Cancers

14 pages, 2171 KiB

Open AccessArticle

Lipid Droplet Accumulation Independently Predicts Poor Clinical Prognosis in High-Grade Serous Ovarian Carcinoma

by Naoyuki Iwahashi, Midori Ikezaki, Masakazu Fujimoto, Yoshihiro Komohara, Yukio Fujiwara, Madoka Yamamoto, Mika Mizoguchi, Kentaro Matsubara, Yudai Watanabe, Ibu Matsuzaki, Shin-ichi Murata, Yoshito Ihara, Kazuhiko Ino and Kazuchika Nishitsuji

Cancers 2021, 13(20), 5251; https://doi.org/10.3390/cancers13205251 - 19 Oct 2021

Cited by 7 | Viewed by 2310

Abstract

High-grade serous ovarian carcinoma (HGSOC) is an epithelial cancer that accounts for most ovarian cancer deaths. Metabolic abnormalities such as extensive aerobic glycolysis and aberrant lipid metabolism are well-known characteristics of cancer cells. Indeed, accumulation of lipid droplets (LDs) in certain types of [...] Read more.

High-grade serous ovarian carcinoma (HGSOC) is an epithelial cancer that accounts for most ovarian cancer deaths. Metabolic abnormalities such as extensive aerobic glycolysis and aberrant lipid metabolism are well-known characteristics of cancer cells. Indeed, accumulation of lipid droplets (LDs) in certain types of malignant tumors has been known for more than 50 years. Here, we investigated the correlation between LD accumulation and clinical prognosis. In 96 HGSOC patients, we found that high expression of the LD marker adipophilin was associated with poor progression-free and overall survival (p = 0.0022 and p = 0.014, respectively). OVCAR-3 ovarian carcinoma cells accumulated LDs in a glucose-dependent manner, which suggested the involvement of aerobic glycolysis and subsequently enhanced lipogenesis, with a result being LD accumulation. The acyl-CoA: cholesterol acyltransferase 1 inhibitor K604 and the hydroxymethylglutaryl-CoA reductase inhibitor pitavastatin blocked LD accumulation in OVCAR-3 cells and reduced phosphorylation of the survival-related kinases Akt and ERK1/2, both of which have been implicated in malignancy. Our cell-based assays thus suggested that enhanced aerobic glycolysis resulted in LD accumulation and activation of survival-related kinases. Overall, our results support the idea that cancers with lipogenic phenotypes are associated with poor clinical prognosis, and we suggest that adipophilin may serve as an independent indicator of a poor prognosis in HGSOC. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Biology and Treatment Strategies for Refractory Ovarian Cancer)

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26 pages, 1129 KiB

Open AccessReview

Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer

by Chaofan Fan, Shing Kam and Pierluigi Ramadori

Cancers 2021, 13(20), 5250; https://doi.org/10.3390/cancers13205250 - 19 Oct 2021

Cited by 6 | Viewed by 3183

Abstract

Metabolic reprogramming and epigenetic changes have been characterized as hallmarks of liver cancer. Independently of etiology, oncogenic pathways as well as the availability of different energetic substrates critically influence cellular metabolism, and the resulting perturbations often cause aberrant epigenetic alterations, not only in [...] Read more.

Metabolic reprogramming and epigenetic changes have been characterized as hallmarks of liver cancer. Independently of etiology, oncogenic pathways as well as the availability of different energetic substrates critically influence cellular metabolism, and the resulting perturbations often cause aberrant epigenetic alterations, not only in cancer cells but also in the hepatic tumor microenvironment. Metabolic intermediates serve as crucial substrates for various epigenetic modulations, from post-translational modification of histones to DNA methylation. In turn, epigenetic changes can alter the expression of metabolic genes supporting on the one hand, the increased energetic demand of cancer cells and, on the other hand, influence the activity of tumor-associated immune cell populations. In this review, we will illustrate the most recent findings about metabolic reprogramming in liver cancer. We will focus on the metabolic changes characterizing the tumor microenvironment and on how these alterations impact on epigenetic mechanisms involved in the malignant progression. Furthermore, we will report our current knowledge about the influence of cancer-specific metabolites on epigenetic reprogramming of immune cells and we will highlight how this favors a tumor-permissive immune environment. Finally, we will review the current strategies to target metabolic and epigenetic pathways and their therapeutic potential in liver cancer, alone or in combinatorial approaches. Full article

