Cancers

22 pages, 7731 KiB

Open AccessArticle

Identification of a Dexamethasone Mediated Radioprotection Mechanism Reveals New Therapeutic Vulnerabilities in Glioblastoma

by Paula Aldaz, Jaione Auzmendi-Iriarte, Maika Durántez, Irene Lasheras-Otero, Estefania Carrasco-Garcia, M. Victoria Zelaya, Laura Bragado, Ana Olías-Arjona, Larraitz Egaña, Nicolás Samprón, Idoia Morilla, Marta Redondo-Muñoz, Mikel Rico, Massimo Squatrito, Marta Maria-Alonso, Joaquín Fernández-Irigoyen, Enrique Santamaria, Iñaki M. Larráyoz, Claudia Wellbrock, Ander Matheu and Imanol Arozarena Show full author list Hide full author list

Cancers 2021, 13(2), 361; https://doi.org/10.3390/cancers13020361 - 19 Jan 2021

Cited by 9 | Viewed by 2922

Abstract

(1) Background: Despite the indisputable effectiveness of dexamethasone (DEXA) to reduce inflammation in glioblastoma (GBM) patients, its influence on tumour progression and radiotherapy response remains controversial. (2) Methods: We analysed patient data and used expression and cell biological analyses to assess effects of [...] Read more.

(1) Background: Despite the indisputable effectiveness of dexamethasone (DEXA) to reduce inflammation in glioblastoma (GBM) patients, its influence on tumour progression and radiotherapy response remains controversial. (2) Methods: We analysed patient data and used expression and cell biological analyses to assess effects of DEXA on GBM cells. We tested the efficacy of tyrosine kinase inhibitors in vitro and in vivo. (3) Results: We confirm in our patient cohort that administration of DEXA correlates with worse overall survival and shorter time to relapse. In GBM cells and glioma stem-like cells (GSCs) DEXA down-regulates genes controlling G2/M and mitotic-spindle checkpoints, and it enables cells to override the spindle assembly checkpoint (SAC). Concurrently, DEXA up-regulates Platelet Derived Growth Factor Receptor (PDGFR) signalling, which stimulates expression of anti-apoptotic regulators BCL2L1 and MCL1, required for survival during extended mitosis. Importantly, the protective potential of DEXA is dependent on intact tyrosine kinase signalling and ponatinib, sunitinib and dasatinib, all effectively overcome the radio-protective and pro-proliferative activity of DEXA. Moreover, we discovered that DEXA-induced signalling creates a therapeutic vulnerability for sunitinib in GSCs and GBM cells in vitro and in vivo. (4) Conclusions: Our results reveal a novel DEXA-induced mechanism in GBM cells and provide a rationale for revisiting the use of tyrosine kinase inhibitors for the treatment of GBM. Full article

(This article belongs to the Section Molecular Cancer Biology)

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19 pages, 318 KiB

Open AccessReview

Immune Checkpoint Inhibitory Therapy in Sarcomas: Is There Light at the End of the Tunnel?

by Vasiliki Siozopoulou, Andreas Domen, Karen Zwaenepoel, Annelies Van Beeck, Evelien Smits, Patrick Pauwels and Elly Marcq

Cancers 2021, 13(2), 360; https://doi.org/10.3390/cancers13020360 - 19 Jan 2021

Cited by 23 | Viewed by 2873

Abstract

Soft tissue and bone sarcomas are a very heterogeneous group of tumors with many subtypes for which diagnosis and treatment remains a very challenging task. On top of that, the treatment choices are limited, and the prognosis of aggressive sarcomas remains poor. Immune [...] Read more.

Soft tissue and bone sarcomas are a very heterogeneous group of tumors with many subtypes for which diagnosis and treatment remains a very challenging task. On top of that, the treatment choices are limited, and the prognosis of aggressive sarcomas remains poor. Immune checkpoint inhibitors (ICIs) have drawn a lot of attention last years because of their promising response rates and their durable effects. ICIs are currently widely used in the daily routine practice for the treatment of a different malignancies, such as melanoma, Hodgkin lymphoma, and non-small cell lung carcinoma. Still, ICIs are not included in the standard treatment protocols of the different sarcoma types. However, a plethora of clinical trials investigates the clinical benefit of ICIs in sarcomas. There is clear need to develop predictive biomarkers to determine which sarcoma patients are most likely to benefit from immune checkpoint blockade. This review will focus on (i) the clinical trial results on the use of ICIs in different sarcoma types; and on (ii) possible biomarkers predictive for the effectiveness of these drugs in sarcomas. Full article

(This article belongs to the Special Issue Management of Soft Tissue Sarcomas and GIST)

11 pages, 587 KiB

Open AccessReview

Global Trends of Latent Prostate Cancer in Autopsy Studies

by Takahiro Kimura, Shun Sato, Hiroyuki Takahashi and Shin Egawa

Cancers 2021, 13(2), 359; https://doi.org/10.3390/cancers13020359 - 19 Jan 2021

Cited by 22 | Viewed by 3088

Abstract

The incidence of prostate cancer (PC) has been increasing in Asian countries, where it was previously low. Although the adoption of a Westernized lifestyle is a possible explanation, the incidence is statistically biased due to the increase in prostate-specific antigen (PSA) screening and [...] Read more.

The incidence of prostate cancer (PC) has been increasing in Asian countries, where it was previously low. Although the adoption of a Westernized lifestyle is a possible explanation, the incidence is statistically biased due to the increase in prostate-specific antigen (PSA) screening and the accuracy of national cancer registration systems. Studies on latent PC provide less biased information. This review included studies evaluating latent PC in several countries after excluding studies using random or single-section evaluations and those that did not mention section thickness. The findings showed that latent PC prevalence has been stable since 1950 in Western countries, but has increased over time in Asian countries. Latent PC in Asian men has increased in both prevalence and number of high-grade cases. Racial differences between Caucasian and Asian men may explain the tumor location of latent PC. In conclusion, the recent increase in latent PC in Asian men is consistent with an increase in clinical PC. Evidence suggests that this increase is caused not only by the increase in PSA screening, but also by the adoption of a more Westernized lifestyle. Autopsy findings suggest the need to reconsider the definition of clinically insignificant PC. Full article

(This article belongs to the Special Issue Urological Cancer 2021)

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14 pages, 1622 KiB

Open AccessSystematic Review

Treatment of Advanced Gastro-Entero-Pancreatic Neuro-Endocrine Tumors: A Systematic Review and Network Meta-Analysis of Phase III Randomized Controlled Trials

by Claudio Ricci, Giuseppe Lamberti, Carlo Ingaldi, Cristina Mosconi, Nico Pagano, Laura Alberici, Valentina Ambrosini, Lisa Manuzzi, Fabio Monari, Deborah Malvi, Francesca Rosini, Francesco Minni, Davide Campana and Riccardo Casadei

Cancers 2021, 13(2), 358; https://doi.org/10.3390/cancers13020358 - 19 Jan 2021

Cited by 13 | Viewed by 2921

Abstract

Several new therapies have been approved to treat advanced gastro-entero-pancreatic neuroendocrine neoplasms (GEP–NENs) in the last twenty years. In this systematic review and meta-analysis, we searched MEDLINE, ISI Web of Science, and Scopus phase III randomized controlled trials (RCTs) comparing two or more [...] Read more.

