB

Open AccessArticle

Identification of a Subtype of Hepatocellular Carcinoma with Poor Prognosis Based on Expression of Genes within the Glucose Metabolic Pathway

by Xiaoli Zhang, Jin Li, Kalpana Ghoshal, Soledad Fernandez and Lang Li

Cancers 2019, 11(12), 2023; https://doi.org/10.3390/cancers11122023 - 14 Dec 2019

Cited by 12 | Viewed by 4024

Abstract

Hepatocellular carcinoma (HCC) is the most prevalent primary cancer and a highly aggressive liver malignancy. Liver cancer cells reprogram their metabolism to meet their needs for rapid proliferation and tumor growth. In the present study, we investigated the alterations in the expression of [...] Read more.

Hepatocellular carcinoma (HCC) is the most prevalent primary cancer and a highly aggressive liver malignancy. Liver cancer cells reprogram their metabolism to meet their needs for rapid proliferation and tumor growth. In the present study, we investigated the alterations in the expression of the genes involved in glucose metabolic pathways as well as their association with the clinical stage and survival of HCC patients. We found that the expressions of around 30% of genes involved in the glucose metabolic pathway are consistently dysregulated with a predominant down-regulation in HCC tumors. Moreover, the differentially expressed genes are associated with an advanced clinical stage and a poor prognosis. More importantly, unsupervised clustering analysis with the differentially expressed genes that were also associated with overall survival (OS) revealed a subgroup of patients with a worse prognosis including reduced OS, disease specific survival, and recurrence-free survival. This aggressive subtype had significantly increased expression of stemness-related genes and down-regulated metabolic genes, as well as increased immune infiltrates that contribute to a poor prognosis. Collectively, this integrative study indicates that expressions of the glucose metabolic genes could be used as potential prognostic markers and/or therapeutic targets, which might be helpful in developing precise treatment for patients with HCC. Full article

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18 pages, 923 KiB

Open AccessReview

Immunotherapy in Pediatric Solid Tumors—A Systematic Review

by Raoud Marayati, Colin H. Quinn and Elizabeth A. Beierle

Cancers 2019, 11(12), 2022; https://doi.org/10.3390/cancers11122022 - 14 Dec 2019

Cited by 12 | Viewed by 4311

Abstract

Despite advances in the treatment of many pediatric solid tumors, children with aggressive and high-risk disease continue to have a dismal prognosis. For those presenting with metastatic or recurrent disease, multiple rounds of intensified chemotherapy and radiation are the typical course of action, [...] Read more.

Despite advances in the treatment of many pediatric solid tumors, children with aggressive and high-risk disease continue to have a dismal prognosis. For those presenting with metastatic or recurrent disease, multiple rounds of intensified chemotherapy and radiation are the typical course of action, but more often than not, this fails to control the progression of the disease. Thus, new therapeutics are desperately needed to improve the outcomes for these children. Recent advances in our understanding of both the immune system’s biology and its interaction with tumors have led to the development of novel immunotherapeutics as alternative treatment options for these aggressive malignancies. Immunotherapeutic approaches have shown promising results for pediatric solid tumors in early clinical trials, but challenges remain concerning safety and anti-tumor efficacy. In this review, we aim to discuss and summarize the main classes of immunotherapeutics used to treat pediatric solid tumors. Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

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18 pages, 3756 KiB

Open AccessArticle

Inhibitor of DNA-Binding Protein 4 Suppresses Cancer Metastasis through the Regulation of Epithelial Mesenchymal Transition in Lung Adenocarcinoma

by Chi-Chung Wang, Yuan-Ling Hsu, Chi-Jen Chang, Chia-Jen Wang, Tzu-Hung Hsiao and Szu-Hua Pan

Cancers 2019, 11(12), 2021; https://doi.org/10.3390/cancers11122021 - 14 Dec 2019

Cited by 11 | Viewed by 3354

Abstract

Metastasis is a predominant cause of cancer death and the major challenge in treating lung adenocarcinoma (LADC). Therefore, exploring new metastasis-related genes and their action mechanisms may provide new insights for developing a new combative approach to treat lung cancer. Previously, our research [...] Read more.