(This article belongs to the Special Issue Cell Death, Inflammation, and Liver Cancer)

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11 pages, 2823 KiB

Open AccessArticle

Landscape of Immune-Related Markers and Potential Therapeutic Targets in Soft Tissue Sarcoma

by Jason Roszik, Lisa Maria Mustachio, John A. Livingston, Roman Groisberg, Roberto Carmagnani Pestana, Vivek Subbiah and Anthony P. Conley

Cancers 2021, 13(20), 5249; https://doi.org/10.3390/cancers13205249 - 19 Oct 2021

Cited by 4 | Viewed by 2217

Abstract

Soft tissue sarcomas, depending on the subtype and grade, frequently recur and become metastatic after localized treatment. There is now great interest in applying immunotherapy to sarcomas to immuno-profile the different subtypes and immune monitor for prognosis. Our group previously showed that key [...] Read more.

Soft tissue sarcomas, depending on the subtype and grade, frequently recur and become metastatic after localized treatment. There is now great interest in applying immunotherapy to sarcomas to immuno-profile the different subtypes and immune monitor for prognosis. Our group previously showed that key immunotherapy target genes are present in sarcomas. Here, we extend our findings by demonstrating that sarcomas with a relatively high mutational load are likely to be more sensitive to immunotherapy compared to sarcomas with a lower mutation load. We also show that sarcomas with a higher mutation load are associated with the expression of key immune-related genes. We found that CD8+ T cells are present in sarcoma subtypes and that PD-L2 is highly expressed. These findings further define potential mechanisms behind the immunotherapy response of specific sarcoma subtypes and can be used to develop more optimal treatments in the future. Full article

(This article belongs to the Special Issue Novel Targets and Approaches in Cancer Therapy)

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22 pages, 5951 KiB

Open AccessArticle

The Oncogene MYCN Modulates Glycolytic and Invasive Genes to Enhance Cell Viability and Migration in Human Retinoblastoma

by Swatishree Sradhanjali, Padmalochan Rout, Devjyoti Tripathy, Swathi Kaliki, Suryasnata Rath, Rahul Modak, Ruchi Mittal, Tirumala Kumar Chowdary and Mamatha M. Reddy

Cancers 2021, 13(20), 5248; https://doi.org/10.3390/cancers13205248 - 19 Oct 2021

Cited by 6 | Viewed by 3396

Abstract

Retinoblastoma is usually initiated by biallelic RB1 gene inactivation. In addition, MYCN copy number alterations also contribute to RB pathogenesis. However, MYCN expression, its role in disease progression and correlation with RB histological risk factors are not well understood. We studied the expression [...] Read more.

Retinoblastoma is usually initiated by biallelic RB1 gene inactivation. In addition, MYCN copy number alterations also contribute to RB pathogenesis. However, MYCN expression, its role in disease progression and correlation with RB histological risk factors are not well understood. We studied the expression of MYCN in enucleated RB patient specimens by immunohistochemistry. MYCN is overexpressed in RB compared to control retina. Our microarray gene expression analysis followed by qRT-PCR validation revealed that genes involved in glucose metabolism and migration are significantly downregulated in MYCN knockdown cells. Further, targeting MYCN in RB cells using small molecule compounds or shRNAs led to decreased cell survival and migration, increased apoptosis and cell cycle arrest, suggesting that MYCN inhibition can be a potential therapeutic strategy. We also noted that MYCN inhibition results in reduction in glucose uptake, lactate production, ROS levels and gelatinolytic activity of active-MMP9, explaining a possible mechanism of MYCN in RB. Taking clues from our findings, we tested a combination treatment of RB cells with carboplatin and MYCN inhibitors to find enhanced therapeutic efficacy compared to single drug treatment. Thus, MYCN inhibition can be a potential therapeutic strategy in combination with existing chemotherapy drugs to restrict tumor cell growth in RB. Full article