Several new therapies have been approved to treat advanced gastro-entero-pancreatic neuroendocrine neoplasms (GEP–NENs) in the last twenty years. In this systematic review and meta-analysis, we searched MEDLINE, ISI Web of Science, and Scopus phase III randomized controlled trials (RCTs) comparing two or more therapies for unresectable GEP–NENs. Network metanalysis was used to overcome the multiarm problem. For each arm, we described the surface under the cumulative ranking (SUCRA) curves. The primary endpoints were progression-free survival and grade 3–4 of toxicity. We included nine studies involving a total of 2362 patients and 5 intervention arms: SSA alone, two IFN-α plus SSA, two Everolimus alone, one Everolimus plus SSA, one Sunitinib alone, one ¹⁷⁷Lu-Dotatate plus SSA, and one Bevacizumab plus SSA. ¹⁷⁷Lu-Dotatate plus SSA had the highest probability (99.6%) of being associated with the longest PFS. This approach was followed by Sunitinib use (64.5%), IFN-α plus SSA one (53.0%), SSA alone (46.6%), Bevacizumab plus SSA one (45.0%), and Everolimus ± SSA one (33.6%). The placebo administration had the lowest probability of being associated with the longest PFS (7.6%). Placebo or Bevacizumab use had the highest probability of being the safest (73.7% and 76.7%), followed by SSA alone (65.0%), IFN-α plus SSA (52.4%), ¹⁷⁷Lu-Dotatate plus SSA (49.4%), and Sunitinib alone (28.8%). The Everolimus-based approach had the lowest probability of being the safest (3.9%). The best approaches were SSA alone or combined with ¹⁷⁷Lu-Dotatate. Full article

(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)

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14 pages, 255 KiB

Open AccessArticle

Estimation of the Potentially Avoidable Excess Deaths Associated with Socioeconomic Inequalities in Cancer Survival in Germany

by Lina Jansen, Josephine Kanbach, Isabelle Finke, Volker Arndt, Katharina Emrich, Bernd Holleczek, Hiltraud Kajüter, Joachim Kieschke, Werner Maier, Ron Pritzkuleit, Eunice Sirri, Lars Schwettmann, Cynthia Erb, Hermann Brenner and for the German Cancer Survival Working Group

Cancers 2021, 13(2), 357; https://doi.org/10.3390/cancers13020357 - 19 Jan 2021

Cited by 8 | Viewed by 2520

Abstract

Many countries have reported survival inequalities due to regional socioeconomic deprivation. To quantify the potential gain from eliminating cancer survival disadvantages associated with area-based deprivation in Germany, we calculated the number of avoidable excess deaths. We used population-based cancer registry data from 11 [...] Read more.

Many countries have reported survival inequalities due to regional socioeconomic deprivation. To quantify the potential gain from eliminating cancer survival disadvantages associated with area-based deprivation in Germany, we calculated the number of avoidable excess deaths. We used population-based cancer registry data from 11 of 16 German federal states. Patients aged ≥15 years diagnosed with an invasive malignant tumor between 2008 and 2017 were included. Area-based socioeconomic deprivation was assessed using the quintiles of the German Index of Multiple Deprivation (GIMD) 2010 on a municipality level nationwide. Five-year age-standardized relative survival for 25 most common cancer sites and for total cancer were calculated using period analysis. Incidence and number of avoidable excess deaths in Germany in 2013–2016 were estimated. Summed over the 25 cancer sites, 4100 annual excess deaths (3.0% of all excess deaths) could have been avoided each year in Germany during the period 2013–2016 if relative survival were in all regions comparable with the least deprived regions. Colorectal, oral and pharynx, prostate, and bladder cancer contributed the largest numbers of avoidable excess deaths. Our results provide a good basis to estimate the potential of intervention programs for reducing socioeconomic inequalities in cancer burden in Germany. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

19 pages, 7849 KiB

Open AccessArticle

A Selective Competitive Inhibitor of Aldehyde Dehydrogenase 1A3 Hinders Cancer Cell Growth, Invasiveness and Stemness In Vitro

by Edoardo L. M. Gelardi, Giorgia Colombo, Francesca Picarazzi, Davide M. Ferraris, Andrea Mangione, Giovanni Petrarolo, Eleonora Aronica, Menico Rizzi, Mattia Mori, Concettina La Motta and Silvia Garavaglia

Cancers 2021, 13(2), 356; https://doi.org/10.3390/cancers13020356 - 19 Jan 2021

Cited by 21 | Viewed by 4139

Abstract

Aldehyde dehydrogenase 1A3 (ALDH1A3) belongs to an enzymatic superfamily composed by 19 different isoforms, with a scavenger role, involved in the oxidation of a plethora of aldehydes to the respective carboxylic acids, through a NAD+-dependent reaction. Previous clinical studies highlighted the high expression [...] Read more.

Aldehyde dehydrogenase 1A3 (ALDH1A3) belongs to an enzymatic superfamily composed by 19 different isoforms, with a scavenger role, involved in the oxidation of a plethora of aldehydes to the respective carboxylic acids, through a NAD+-dependent reaction. Previous clinical studies highlighted the high expression of ALDH1A3 in cancer stem cells (CSCs) correlated to a higher risk of cancer relapses, chemoresistance and a poor clinical outcome. We report on the structural, biochemical, and cellular characterization of NR6, a new selective ALDH1A3 inhibitor derived from an already published ALDH non-selective inhibitor with cytotoxic activity on glioblastoma and colorectal cancer cells. Crystal structure, through X-Ray analysis, showed that NR6 binds a non-conserved tyrosine residue of ALDH1A3 which drives the selectivity towards this isoform, as supported by computational binding simulations. Moreover, NR6 shows anti-metastatic activity in wound healing and invasion assays and induces the downregulation of cancer stem cell markers. Overall, our work confirms the role of ALDH1A3 as an important target in glioblastoma and colorectal cells and propose NR6 as a promising molecule for future preclinical studies. Full article

(This article belongs to the Section Cancer Therapy)

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12 pages, 2184 KiB

Open AccessArticle

[¹⁸F]FET PET Uptake Indicates High Tumor and Low Necrosis Content in Brain Metastasis

by Hanno S. Meyer, Friederike Liesche-Starnecker, Mona Mustafa, Igor Yakushev, Benedikt Wiestler, Bernhard Meyer and Jens Gempt

Cancers 2021, 13(2), 355; https://doi.org/10.3390/cancers13020355 - 19 Jan 2021

Cited by 5 | Viewed by 2809

Abstract

Amino acid positron emission tomography (PET) has been employed in the management of brain metastases. Yet, histopathological correlates of PET findings remain poorly understood. We investigated the relationship of O-(2-[¹⁸F]Fluoroethyl)-L-tyrosine ([¹⁸F]FET) PET, magnetic resonance imaging (MRI), and histology in [...] Read more.

Amino acid positron emission tomography (PET) has been employed in the management of brain metastases. Yet, histopathological correlates of PET findings remain poorly understood. We investigated the relationship of O-(2-[¹⁸F]Fluoroethyl)-L-tyrosine ([¹⁸F]FET) PET, magnetic resonance imaging (MRI), and histology in brain metastases. Fifteen patients undergoing brain metastasis resection were included prospectively. Using intraoperative navigation, 39 targeted biopsies were obtained from parts of the metastases that were either PET-positive or negative and MRI-positive or negative. Tumor and necrosis content, proliferation index, lymphocyte infiltration, and vascularization were determined histopathologically. [¹⁸F]FET PET had higher specificity than MRI (66% vs. 56%) and increased sensitivity for tumor from 73% to 93% when combined with MRI. Tumor content per sample increased with PET uptake (r_s = 0.3, p = 0.045), whereas necrosis content decreased (r_s = −0.4, p = 0.014). PET-positive samples had more tumor (median: 75%; interquartile range: 10–97%; p = 0.016) than PET-negative samples. The other investigated histological properties were not correlated with [¹⁸F]FET PET intensity. Tumors were heterogeneous at the levels of imaging and histology. [¹⁸F]FET PET can be a valuable tool in the management of brain metastases. In biopsies, one should aim for PET hotspots to increase the chance for retrieval of samples with high tumor cell concentrations. Multiple biopsies should be performed to account for intra-tumor heterogeneity. PET could be useful for differentiating treatment-related changes (e.g., radiation necrosis) from tumor recurrence. Full article