Metastasis is a predominant cause of cancer death and the major challenge in treating lung adenocarcinoma (LADC). Therefore, exploring new metastasis-related genes and their action mechanisms may provide new insights for developing a new combative approach to treat lung cancer. Previously, our research team discovered that the expression of the inhibitor of DNA binding 4 (Id4) was inversely related to cell invasiveness in LADC cells by cDNA microarray screening. However, the functional role of Id4 and its mechanism of action in lung cancer metastasis remain unclear. In this study, we report that the expression of Id4 could attenuate cell migration and invasion in vitro and cancer metastasis in vivo. Detailed analyses indicated that Id4 could promote E-cadherin expression through the binding of Slug, cause the occurrence of mesenchymal-epithelial transition (MET), and inhibit cancer metastasis. Moreover, the examination of the gene expression database (GSE31210) also revealed that high-level expression of Id4/E-cadherin and low-level expression of Slug were associated with a better clinical outcome in LADC patients. In summary, Id4 may act as a metastatic suppressor, which could not only be used as an independent predictor but also serve as a potential therapeutic for LADC treatment. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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12 pages, 578 KiB

Open AccessArticle

Low Systemic Levels of Chemokine C-C Motif Ligand 3 (CCL3) are Associated with a High Risk of Venous Thromboembolism in Patients with Glioma

by Pegah Mir Seyed Nazari, Christine Marosi, Florian Moik, Julia Riedl, Öykü Özer, Anna Sophie Berghoff, Matthias Preusser, Johannes A. Hainfellner, Ingrid Pabinger, Gerhard J. Zlabinger and Cihan Ay

Cancers 2019, 11(12), 2020; https://doi.org/10.3390/cancers11122020 - 14 Dec 2019

Cited by 11 | Viewed by 2800

Abstract

A tight interplay between inflammation and hemostasis has been described as a potential driver for developing venous thromboembolism (VTE). Here, we investigated the association of systemic cytokine levels and risk of VTE in patients with glioma. This analysis was conducted within the prospective, [...] Read more.

A tight interplay between inflammation and hemostasis has been described as a potential driver for developing venous thromboembolism (VTE). Here, we investigated the association of systemic cytokine levels and risk of VTE in patients with glioma. This analysis was conducted within the prospective, observational Vienna Cancer and Thrombosis Study. Patients with glioma were included at time of diagnosis or progression and were observed for a maximum of two years. Primary endpoint was objectively confirmed VTE. At study entry, a single blood draw was performed. A panel of nine cytokines was measured in serum samples with the xMAP technology developed by Luminex. Results: Overall, 76 glioma patients were included in this analysis, and 10 (13.2%) of them developed VTE during the follow-up. Chemokine C-C motif ligand 3 (CCL3) levels were inversely associated with risk of VTE (hazard ratio [HR] per double increase, 95% confidence interval [CI]: 0.385, 95% CI: 0.161–0.925, p = 0.033), while there was no association between the risk of VTE and serum levels of interleukin (IL)-1β, IL-4, IL-6, IL-8, IL-10, IL-11, tumor necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF), respectively. In conclusion, low serum levels of CCL3 were associated with an increased risk of VTE. CCL3 might serve as a potential biomarker to predict VTE risk in patients with glioma. Full article

(This article belongs to the Special Issue Treatment of Cancer-Associated Thrombosis)

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14 pages, 1895 KiB

Open AccessArticle

Tumor Suppressor Function of miR-127-3p and miR-376a-3p in Osteosarcoma Cells

by Joerg Fellenberg, Burkhard Lehner, Heiner Saehr, Astrid Schenker and Pierre Kunz

Cancers 2019, 11(12), 2019; https://doi.org/10.3390/cancers11122019 - 14 Dec 2019

Cited by 25 | Viewed by 2964

Abstract

Since the introduction of high-dose chemotherapy about 35 years ago, survival rates of osteosarcoma patients have not been significantly improved. New therapeutic strategies replacing or complementing conventional chemotherapy are therefore urgently required. MicroRNAs represent promising targets for such new therapies, as they are [...] Read more.