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15 pages, 2801 KiB

Open AccessArticle

Antigen Presenting Cells from Tumor and Colon of Colorectal Cancer Patients Are Distinct in Activation and Functional Status, but Comparably Responsive to Activated T Cells

by Frank Liang, Azar Rezapour, Louis Szeponik, Samuel Alsén, Yvonne Wettergren, Elinor Bexe Lindskog, Marianne Quiding-Järbrink and Ulf Yrlid

Cancers 2021, 13(20), 5247; https://doi.org/10.3390/cancers13205247 - 19 Oct 2021

Cited by 3 | Viewed by 2194

Abstract

Although mouse models of CRC treatments have demonstrated robust immune activation, it remains unclear to what extent CRC patients’ APCs and TILs interact to fuel or quench treatment-induced immune responses. Our ex vivo characterization of tumor and adjacent colon cell suspensions suggest that [...] Read more.

Although mouse models of CRC treatments have demonstrated robust immune activation, it remains unclear to what extent CRC patients’ APCs and TILs interact to fuel or quench treatment-induced immune responses. Our ex vivo characterization of tumor and adjacent colon cell suspensions suggest that contrasting environments in these tissues promoted inversed expression of T cell co-stimulatory CD80, and co-inhibitory programmed death (PD)-ligand1 (PD-L1) on intratumoral vs. colonic APCs. While putative tumor-specific CD103+CD39+CD8+ TILs expressed lower CD69 (early activation marker) and higher PD-1 (extended activation/exhaustion marker) than colonic counterparts, the latter had instead higher CD69 and lower PD-1 levels. Functional comparisons showed that intratumoral APCs were inferior to colonic APCs regarding protein uptake and upregulation of CD80 and PD-L1 after protein degradation. Our attempt to model CRC treatment-induced T cell activation in vitro showed less interferon (IFN)-γ production by TILs than colonic T cells. In this model, we also measured APCs’ CD80 and PD-L1 expression in response to activated co-residing T cells. These markers were comparable in the two tissues, despite higher IFN- γ exposure for colonic APCs. Thus, APCs within distinct intratumoral and colonic milieus showed different activation and functional status, but were similarly responsive to signals from induced T cell activation. Full article

(This article belongs to the Special Issue Cancer Immunology)

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25 pages, 6772 KiB

Open AccessEditor’s ChoiceReview

Cancer-Associated Fibroblast Functions as a Road-Block in Cancer Therapy

by Pradip De, Jennifer Aske and Nandini Dey

Cancers 2021, 13(20), 5246; https://doi.org/10.3390/cancers13205246 - 19 Oct 2021

Cited by 22 | Viewed by 4151

Abstract

The journey of a normal resident fibroblast belonging to the tumor microenvironment (TME) from being a tumor pacifier to a tumor patron is fascinating. We introduce cancer-associated fibroblast (CAF) as a crucial component of the TME. Activated-CAF partners with tumor cells and all [...] Read more.

The journey of a normal resident fibroblast belonging to the tumor microenvironment (TME) from being a tumor pacifier to a tumor patron is fascinating. We introduce cancer-associated fibroblast (CAF) as a crucial component of the TME. Activated-CAF partners with tumor cells and all components of TME in an established solid tumor. We briefly overview the origin, activation, markers, and overall functions of CAF with a particular reference to how different functions of CAF in an established tumor are functionally connected to the development of resistance to cancer therapy in solid tumors. We interrogate the role of CAF in mediating resistance to different modes of therapies. Functional diversity of CAF in orchestrating treatment resistance in solid tumors portrays CAF as a common orchestrator of treatment resistance; a roadblock in cancer therapy Full article

(This article belongs to the Special Issue Targeted Cancer Therapy: Targeting Tyrosine/Serine Kinases by Small Molecule Inhibitors, Immune Modulators, and Monoclonal Antibodies)