(This article belongs to the Special Issue Advanced Neuroimaging Approaches for Malignant Brain Tumors)

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Graphical abstract

8 pages, 570 KiB

Open AccessBrief Report

Ex Vivo Mitochondrial Respiration Parallels Biochemical Response to Ibrutinib in CLL Cells

by Subir Roy Chowdhury, Cheryl Peltier, Sen Hou, Amandeep Singh, James B. Johnston, Spencer B. Gibson, Aaron J. Marshall and Versha Banerji

Cancers 2021, 13(2), 354; https://doi.org/10.3390/cancers13020354 - 19 Jan 2021

Cited by 1 | Viewed by 2413

Abstract

Mitochondrial respiration is becoming more commonly used as a preclinical tool and potential biomarker for chronic lymphocytic leukemia (CLL) and activated B-cell receptor (BCR) signaling. However, respiration parameters have not been evaluated with respect to dose of ibrutinib given in clinical practice or [...] Read more.

Mitochondrial respiration is becoming more commonly used as a preclinical tool and potential biomarker for chronic lymphocytic leukemia (CLL) and activated B-cell receptor (BCR) signaling. However, respiration parameters have not been evaluated with respect to dose of ibrutinib given in clinical practice or the effect of progression on ibrutinib treatment on respiration of CLL cells. We evaluated the impact of low and standard dose ibrutinib on CLL cells from patients treated in vivo on mitochondrial respiration using Oroboros oxygraph. Cytokines CCL3 and CCL4 were evaluated using the Mesoscale. Western blot analysis was used to evaluate the BCR and apoptotic pathways. We observed no difference in the mitochondrial respiration rates or levels of plasma chemokine (C-C motif) ligands 3 and 4 (CCL3/CCL4), β-2 microglobulin (β-2 M) and lactate dehydrogenase (LDH) between low and standard doses of ibrutinib. This may confirm why clinical observations of the safety and efficacy of low dose ibrutinib are observed in practice. Of interest, we also observed that the mitochondrial respiration of CLL cells paralleled the increase in β-2 M and LDH at progression. Our study further supports mitochondrial respiration as a biomarker for response and progression on ibrutinib in CLL cells and a valuable pre-clinical tool. Full article

(This article belongs to the Special Issue Novel Drug Targets and Advances in Treatment of CLL)

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20 pages, 3780 KiB

Open AccessArticle

Physical Interaction between HPV16E7 and the Actin-Binding Protein Gelsolin Regulates Epithelial-Mesenchymal Transition via HIPPO-YAP Axis

by Paola Matarrese, Rosa Vona, Barbara Ascione, Marco G. Paggi and Anna Maria Mileo

Cancers 2021, 13(2), 353; https://doi.org/10.3390/cancers13020353 - 19 Jan 2021

Cited by 9 | Viewed by 2647

Abstract

Human papillomavirus 16 (HPV16) exhibits a strong oncogenic potential mainly in cervical, anogenital and oropharyngeal cancers. The E6 and E7 viral oncoproteins, acting via specific interactions with host cellular targets, are required for cell transformation and maintenance of the transformed phenotype as well. [...] Read more.

Human papillomavirus 16 (HPV16) exhibits a strong oncogenic potential mainly in cervical, anogenital and oropharyngeal cancers. The E6 and E7 viral oncoproteins, acting via specific interactions with host cellular targets, are required for cell transformation and maintenance of the transformed phenotype as well. We previously demonstrated that HPV16E7 interacts with the actin-binding protein gelsolin, involved in cytoskeletal F-actin dynamics. Herein, we provide evidence that the E7/gelsolin interaction promotes the cytoskeleton rearrangement leading to epithelial-mesenchymal transition-linked morphological and transcriptional changes. E7-mediated cytoskeletal actin remodeling induces the HIPPO pathway by promoting the cytoplasmic retention of inactive P-YAP. These results suggest that YAP could play a role in the “de-differentiation” process underlying the acquisition of a more aggressive phenotype in HPV16-transformed cells. A deeper comprehension of the multifaceted mechanisms elicited by the HPV infection is vital for providing novel strategies to block the biological and clinical features of virus-related cancers. Full article

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12 pages, 538 KiB

Open AccessArticle

Predicting of Sentinel Lymph Node Status in Breast Cancer Patients with Clinically Negative Nodes: A Validation Study

by Annarita Fanizzi, Domenico Pomarico, Angelo Paradiso, Samantha Bove, Sergio Diotaiuti, Vittorio Didonna, Francesco Giotta, Daniele La Forgia, Agnese Latorre, Maria Irene Pastena, Pasquale Tamborra, Alfredo Zito, Vito Lorusso and Raffaella Massafra

Cancers 2021, 13(2), 352; https://doi.org/10.3390/cancers13020352 - 19 Jan 2021

Cited by 31 | Viewed by 3948

Abstract

In the absence of lymph node abnormalities detectable on clinical examination or imaging, the guidelines provide for the dissection of the first axillary draining lymph nodes during surgery. It is not always possible to arrive at surgery without diagnostic doubts, and machine learning [...] Read more.

In the absence of lymph node abnormalities detectable on clinical examination or imaging, the guidelines provide for the dissection of the first axillary draining lymph nodes during surgery. It is not always possible to arrive at surgery without diagnostic doubts, and machine learning algorithms can support clinical decisions. The web calculator CancerMath (CM) allows you to estimate the probability of having positive lymph nodes valued on the basis of tumor size, age, histologic type, grading, expression of estrogen receptor, and progesterone receptor. We collected 993 patients referred to our institute with clinically negative results characterized by sentinel lymph node status, prognostic factors defined by CM, and also human epidermal growth factor receptor 2 (HER2) and Ki-67. Area Under the Curve (AUC) values obtained by the online CM application were comparable with those obtained after training its algorithm on our database. Nevertheless, by training the CM model on our dataset and using the same feature, we reached a sensitivity median value of 72%, whereas the online one was equal to 46%, despite a specificity reduction. We found that the addition of the prognostic factors Her2 and Ki67 could help improve performances on the classification of particular types of patients with the aim of reducing as much as possible the false positives that lead to axillary dissection. As showed by our experimental results, it is not particularly suitable for use as a support instrument for the prediction of metastatic lymph nodes on clinically negative patients. Full article

(This article belongs to the Section Cancer Causes, Screening and Diagnosis)

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20 pages, 4350 KiB

Open AccessArticle

EGR1/GADD45α Activation by ROS of Non-Thermal Plasma Mediates Cell Death in Thyroid Carcinoma

by Seung-Nam Jung, Chan Oh, Jae Won Chang, Lihua Liu, Mi Ae Lim, Yan Li Jin, Yudan Piao, Hae Jong Kim, Ho-Ryun Won, Seong Eun Lee, Min Joung Lee, Jun Young Heo, Sangmi Jun, Doheon Lee, Woo Seok Kang, Dae-Woong Kim, Ki-Sang Rha, Young Il Kim, Yea Eun Kang and Bon Seok Koo

Cancers 2021, 13(2), 351; https://doi.org/10.3390/cancers13020351 - 19 Jan 2021

Cited by 13 | Viewed by 3419

Abstract

(1) Background: Nonthermal plasma (NTP) induces cell death in various types of cancer cells, providing a promising alternative treatment strategy. Although recent studies have identified new mechanisms of NTP in several cancers, the molecular mechanisms underlying its therapeutic effect on thyroid cancer (THCA) [...] Read more.