Since the introduction of high-dose chemotherapy about 35 years ago, survival rates of osteosarcoma patients have not been significantly improved. New therapeutic strategies replacing or complementing conventional chemotherapy are therefore urgently required. MicroRNAs represent promising targets for such new therapies, as they are involved in the pathology of multiple types of cancer, and aberrant expression of several miRNAs has already been shown in osteosarcoma. In this study, we identified silencing of miR-127-3p and miR-376a-3p in osteosarcoma cell lines and tissues and investigated their role as potential tumor suppressors in vitro and in vivo. Transfection of osteosarcoma cells (n = 6) with miR-127-3p and miR-376a-3p mimics significantly inhibited proliferation and reduced the colony formation capacity of these cells. In contrast, we could not detect any influence of miRNA restoration on cell cycle and apoptosis induction. The effects of candidate miRNA restoration on tumor engraftment and growth in vivo were analyzed using a chicken chorioallantoic membrane (CAM) assay. Cells transfected with mir-127-3p and miR-376a-3p showed reduced tumor take rates and tumor volumes and a significant decrease of the cumulative tumor volumes to 41% and 54% compared to wildtype cells. The observed tumor suppressor function of both analyzed miRNAs indicates these miRNAs as potentially valuable targets for the development of new therapeutic strategies for the treatment of osteosarcoma. Full article

(This article belongs to the Special Issue Bone and Soft Tissue Tumors)

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29 pages, 1836 KiB

Open AccessReview

What Is the Role of Interleukins in Breast Cancer Bone Metastases? A Systematic Review of Preclinical and Clinical Evidence

by Francesca Salamanna, Veronica Borsari, Deyanira Contartese, Viviana Costa, Gianluca Giavaresi and Milena Fini

Cancers 2019, 11(12), 2018; https://doi.org/10.3390/cancers11122018 - 13 Dec 2019

Cited by 15 | Viewed by 3001

Abstract

Breast cancer cells produce stimulators of bone resorption known as interleukins (ILs). However, data on the functional roles of ILs in the homing of metastatic breast cancer to bone are still fragmented. A systematic search was carried out in three databases (PubMed, Scopus, [...] Read more.

Breast cancer cells produce stimulators of bone resorption known as interleukins (ILs). However, data on the functional roles of ILs in the homing of metastatic breast cancer to bone are still fragmented. A systematic search was carried out in three databases (PubMed, Scopus, Web of Science Core Collection) to identify preclinical reports, and in three clinical registers (ClinicalTrials.gov, World Health Organization (WHO) International Clinical Trials Registry Platform, European Union (EU) Clinical Trials Register) to identify clinical trials, from 2008 to 2019. Sixty-seven preclinical studies and 11 clinical trials were recognized as eligible. Although preclinical studies identified specific key ILs which promote breast cancer bone metastases, which have pro-metastatic effects (e.g., IL-6, IL-8, IL-1β, IL-11), and whose inhibition also shows potential preclinical therapeutic effects, the clinical trials focused principally on ILs (IL-2 and IL-12), which have an anti-metastatic effect and a potential to generate a localized and systemic antitumor response. However, these clinical trials are yet to post any results or conclusions. This inconsistency indicates that further studies are necessary to further develop the understanding of cellular and molecular relations, as well as signaling pathways, both up- and downstream of ILs, which could represent a novel strategy to treat tumors that are resistant to standard care therapies for patients affected by breast cancer bone disease. Full article

(This article belongs to the Special Issue Targeting Bone Metastasis in Cancers)

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25 pages, 6318 KiB

Open AccessArticle

Aberrant Protein Phosphorylation in Cancer by Using Raman Biomarkers

by Halina Abramczyk, Anna Imiela, Beata Brożek-Płuska, Monika Kopeć, Jakub Surmacki and Agnieszka Śliwińska

Cancers 2019, 11(12), 2017; https://doi.org/10.3390/cancers11122017 - 13 Dec 2019

Cited by 33 | Viewed by 5642

Abstract

(1) Background: Novel methods are required for analysing post-translational modifications of protein phosphorylation by visualizing biochemical landscapes of proteins in human normal and cancerous tissues and cells. (2) Methods: A label-free Raman method is presented for detecting spectral changes that arise in proteins [...] Read more.