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11 pages, 1967 KiB

Open AccessArticle

Occurrence of Sinonasal Intestinal-Type Adenocarcinoma and Non-Intestinal-Type Adenocarcinoma in Two Countries with Different Patterns of Wood Dust Exposure

by Ilmo Leivo, Reetta Holmila, Danièle Luce, Torben Steiniche, Michael Dictor, Pirjo Heikkilä, Kirsti Husgafvel-Pursiainen and Henrik Wolff

Cancers 2021, 13(20), 5245; https://doi.org/10.3390/cancers13205245 - 19 Oct 2021

Cited by 8 | Viewed by 2573

Abstract

Sinonasal intestinal-type adenocarcinoma is strongly associated with hardwood dust exposure. Non-intestinal-type adenocarcinoma is a rarer and less well-known subtype considered not to be related with wood dust exposure. We determined the relative numbers of these two tumor types in 56 sinonasal adenocarcinoma patients [...] Read more.

Sinonasal intestinal-type adenocarcinoma is strongly associated with hardwood dust exposure. Non-intestinal-type adenocarcinoma is a rarer and less well-known subtype considered not to be related with wood dust exposure. We determined the relative numbers of these two tumor types in 56 sinonasal adenocarcinoma patients in France and Finland, relating them with carefully assessed wood dust exposure histories. Diagnostic workup including immunohistochemistry for the intestinal markers CDX2 and CK20 indicated that the proportions of the two tumors differed significantly between France and Finland. In Finnish samples non-intestinal adenocarcinomas were more common than intestinal-type adenocarcinomas (12 non-intestinal vs. nine intestinal), while in the French samples the reverse was true (six non-intestinal vs. 29 intestinal). Such remarkably dissimilar occurrence of these tumors in France and Finland presumably reflects different pathogenetic circumstances in the two countries, and perhaps their different patterns of wood dust exposure. In France the main source of wood dust is from hardwoods. In Finland it is derived from softwoods. This is the first systematic comparison of the occurrence of intestinal-type adenocarcinoma and non-intestinal-type adenocarcinoma in two countries with different wood usage. It appears to be the first systematic study on differences in wood dust exposure between intestinal-type adenocarcinoma and non-intestinal-type adenocarcinoma. Full article

(This article belongs to the Special Issue Sinonasal Cancer: Improving Classification, Stratification and Therapeutic Options)

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15 pages, 1637 KiB

Open AccessArticle

Long-Term Follow-Up of Patients Receiving Neoadjuvant Treatment Modalties for Soft Tissue Sarcomas of the Extremities

by Miriam Rauch, Abbas Agaimy, Sabine Semrau, Alexander Willner, Oliver Ott, Rainer Fietkau, Werner Hohenberger, Roland S. Croner, Robert Grützmann, Katja Fechner and Nikolaos Vassos

Cancers 2021, 13(20), 5244; https://doi.org/10.3390/cancers13205244 - 19 Oct 2021

Cited by 1 | Viewed by 1677

Abstract

Background: Neoadjuvant treatment modalities in soft tissue sarcoma (STS) of the extremities have become more popular in recent years, but because of the rarity and heterogeneity of STS, there are yet few studies on the long-term impact of neoadjuvant treatment modalities, especially in [...] Read more.

Background: Neoadjuvant treatment modalities in soft tissue sarcoma (STS) of the extremities have become more popular in recent years, but because of the rarity and heterogeneity of STS, there are yet few studies on the long-term impact of neoadjuvant treatment modalities, especially in terms of neoadjuvant radiochemotherapy. Methods: The study enrolled 136 patients with primary STS of the extremities who underwent surgery with curative intent or neoadjuvant therapy, followed by surgery in a 15-year period. Neoadjuvant treatment consisted of radiotherapy (RT) with 60 Gy and in most cases simultaneous chemotherapy (CTx) with ifosfamide (1.5 g/m²/d, d1–5, q28) and doxorubicine (50 mg/m²/d, d3, q28). We investigated the clinical, (post)-operative and histopathological data and the oncological follow-up as well. The median follow-up period was 82 months (range 6–202). Results: A total of 136 patients (M:F = 73:63) with a mean age of 62 years (range; 21–93) was observed. Seventy-four patients (54.4%) received neoadjuvant therapy (NT), 62 patients (45.6%) received primary surgery (PS). When receiving NT, patients with high-risk STS had a lower risk to develop distant metastasis (p = 0.025). Age, histological type, tumor size and surgical margins (R0 vs. R1) had no influence on any survival rates. There was an association between NT and the occurrence of postoperative complications (p = 0.001). The 5-year local recurrence free survival (LRFS), metastasis free survival (MFS), disease free survival (DFS) and overall survival (OS) rate of the whole cohort was 89.9%, 77.0%, 70.6% and 72.6%; whereas the 5-year LRFS, MFS, DFS and OS rate was 90.5%, 67.2%, 64.1% and 62.8% for the NT group and 89.5%, 88.3%. 78.4% and 83.8% for the PS group. Conclusions: Multimodal treatment strategies in patients with STS of extremities lead to excellent oncological outcomes. Patients with high-risk STS had a significantly better MFS when receiving NT than patients with low-risk STS. NT was associated with a higher probability of postoperative but well-manageable complications. Full article