(1) Background: Nonthermal plasma (NTP) induces cell death in various types of cancer cells, providing a promising alternative treatment strategy. Although recent studies have identified new mechanisms of NTP in several cancers, the molecular mechanisms underlying its therapeutic effect on thyroid cancer (THCA) have not been elucidated. (2) Methods: To investigate the mechanism of NTP-induced cell death, THCA cell lines were treated with NTP-activated medium -(NTPAM), and gene expression profiles were evaluated using RNA sequencing. (3) Results: NTPAM upregulated the gene expression of early growth response 1 (EGR1). NTPAM-induced THCA cell death was enhanced by EGR1 overexpression, whereas EGR1 small interfering RNA had the opposite effect. NTPAM-derived reactive oxygen species (ROS) affected EGR1 expression and apoptotic cell death in THCA. NTPAM also induced the gene expression of growth arrest and regulation of DNA damage-inducible 45α (GADD45A) gene, and EGR1 regulated GADD45A through direct binding to its promoter. In xenograft in vivo tumor models, NTPAM inhibited tumor progression of THCA by increasing EGR1 levels. (4) Conclusions: Our findings suggest that NTPAM induces apoptotic cell death in THCA through a novel mechanism by which NTPAM-induced ROS activates EGR1/GADD45α signaling. Furthermore, our data provide evidence that the regulation of the EGR1/GADD45α axis can be a novel strategy for the treatment of THCA. Full article

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31 pages, 2816 KiB

Open AccessReview

Roles of HIF and 2-Oxoglutarate-Dependent Dioxygenases in Controlling Gene Expression in Hypoxia

by Julianty Frost, Mark Frost, Michael Batie, Hao Jiang and Sonia Rocha

Cancers 2021, 13(2), 350; https://doi.org/10.3390/cancers13020350 - 19 Jan 2021

Cited by 21 | Viewed by 5659

Abstract

Hypoxia—reduction in oxygen availability—plays key roles in both physiological and pathological processes. Given the importance of oxygen for cell and organism viability, mechanisms to sense and respond to hypoxia are in place. A variety of enzymes utilise molecular oxygen, but of particular importance [...] Read more.

Hypoxia—reduction in oxygen availability—plays key roles in both physiological and pathological processes. Given the importance of oxygen for cell and organism viability, mechanisms to sense and respond to hypoxia are in place. A variety of enzymes utilise molecular oxygen, but of particular importance to oxygen sensing are the 2-oxoglutarate (2-OG) dependent dioxygenases (2-OGDs). Of these, Prolyl-hydroxylases have long been recognised to control the levels and function of Hypoxia Inducible Factor (HIF), a master transcriptional regulator in hypoxia, via their hydroxylase activity. However, recent studies are revealing that dioxygenases are involved in almost all aspects of gene regulation, including chromatin organisation, transcription and translation. We highlight the relevance of HIF and 2-OGDs in the control of gene expression in response to hypoxia and their relevance to human biology and health. Full article

(This article belongs to the Special Issue Novel Perspectives on Hypoxia in Cancer)

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10 pages, 13279 KiB

Open AccessArticle

An Analysis of Vertebral Body Growth after Proton Beam Therapy for Pediatric Cancer

by Keiichiro Baba, Masashi Mizumoto, Yoshiko Oshiro, Shosei Shimizu, Masatoshi Nakamura, Yuichi Hiroshima, Takashi Iizumi, Takashi Saito, Haruko Numajiri, Kei Nakai, Hitoshi Ishikawa, Toshiyuki Okumura, Kazushi Maruo and Hideyuki Sakurai

Cancers 2021, 13(2), 349; https://doi.org/10.3390/cancers13020349 - 19 Jan 2021

Cited by 7 | Viewed by 2391

Abstract

Impairment of bone growth after radiotherapy for pediatric bone cancer is a well-known adverse event. However, there is limited understanding of the relationship between bone growth and irradiation dose. In this study, we retrospectively analyzed bone growth impairment after proton beam therapy for [...] Read more.

Impairment of bone growth after radiotherapy for pediatric bone cancer is a well-known adverse event. However, there is limited understanding of the relationship between bone growth and irradiation dose. In this study, we retrospectively analyzed bone growth impairment after proton beam therapy for pediatric cancer. A total of 353 vertebral bodies in 23 patients under 12 years old who received proton beam therapy were evaluated. Compared to the non-irradiated vertebral body growth rate, the irradiated vertebral body rate (%/year) was significantly lower: 77.2%, 57.6%, 40.8%, 26.4%, and 14.1% at 10, 20, 30, 40, and 50 Gy (RBE) irradiation, respectively. In multivariate analysis, radiation dose was the only factor correlated with vertebral body growth. Age, gender, and vertebral body site were not significant factors. These results suggest that the growth rate of the vertebral body is dose-dependent and decreases even at a low irradiated dose. This is the first report to show that proton beam therapy has the same growth inhibitory effect as photon radiotherapy within the irradiated field. Full article

(This article belongs to the Special Issue Proton Therapy For Cancers)

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23 pages, 6910 KiB

Open AccessArticle

Discovery of Functional Alternatively Spliced PKM Transcripts in Human Cancers

by Xiangyu Li, Woonghee Kim, Muhammad Arif, Chunxia Gao, Andreas Hober, David Kotol, Linnéa Strandberg, Björn Forsström, Åsa Sivertsson, Per Oksvold, Hasan Turkez, Morten Grøtli, Yusuke Sato, Haruki Kume, Seishi Ogawa, Jan Boren, Jens Nielsen, Mathias Uhlen, Cheng Zhang and Adil Mardinoglu

Cancers 2021, 13(2), 348; https://doi.org/10.3390/cancers13020348 - 19 Jan 2021

Cited by 9 | Viewed by 4150

Abstract

Pyruvate kinase muscle type (PKM) is a key enzyme in glycolysis and plays an important oncological role in cancer. However, the association of PKM expression and the survival outcome of patients with different cancers is controversial. We employed systems biology methods [...] Read more.

Pyruvate kinase muscle type (PKM) is a key enzyme in glycolysis and plays an important oncological role in cancer. However, the association of PKM expression and the survival outcome of patients with different cancers is controversial. We employed systems biology methods to reveal prognostic value and potential biological functions of PKM transcripts in different human cancers. Protein products of transcripts were shown and detected by western blot and mass spectrometry analysis. We focused on different transcripts of PKM and investigated the associations between their mRNA expression and the clinical survival of the patients in 25 different cancers. We find that the transcripts encoding PKM2 and three previously unstudied transcripts, namely ENST00000389093, ENST00000568883, and ENST00000561609, exhibited opposite prognostic indications in different cancers. Moreover, we validated the prognostic effect of these transcripts in an independent kidney cancer cohort. Finally, we revealed that ENST00000389093 and ENST00000568883 possess pyruvate kinase enzymatic activity and may have functional roles in metabolism, cell invasion, and hypoxia response in cancer cells. Our study provided a potential explanation to the controversial prognostic indication of PKM, and could invoke future studies focusing on revealing the biological and oncological roles of these alternative spliced variants of PKM. Full article

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3 pages, 183 KiB

Open AccessEditorial

Pathogenesis and Diagnosis of Genitourinary Cancer

by Charles C. Guo, Steven S. Shen and Jae Y. Ro

Cancers 2021, 13(2), 347; https://doi.org/10.3390/cancers13020347 - 19 Jan 2021

Cited by 3 | Viewed by 1645

Abstract

Genitourinary (GU) cancers are among the most common malignant diseases in men [...] Full article

(This article belongs to the Special Issue Pathogenesis and Diagnosis of Genitourinary Cancer)

22 pages, 937 KiB

Open AccessEditor’s ChoiceReview

ctDNA and Adjuvant Therapy for Colorectal Cancer: Time to Re-Invent Our Treatment Paradigm

by Mahendra Naidoo, Peter Gibbs and Jeanne Tie

Cancers 2021, 13(2), 346; https://doi.org/10.3390/cancers13020346 - 19 Jan 2021

Cited by 41 | Viewed by 6758

Abstract

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. While there have been significant developments in the treatments for patients with metastatic CRC in recent years, improving outcomes in the adjuvant setting has been more challenging. Recent technological advances [...] Read more.