(1) Background: Novel methods are required for analysing post-translational modifications of protein phosphorylation by visualizing biochemical landscapes of proteins in human normal and cancerous tissues and cells. (2) Methods: A label-free Raman method is presented for detecting spectral changes that arise in proteins due to phosphorylation in the tissue of human breasts, small intestines, and brain tumours, as well as in the normal human astrocytes and primary glioblastoma U-87 MG cell lines. Raman spectroscopy and Raman imaging are effective tools for monitoring and analysing the vibrations of functional groups involved in aberrant phosphorylation in cancer without any phosphorecognition of tag molecules. (3) Results: Our results based on 35 fresh human cancer and normal tissues prove that the aberrant tyrosine phosphorylation monitored by the unique spectral signatures of Raman vibrations is a universal characteristic in the metabolic regulation in different types of cancers. Overexpressed tyrosine phosphorylation in the human breast, small intestine and brain tissues and in the human primary glioblastoma U-87 MG cell line was monitored by using Raman biomarkers. (4) We showed that the bands at 1586 cm⁻¹ and 829 cm⁻¹, corresponding to phosphorylated tyrosine, play a pivotal role as a Raman biomarker of the phosphorylation status in aggressive cancers. We found that the best Raman biomarker of phosphorylation is the 1586/829 ratio showing the statistical significance at p Values of ≤ 0.05. (5) Conclusions: Raman spectroscopy and imaging have the potential to be used as screening functional assays to detect phosphorylated target proteins and will help researchers to understand the role of phosphorylation in cellular processes and cancer progression. The abnormal and excessive high level of tyrosine phosphorylation in cancer samples compared with normal samples was found in the cancerous human tissue of breasts, small intestines and brain tumours, as well as in the mitochondria and lipid droplets of the glioblastoma U-87 MG cell line. Detailed insights are presented into the intracellular oncogenic metabolic pathways mediated by phosphorylated tyrosine. Full article

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10 pages, 228 KiB

Open AccessArticle

Dose-Limiting Organs at Risk in Carbon Ion Re-Irradiation of Head and Neck Malignancies: An Individual Risk-Benefit Tradeoff

by Thomas Held, Semi B. Harrabi, Kristin Lang, Sati Akbaba, Paul Windisch, Denise Bernhardt, Stefan Rieken, Klaus Herfarth, Jürgen Debus and Sebastian Adeberg

Cancers 2019, 11(12), 2016; https://doi.org/10.3390/cancers11122016 - 13 Dec 2019

Cited by 6 | Viewed by 2283

Abstract

Background: Carbon ion re-irradiation (CIR) was evaluated to investigate treatment planning and the consequences of individual risk-benefit evaluations concerning dose-limiting organs at risk (OAR). Methods: A total of 115 consecutive patients with recurrent head and neck cancer (HNC) were analyzed after [...] Read more.

Background: Carbon ion re-irradiation (CIR) was evaluated to investigate treatment planning and the consequences of individual risk-benefit evaluations concerning dose-limiting organs at risk (OAR). Methods: A total of 115 consecutive patients with recurrent head and neck cancer (HNC) were analyzed after initial radiotherapy and CIR at the same anatomical site. Toxicities were evaluated in line with the Common Terminology Criteria for Adverse Events 4.03. Results: The median maximum cumulative equivalent doses applied in fractions of 2 Gy (EQD2) to the brainstem, optic chiasm, ipsilateral optic nerve, and spinal cord were 56.8 Gy (range 0.94–103.9), 51.4 Gy (range 0–120.3 Gy), 63.6 Gy (range 0–146.1 Gy), and 28.8 Gy (range 0.2–87.7 Gy). The median follow up after CIR was 24.0 months (range 2.5–72.0 months). The cumulative rates of acute and late severe (≥grade III) side effects after CIR were 1.8% and 14.3%. Conclusion: In recurrent HNC, an individual risk-benefit tradeoff is frequently inevitable due to unfavorable location of tumors in close proximity to vital OAR. There are uncertainties about the dose tolerance of OAR after CIR, which warrant increased awareness about the potential treatment toxicity and further studies on heavy ion re-irradiation. Full article