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. While there have been significant developments in the treatments for patients with metastatic CRC in recent years, improving outcomes in the adjuvant setting has been more challenging. Recent technological advances in circulating tumour DNA (ctDNA) assay with the ability to detect minimal residual disease (MRD) after curative intent surgery will fundamentally change how we assess recurrence risk and conduct adjuvant trials. Studies in non-metastatic CRC have now demonstrated the prognostic impact of ctDNA analysis after curative intent surgery over and above current standard of care clinicopathological criteria. This ability of ctDNA analysis to stratify patients into low- and very-high-risk groups provides a window of opportunity to personalise adjuvant treatment where escalation/de-escalation of adjuvant systemic therapy could potentially increase cure rates and also reduce treatment-related physical and financial toxicity. Emerging data suggest that conversion of ctDNA from detectable to undetectable after adjuvant chemotherapy may reflect treatment efficacy. This real-time assessment of treatment benefit could be used as a surrogate endpoint for adjuvant novel drug development. Several ctDNA-based randomized adjuvant trials are ongoing internationally to confirm the clinical utility of ctDNA in colorectal cancer. Full article

(This article belongs to the Special Issue Adjuvant Chemotherapy for Colorectal Cancer)

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24 pages, 7171 KiB

Open AccessArticle

The Transcriptomic Landscape of Prostate Cancer Development and Progression: An Integrative Analysis

by Jacek Marzec, Helen Ross-Adams, Stefano Pirrò, Jun Wang, Yanan Zhu, Xueying Mao, Emanuela Gadaleta, Amar S. Ahmad, Bernard V. North, Solène-Florence Kammerer-Jacquet, Elzbieta Stankiewicz, Sakunthala C. Kudahetti, Luis Beltran, Guoping Ren, Daniel M. Berney, Yong-Jie Lu and Claude Chelala

Cancers 2021, 13(2), 345; https://doi.org/10.3390/cancers13020345 - 19 Jan 2021

Cited by 6 | Viewed by 3352

Abstract

Next-generation sequencing of primary tumors is now standard for transcriptomic studies, but microarray-based data still constitute the majority of available information on other clinically valuable samples, including archive material. Using prostate cancer (PC) as a model, we developed a robust analytical framework to [...] Read more.

Next-generation sequencing of primary tumors is now standard for transcriptomic studies, but microarray-based data still constitute the majority of available information on other clinically valuable samples, including archive material. Using prostate cancer (PC) as a model, we developed a robust analytical framework to integrate data across different technical platforms and disease subtypes to connect distinct disease stages and reveal potentially relevant genes not identifiable from single studies alone. We reconstructed the molecular profile of PC to yield the first comprehensive insight into its development, by tracking changes in mRNA levels from normal prostate to high-grade prostatic intraepithelial neoplasia, and metastatic disease. A total of nine previously unreported stage-specific candidate genes with prognostic significance were also found. Here, we integrate gene expression data from disparate sample types, disease stages and technical platforms into one coherent whole, to give a global view of the expression changes associated with the development and progression of PC from normal tissue through to metastatic disease. Summary and individual data are available online at the Prostate Integrative Expression Database (PIXdb), a user-friendly interface designed for clinicians and laboratory researchers to facilitate translational research. Full article

(This article belongs to the Collection Application of Bioinformatics in Cancers)

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16 pages, 3410 KiB

Open AccessArticle

Integrin α3β1 Represses Reelin Expression in Breast Cancer Cells to Promote Invasion

by Abibatou Ndoye, Rakshitha Pandulal Miskin and C. Michael DiPersio

Cancers 2021, 13(2), 344; https://doi.org/10.3390/cancers13020344 - 19 Jan 2021

Cited by 12 | Viewed by 2739

Abstract

Integrin α3β1, a cell adhesion receptor for certain laminins, is known to promote breast tumor growth and invasion. Our previous gene microarray study showed that the RELN gene, which encodes the extracellular glycoprotein Reelin, was upregulated in α3β1-deficient (i.e., α3 knockdown) MDA-MB-231 cells. [...] Read more.

Integrin α3β1, a cell adhesion receptor for certain laminins, is known to promote breast tumor growth and invasion. Our previous gene microarray study showed that the RELN gene, which encodes the extracellular glycoprotein Reelin, was upregulated in α3β1-deficient (i.e., α3 knockdown) MDA-MB-231 cells. In breast cancer, reduced RELN expression is associated with increased invasion and poor prognosis. In this study we demonstrate that α3β1 represses RELN expression to enhance breast cancer cell invasion. RELN mRNA was significantly increased upon RNAi-mediated α3 knockdown in two triple-negative breast cancer cell lines, MDA-MB-231 and SUM159. Modulation of baseline Reelin levels altered invasive potential, where enhanced Reelin expression in MDA-MB-231 cells reduced invasion, while RNAi-mediated suppression of Reelin in SUM159 cells increased invasion. Moreover, treatment of α3β1-expressing MDA-MB-231 cells with culture medium that was conditioned by α3 knockdown MDA-MB-231 cells led to decreased invasion. RNAi-mediated suppression of Reelin in α3 knockdown MDA-MB-231 cells mitigated this effect of conditioned-medium, identifying secreted Reelin as an inhibitor of cell invasion. These results demonstrate a novel role for α3β1 in repressing Reelin in breast cancer cells to promote invasion, supporting this integrin as a potential therapeutic target. Full article

(This article belongs to the Special Issue Treating the Cancer Matrix: Progress in the Identification of Potential Therapeutic Targets)

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14 pages, 2994 KiB

Open AccessArticle

RNA-Binding Protein La Mediates TGFβ-Induced Epithelial to Mesenchymal Transition and Cancer Stem Cell Properties

by Tilman Heise and Gunhild Sommer

Cancers 2021, 13(2), 343; https://doi.org/10.3390/cancers13020343 - 19 Jan 2021

Cited by 6 | Viewed by 2353

Abstract

Background: the aberrant overexpression of predominantly nuclear localizing RNA-binding protein (RBP) La contributes to proliferation, mobility, and chemoresistance of cancer cells and tumor growth in mice. Methods: studies included cancer tissue microarrays (TMAs) analyses, cancer tissue data mining, transforming growth factor β (TGFβ)-induced [...] Read more.

Background: the aberrant overexpression of predominantly nuclear localizing RNA-binding protein (RBP) La contributes to proliferation, mobility, and chemoresistance of cancer cells and tumor growth in mice. Methods: studies included cancer tissue microarrays (TMAs) analyses, cancer tissue data mining, transforming growth factor β (TGFβ)-induced cancer cell plasticity studies, three dimensional sphere growth, epithelial to mesenchymal transition (EMT) assays, analysis of cancer stem cell (CSC) marker expression, and post-translational modification of cancer-associated La protein. Results: we demonstrated that significant overexpression of RBP La in lung and head and neck cancer tissue correlates with poor overall survival. Furthermore, small interfering RNA-mediated depletion of La reduced proliferation and migration of cancer cells, blocked TGFβ-induced EMT, and diminished both EMT and CSC marker expression. Rescue experiments with La wildtype but not RNA chaperone domain activity-defective La mutant increased the expression of those cancer progression markers, suggesting a critical role of La’s RNA chaperone activity in this process. La depletion in cancer cells also significantly decreased sphere growth in the presence of TGFβ. Interestingly, TGFβ treatment induced phosphorylation of La at threonine 389 (pLa^T389) only in adherents but not in 3D growing cultures. Conclusion: our study suggests that the TGFβ/AKT/pLa^T389 signaling pathway regulates cancer cell plasticity. Full article

(This article belongs to the Special Issue Nuclear Architecture in Cancer)

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15 pages, 1587 KiB

Open AccessReview

Parvovirus-Based Combinatorial Immunotherapy: A Reinforced Therapeutic Strategy against Poor-Prognosis Solid Cancers

by Assia Angelova, Tiago Ferreira, Clemens Bretscher, Jean Rommelaere and Antonio Marchini

Cancers 2021, 13(2), 342; https://doi.org/10.3390/cancers13020342 - 19 Jan 2021

Cited by 15 | Viewed by 3484

Abstract

Resistance to anticancer treatments poses continuing challenges to oncology researchers and clinicians. The underlying mechanisms are complex and multifactorial. However, the immunologically “cold” tumor microenvironment (TME) has recently emerged as one of the critical players in cancer progression and therapeutic resistance. Therefore, TME [...] Read more.

Resistance to anticancer treatments poses continuing challenges to oncology researchers and clinicians. The underlying mechanisms are complex and multifactorial. However, the immunologically “cold” tumor microenvironment (TME) has recently emerged as one of the critical players in cancer progression and therapeutic resistance. Therefore, TME modulation through induction of an immunological switch towards inflammation (“warming up”) is among the leading approaches in modern oncology. Oncolytic viruses (OVs) are seen today not merely as tumor cell-killing (oncolytic) agents, but also as cancer therapeutics with multimodal antitumor action. Due to their intrinsic or engineered capacity for overcoming immune escape mechanisms, warming up the TME and promoting antitumor immune responses, OVs hold the potential for creating a proinflammatory background, which may in turn facilitate the action of other (immunomodulating) drugs. The latter provides the basis for the development of OV-based immunostimulatory anticancer combinations. This review deals with the smallest among all OVs, the H-1 parvovirus (H-1PV), and focuses on H-1PV-based combinatorial approaches, whose efficiency has been proven in preclinical and/or clinical settings. Special focus is given to cancer types with the most devastating impact on life expectancy that urgently call for novel therapies. Full article

(This article belongs to the Special Issue Oncolytic Virus Immunotherapy)

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14 pages, 3356 KiB

Open AccessArticle

The Giant HECT E3 Ubiquitin Ligase HERC1 Is Aberrantly Expressed in Myeloid Related Disorders and It Is a Novel BCR-ABL1 Binding Partner

by Muhammad Shahzad Ali, Cristina Panuzzo, Chiara Calabrese, Alessandro Maglione, Rocco Piazza, Daniela Cilloni, Giuseppe Saglio, Barbara Pergolizzi and Enrico Bracco

Cancers 2021, 13(2), 341; https://doi.org/10.3390/cancers13020341 - 19 Jan 2021

Cited by 4 | Viewed by 3785

Abstract

HERC E3 subfamily members are parts of the E3 ubiquitin ligases and key players for a wide range of cellular functions. Though the involvement of the Ubiquitin Proteasome System in blood disorders has been broadly studied, so far the role of large HERCs [...] Read more.

HERC E3 subfamily members are parts of the E3 ubiquitin ligases and key players for a wide range of cellular functions. Though the involvement of the Ubiquitin Proteasome System in blood disorders has been broadly studied, so far the role of large HERCs in this context remains unexplored. In the present study we examined the expression of the large HECT E3 Ubiquitin Ligase, HERC1, in blood disorders. Our findings revealed that HERC1 gene expression was severely downregulated both in acute and in chronic myelogenous leukemia at diagnosis, while it is restored after complete remission achievement. Instead, in Philadelphia the negative myeloproliferative neoplasm HERC1 level was peculiarly controlled, being very low in Primary Myelofibrosis and significantly upregulated in those Essential Thrombocytemia specimens harboring the mutation in the calreticulin gene. Remarkably, in CML cells HERC1 mRNA level was associated with the BCR-ABL1 kinase activity and the HERC1 protein physically interacted with BCR-ABL1. Furthermore, we found that HERC1 was directly tyrosine phosphorylated by the ABL kinase. Overall and for the first time, we provide original evidence on the potential tumor-suppressing or -promoting properties, depending on the context, of HERC1 in myeloid related blood disorders. Full article

(This article belongs to the Special Issue The Role of the Ubiquitin-Proteasome-System in Human Cancer)

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17 pages, 4035 KiB

Open AccessArticle

T-Cell Lymphoma Clonality by Copy Number Variation Analysis of T-Cell Receptor Genes

by Ming Liang Oon, Jing Quan Lim, Bernett Lee, Sai Mun Leong, Gwyneth Shook-Ting Soon, Zi Wei Wong, Evelyn Huizi Lim, Zhenhua Li, Allen Eng Juh Yeoh, Shangying Chen, Kenneth Hon Kim Ban, Tae-Hoon Chung, Soo-Yong Tan, Shih-Sung Chuang, Seiichi Kato, Shigeo Nakamura, Emiko Takahashi, Yong-Howe Ho, Joseph D. Khoury, Rex K. H. Au-Yeung, Chee-Leong Cheng, Soon-Thye Lim, Wee-Joo Chng, Claudio Tripodo, Olaf Rotzschke, Choon Kiat Ong and Siok-Bian Ng Show full author list Hide full author list

Cancers 2021, 13(2), 340; https://doi.org/10.3390/cancers13020340 - 19 Jan 2021

Cited by 4 | Viewed by 4401

Abstract

T-cell lymphomas arise from a single neoplastic clone and exhibit identical patterns of deletions in T-cell receptor (TCR) genes. Whole genome sequencing (WGS) data represent a treasure trove of information for the development of novel clinical applications. However, the use of WGS to [...] Read more.

T-cell lymphomas arise from a single neoplastic clone and exhibit identical patterns of deletions in T-cell receptor (TCR) genes. Whole genome sequencing (WGS) data represent a treasure trove of information for the development of novel clinical applications. However, the use of WGS to identify clonal T-cell proliferations has not been systematically studied. In this study, based on WGS data, we identified monoclonal rearrangements (MRs) of T-cell receptors (TCR) genes using a novel segmentation algorithm and copy number computation. We evaluated the feasibility of this technique as a marker of T-cell clonality using T-cell lymphomas (TCL, n = 44) and extranodal NK/T-cell lymphomas (ENKTLs, n = 20), and identified 98% of TCLs with one or more TCR gene MRs, against 91% detected using PCR. TCR MRs were absent in all ENKTLs and NK cell lines. Sensitivity-wise, this platform is sufficiently competent, with MRs detected in the majority of samples with tumor content under 25% and it can also distinguish monoallelic from biallelic MRs. Understanding the copy number landscape of TCR using WGS data may engender new diagnostic applications in hematolymphoid pathology, which can be readily adapted to the analysis of B-cell receptor loci for B-cell clonality determination. Full article

(This article belongs to the Special Issue Innovations in Cancer Diagnostic Evaluation and Biomarker Detection)

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15 pages, 11314 KiB

Open AccessArticle

Radiomics and Dosiomics for Predicting Local Control after Carbon-Ion Radiotherapy in Skull-Base Chordoma

by Giulia Buizza, Chiara Paganelli, Emma D’Ippolito, Giulia Fontana, Silvia Molinelli, Lorenzo Preda, Giulia Riva, Alberto Iannalfi, Francesca Valvo, Ester Orlandi and Guido Baroni

Cancers 2021, 13(2), 339; https://doi.org/10.3390/cancers13020339 - 18 Jan 2021

Cited by 27 | Viewed by 3473

Abstract

Skull-base chordoma (SBC) can be treated with carbon ion radiotherapy (CIRT) to improve local control (LC). The study aimed to explore the role of multi-parametric radiomic, dosiomic and clinical features as prognostic factors for LC in SBC patients undergoing CIRT. Before CIRT, 57 [...] Read more.