(This article belongs to the Special Issue New Horizons in Particle Therapy)

38 pages, 600 KiB

Open AccessReview

Pursuing a Curative Approach in Multiple Myeloma: A Review of New Therapeutic Strategies

by Mattia D'Agostino, Luca Bertamini, Stefania Oliva, Mario Boccadoro and Francesca Gay

Cancers 2019, 11(12), 2015; https://doi.org/10.3390/cancers11122015 - 13 Dec 2019

Cited by 25 | Viewed by 6787

Abstract

Multiple myeloma (MM) is still considered an incurable hematologic cancer and, in the last decades, the treatment goal has been to obtain a long-lasting disease control. However, the recent availability of new effective drugs has led to unprecedented high-quality responses and prolonged progression-free [...] Read more.

Multiple myeloma (MM) is still considered an incurable hematologic cancer and, in the last decades, the treatment goal has been to obtain a long-lasting disease control. However, the recent availability of new effective drugs has led to unprecedented high-quality responses and prolonged progression-free survival and overall survival. The improvement of response rates has prompted the development of new, very sensitive methods to measure residual disease, even when monoclonal components become undetectable in patients’ serum and urine. Several scientific efforts have been made to develop reliable and validated techniques to measure minimal residual disease (MRD), both within and outside the bone marrow. With the newest multidrug combinations, a good proportion of MM patients can achieve MRD negativity. Long-lasting MRD negativity may prove to be a marker of “operational cure”, although the follow-up of the currently ongoing studies is still too short to draw conclusions. In this article, we focus on results obtained with new-generation multidrug combinations in the treatment of high-risk smoldering MM and newly diagnosed MM, including the potential role of MRD and MRD-driven treatment strategies in clinical trials, in order to optimize and individualize treatment. Full article

(This article belongs to the Special Issue Latest Development in Multiple Myeloma)

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17 pages, 2544 KiB

Open AccessArticle

HuR Reduces Radiation-Induced DNA Damage by Enhancing Expression of ARID1A

by Daniel Andrade, Meghna Mehta, James Griffith, Sangphil Oh, Joshua Corbin, Anish Babu, Supriyo De, Allshine Chen, Yan D. Zhao, Sanam Husain, Sudeshna Roy, Liang Xu, Jeffrey Aube, Ralf Janknecht, Myriam Gorospe, Terence Herman, Rajagopal Ramesh and Anupama Munshi

Cancers 2019, 11(12), 2014; https://doi.org/10.3390/cancers11122014 - 13 Dec 2019

Cited by 23 | Viewed by 3890

Abstract

Tumor suppressor ARID1A, a subunit of the chromatin remodeling complex SWI/SNF, regulates cell cycle progression, interacts with the tumor suppressor TP53, and prevents genomic instability. In addition, ARID1A has been shown to foster resistance to cancer therapy. By promoting non-homologous end joining (NHEJ), [...] Read more.

Tumor suppressor ARID1A, a subunit of the chromatin remodeling complex SWI/SNF, regulates cell cycle progression, interacts with the tumor suppressor TP53, and prevents genomic instability. In addition, ARID1A has been shown to foster resistance to cancer therapy. By promoting non-homologous end joining (NHEJ), ARID1A enhances DNA repair. Consequently, ARID1A has been proposed as a promising therapeutic target to sensitize cancer cells to chemotherapy and radiation. Here, we report that ARID1A is regulated by human antigen R (HuR), an RNA-binding protein that is highly expressed in a wide range of cancers and enables resistance to chemotherapy and radiation. Our results indicate that HuR binds ARID1A mRNA, thereby increasing its stability in breast cancer cells. We further find that ARID1A expression suppresses the accumulation of DNA double-strand breaks (DSBs) caused by radiation and can rescue the loss of radioresistance triggered by HuR inhibition, suggesting that ARID1A plays an important role in HuR-driven resistance to radiation. Taken together, our work shows that HuR and ARID1A form an important regulatory axis in radiation resistance that can be targeted to improve radiotherapy in breast cancer patients. Full article

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Cancers, Volume 11, Issue 12 (December 2019) – 223 articles

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