Skull-base chordoma (SBC) can be treated with carbon ion radiotherapy (CIRT) to improve local control (LC). The study aimed to explore the role of multi-parametric radiomic, dosiomic and clinical features as prognostic factors for LC in SBC patients undergoing CIRT. Before CIRT, 57 patients underwent MR and CT imaging, from which tumour contours and dose maps were obtained. MRI and CT-based radiomic, and dosiomic features were selected and fed to two survival models, singularly or by combining them with clinical factors. Adverse LC was given by in-field recurrence or tumour progression. The dataset was split in development and test sets and the models’ performance evaluated using the concordance index (C-index). Patients were then assigned a low- or high-risk score. Survival curves were estimated, and risk groups compared through log-rank tests (after Bonferroni correction α = 0.0083). The best performing models were built on features describing tumour shape and dosiomic heterogeneity (median/interquartile range validation C-index: 0.80/024 and 0.79/0.26), followed by combined (0.73/0.30 and 0.75/0.27) and CT-based models (0.77/0.24 and 0.64/0.28). Dosiomic and combined models could consistently stratify patients in two significantly different groups. Dosiomic and multi-parametric radiomic features showed to be promising prognostic factors for LC in SBC treated with CIRT. Full article

(This article belongs to the Special Issue New Challenges in Cancer Imaging)

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15 pages, 4977 KiB

Open AccessEditor’s ChoiceReview

Recent Advances and Future Directions in Clinical Management of Head and Neck Squamous Cell Carcinoma

by Jameel Muzaffar, Shahla Bari, Kedar Kirtane and Christine H. Chung

Cancers 2021, 13(2), 338; https://doi.org/10.3390/cancers13020338 - 18 Jan 2021

Cited by 68 | Viewed by 5743

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the most common cancer arising in the head and neck region. The most common risk factors are smoking, excessive drinking, and human papillomavirus (HPV) infection. While the overall incidence of smoking is decreasing, the incidence [...] Read more.

Head and neck squamous cell carcinoma (HNSCC) is the most common cancer arising in the head and neck region. The most common risk factors are smoking, excessive drinking, and human papillomavirus (HPV) infection. While the overall incidence of smoking is decreasing, the incidence of HPV-related HNSCC is increasing in the United States and Western Europe, which led to a shift in understanding of the pathophysiology, treatment, and prognosis of this disease. The outcomes for non-metastatic HNSCC remains very encouraging and continues to improve. Advances in radiation technology and techniques, better organ preserving surgical options, and multidisciplinary treatment modalities have improved cure rates for locally advanced HNSCC patients. The treatment of metastatic disease, however, remains an area of need. The advancement of immune checkpoint inhibitors has provided significantly better outcomes, but only a small proportion of patients obtain benefits. Most recurrent and/or metastatic HNSCC patients continue to have poor survival. This has led to the vigorous investigation of new biomarkers and biomarker-based therapies. Novel therapeutic options including adaptive cellular therapy and therapeutic vaccines are also on the horizon. In this review, we highlight the latest advances in the field of HNSCC and the future direction of research. Full article

(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma (HNSCC))

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23 pages, 2216 KiB

Open AccessReview

Tiny miRNAs Play a Big Role in the Treatment of Breast Cancer Metastasis

by Andrea York Tiang Teo, Xiaoqiang Xiang, Minh TN Le, Andrea Li-Ann Wong, Qi Zeng, Lingzhi Wang and Boon-Cher Goh

Cancers 2021, 13(2), 337; https://doi.org/10.3390/cancers13020337 - 18 Jan 2021

Cited by 13 | Viewed by 3154

Abstract

Distant organ metastases accounts for the majority of breast cancer deaths. Given the prevalence of breast cancer in women, it is imperative to understand the underlying mechanisms of its metastatic progression and identify potential targets for therapy. Since their discovery in 1993, microRNAs [...] Read more.

Distant organ metastases accounts for the majority of breast cancer deaths. Given the prevalence of breast cancer in women, it is imperative to understand the underlying mechanisms of its metastatic progression and identify potential targets for therapy. Since their discovery in 1993, microRNAs (miRNAs) have emerged as important regulators of tumour progression and metastasis in various cancers, playing either oncogenic or tumour suppressor roles. In the following review, we discuss the roles of miRNAs that potentiate four key areas of breast cancer metastasis—angiogenesis, epithelial-mesenchymal transition, the Warburg effect and the tumour microenvironment. We then evaluate the recent developments in miRNA-based therapies in breast cancer, which have shown substantial promise in controlling tumour progression and metastasis. Yet, certain challenges must be overcome before these strategies can be implemented in clinical trials. Full article

(This article belongs to the Special Issue Targeting Cancer Metastasis)

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15 pages, 1547 KiB

Open AccessArticle

Prognostic Impacts of D816V KIT Mutation and Peri-Transplant RUNX1–RUNX1T1 MRD Monitoring on Acute Myeloid Leukemia with RUNX1–RUNX1T1

by Byung-Sik Cho, Gi-June Min, Sung-Soo Park, Silvia Park, Young-Woo Jeon, Seung-Hwan Shin, Seung-Ah Yahng, Jae-Ho Yoon, Sung-Eun Lee, Ki-Seong Eom, Yoo-Jin Kim, Seok Lee, Chang-Ki Min, Seok-Goo Cho, Dong-Wook Kim, Jong Wook-Lee, Myung-Shin Kim, Yong-Goo Kim and Hee-Je Kim

Cancers 2021, 13(2), 336; https://doi.org/10.3390/cancers13020336 - 18 Jan 2021

Cited by 2 | Viewed by 2232

Abstract

The prognostic significance of KIT mutations and optimal thresholds and time points of measurable residual disease (MRD) monitoring for acute myeloid leukemia (AML) with RUNX1-RUNX1T1 remain controversial in the setting of hematopoietic stem cell transplantation (HSCT). We retrospectively evaluated 166 high-risk patients who [...] Read more.

The prognostic significance of KIT mutations and optimal thresholds and time points of measurable residual disease (MRD) monitoring for acute myeloid leukemia (AML) with RUNX1-RUNX1T1 remain controversial in the setting of hematopoietic stem cell transplantation (HSCT). We retrospectively evaluated 166 high-risk patients who underwent allogeneic (Allo-HSCT, n = 112) or autologous HSCT (Auto-HSCT, n = 54). D816V KIT mutation, a subtype of exon 17 mutations, was significantly associated with post-transplant relapse and poor survival, while other types of mutations in exons 17 and 8 were not associated with post-transplant relapse. Pre- and post-transplant RUNX1–RUNX1T1 MRD assessments were useful for predicting post-transplant relapse and poor survival with a higher sensitivity at later time points. Survival analysis for each stratified group by D816V KIT mutation and pre-transplant RUNX1–RUNX1T1 MRD status demonstrated that Auto-HSCT was superior to Allo-HSCT in MRD-negative patients without D816V KIT mutation, while Allo-HSCT was superior to Auto-HSCT in MRD-negative patients with D816V KIT mutation. Very poor outcomes of pre-transplant MRD-positive patients with D816V KIT mutation suggested that this group should be treated in clinical trials. Risk stratification by both D816V KIT mutation and RUNX1–RUNX1T1 MRD status will provide a platform for decision-making or risk-adapted therapeutic approaches. Full article

(This article belongs to the Special Issue Minimal Residual Disease of Cancers)

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15 pages, 858 KiB

Open AccessFeature PaperReview

Targeting E-selectin to Tackle Cancer Using Uproleselan

by Barbara Muz, Anas Abdelghafer, Matea Markovic, Jessica Yavner, Anupama Melam, Noha Nabil Salama and Abdel Kareem Azab

Cancers 2021, 13(2), 335; https://doi.org/10.3390/cancers13020335 - 18 Jan 2021

Cited by 33 | Viewed by 4821

Abstract

E-selectin is a vascular adhesion molecule expressed mainly on endothelium, and its primary role is to facilitate leukocyte cell trafficking by recognizing ligand surface proteins. E-selectin gained a new role since it was demonstrated to be involved in cancer cell trafficking, stem-like properties [...] Read more.

E-selectin is a vascular adhesion molecule expressed mainly on endothelium, and its primary role is to facilitate leukocyte cell trafficking by recognizing ligand surface proteins. E-selectin gained a new role since it was demonstrated to be involved in cancer cell trafficking, stem-like properties and therapy resistance. Therefore, being expressed in the tumor microenvironment, E-selectin can potentially be used to eradicate cancer. Uproleselan (also known as GMI-1271), a specific E-selectin antagonist, has been tested on leukemia, myeloma, pancreatic, colon and breast cancer cells, most of which involve the bone marrow as a primary or as a metastatic tumor site. This novel therapy disrupts the tumor microenvironment by affecting the two main steps of metastasis—extravasation and adhesion—thus blocking E-selectin reduces tumor dissemination. Additionally, uproleselan mobilized cancer cells from the protective vascular niche into the circulation, making them more susceptible to chemotherapy. Several preclinical and clinical studies summarized herein demonstrate that uproleselan has favorable safety and pharmacokinetics and is a tumor microenvironment-disrupting agent that improves the efficacy of chemotherapy, reduces side effects such as neutropenia, intestinal mucositis and infections, and extends overall survival. This review highlights the critical contribution of E-selectin and its specific antagonist, uproleselan, in the regulation of cancer growth, dissemination, and drug resistance in the context of the bone marrow microenvironment. Full article

(This article belongs to the Special Issue Angiogenesis in Cancers)

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22 pages, 2037 KiB

Open AccessEditor’s ChoiceReview

Immunotherapy and Immunotherapy Combinations in Metastatic Castration-Resistant Prostate Cancer

by Dhruv Bansal, Melissa A. Reimers, Eric M. Knoche and Russell K. Pachynski

Cancers 2021, 13(2), 334; https://doi.org/10.3390/cancers13020334 - 18 Jan 2021

Cited by 42 | Viewed by 5602

Abstract

Although most prostate cancers are localized, and the majority are curable, recurrences occur in approximately 35% of men. Among patients with prostate-specific antigen (PSA) recurrence and PSA doubling time (PSADT) less than 15 months after radical prostatectomy, prostate cancer accounted for approximately 90% [...] Read more.

Although most prostate cancers are localized, and the majority are curable, recurrences occur in approximately 35% of men. Among patients with prostate-specific antigen (PSA) recurrence and PSA doubling time (PSADT) less than 15 months after radical prostatectomy, prostate cancer accounted for approximately 90% of the deaths by 15 years after recurrence. An immunosuppressive tumor microenvironment (TME) and impaired cellular immunity are likely largely responsible for the limited utility of checkpoint inhibitors (CPIs) in advanced prostate cancer compared with other tumor types. Thus, for immunologically “cold” malignancies such as prostate cancer, clinical trial development has pivoted towards novel approaches to enhance immune responses. Numerous clinical trials are currently evaluating combination immunomodulatory strategies incorporating vaccine-based therapies, checkpoint inhibitors, and chimeric antigen receptor (CAR) T cells. Other trials evaluate the efficacy and safety of these immunomodulatory agents’ combinations with standard approaches such as androgen deprivation therapy (ADT), taxane-based chemotherapy, radiotherapy, and targeted therapies such as tyrosine kinase inhibitors (TKI) and poly ADP ribose polymerase (PARP) inhibitors. Here, we will review promising immunotherapies in development and ongoing trials for metastatic castration-resistant prostate cancer (mCRPC). These novel trials will build on past experiences and promise to usher a new era to treat patients with mCRPC. Full article

(This article belongs to the Special Issue The Use of Combination Therapies to Treat Castration-Resistant Prostate Cancer)

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2 pages, 174 KiB

Open AccessEditorial

Recent Research on Gastrointestinal Carcinoma

by Giulia Rovesti, Giorgia Marisi and Andrea Casadei-Gardini

Cancers 2021, 13(2), 333; https://doi.org/10.3390/cancers13020333 - 18 Jan 2021

Cited by 1 | Viewed by 1337

Abstract

This series of 10 articles (eight original articles and two reviews) is presented by international leaders in gastrointestinal cancer research [...] Full article

(This article belongs to the Special Issue Recent Research on Gastrointestinal Carcinoma)

20 pages, 1086 KiB

Open AccessReview

CDK4/6 Inhibitor Treatments in Patients with Hormone Receptor Positive, Her2 Negative Advanced Breast Cancer: Potential Molecular Mechanisms, Clinical Implications and Future Perspectives

by Michela Roberto, Antonio Astone, Andrea Botticelli, Luisa Carbognin, Alessandra Cassano, Giuliana D’Auria, Agnese Fabbri, Alessandra Fabi, Teresa Gamucci, Eriseld Krasniqi, Mauro Minelli, Armando Orlandi, Francesco Pantano, Ida Paris, Laura Pizzuti, Ilaria Portarena, Nello Salesi, Simone Scagnoli, Paola Scavina, Giuseppe Tonini, Patrizia Vici and Paolo Marchetti Show full author list Hide full author list

Cancers 2021, 13(2), 332; https://doi.org/10.3390/cancers13020332 - 18 Jan 2021

Cited by 39 | Viewed by 7068

Abstract

Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer is the most common breast cancer subtype, and endocrine therapy (ET) remains its therapeutic backbone. Although anti-estrogen therapies are usually effective initially, approximately 50% of HR+ patients develop resistance to ET [...] Read more.

Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer is the most common breast cancer subtype, and endocrine therapy (ET) remains its therapeutic backbone. Although anti-estrogen therapies are usually effective initially, approximately 50% of HR+ patients develop resistance to ET within their lifetime, ultimately leading to disease recurrence and limited clinical benefit. The recent addition of cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (palbociclib, ribociclib, abemaciclib) to ET have remarkably improved the outcome of patients with HR+ advanced breast cancer (ABC) compared with anti-estrogens alone, by targeting the cell-cycle machinery and overcoming some aspects of endocrine resistance. However, which patients are the better candidates for these drugs, which are the main characteristics for a better selection of patients or if there are predictive biomarkers of response, is still unknown. In this review we reported the mechanism of action of CDK4/6 inhibitors as well as their potential mechanism of resistance, their implications in clinical practice and the forthcoming strategies to enhance their efficacy in improving survival and quality of life of patients affected with HR+, HER2−, ABC. Full article

(This article belongs to the Special Issue Advanced Breast Cancer: From Biology to Cure)

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