(This article belongs to the Special Issue New Directions for Treating Soft Tissue Sarcomas)

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18 pages, 2432 KiB

Open AccessArticle

Activation of Vitamin D Receptor Pathway Enhances Differentiating Capacity in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations

by Marie Sabatier, Emeline Boet, Sonia Zaghdoudi, Nathan Guiraud, Alexis Hucteau, Nathaniel Polley, Guillaume Cognet, Estelle Saland, Laura Lauture, Thomas Farge, Ambrine Sahal, Vera Pancaldi, Emeline Chu-Van, Florence Castelli, Sarah Bertoli, Pierre Bories, Christian Récher, Héléna Boutzen, Véronique Mansat-De Mas, Lucille Stuani and Jean-Emmanuel Sarry Show full author list Hide full author list

Cancers 2021, 13(20), 5243; https://doi.org/10.3390/cancers13205243 - 19 Oct 2021

Cited by 6 | Viewed by 2452

Abstract

Relapses and resistance to therapeutic agents are major barriers in the treatment of acute myeloid leukemia (AML) patients. These unfavorable outcomes emphasize the need for new strategies targeting drug-resistant cells. As IDH mutations are present in the preleukemic stem cells and systematically conserved [...] Read more.

Relapses and resistance to therapeutic agents are major barriers in the treatment of acute myeloid leukemia (AML) patients. These unfavorable outcomes emphasize the need for new strategies targeting drug-resistant cells. As IDH mutations are present in the preleukemic stem cells and systematically conserved at relapse, targeting IDH mutant cells could be essential to achieve a long-term remission in the IDH mutant AML subgroup. Here, using a panel of human AML cell lines and primary AML patient specimens harboring IDH mutations, we showed that the production of an oncometabolite (R)-2-HG by IDH mutant enzymes induces vitamin D receptor-related transcriptional changes, priming these AML cells to differentiate with pharmacological doses of ATRA and/or VD. This activation occurs in a CEBPα-dependent manner. Accordingly, our findings illuminate potent and cooperative effects of IDH mutations and the vitamin D receptor pathway on differentiation in AML, revealing a novel therapeutic approach easily transferable/immediately applicable to this subgroup of AML patients. Full article

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14 pages, 1796 KiB

Open AccessArticle

Genomic Sub-Classification of Ovarian Clear Cell Carcinoma Revealed by Distinct Mutational Signatures

by Douglas V. N. P. Oliveira, Tine H. Schnack, Tim S. Poulsen, Anne P. Christiansen, Claus K. Høgdall and Estrid V. Høgdall

Cancers 2021, 13(20), 5242; https://doi.org/10.3390/cancers13205242 - 19 Oct 2021

Cited by 10 | Viewed by 2417

Abstract

Ovarian clear cell carcinoma (OCCC) is characterized by dismal prognosis, partially due to its low sensitivity to standard chemotherapy regimen. It is also well-known for presenting unique molecular features in comparison to other epithelial ovarian cancer subtypes. Here, we aim to identify potential [...] Read more.

Ovarian clear cell carcinoma (OCCC) is characterized by dismal prognosis, partially due to its low sensitivity to standard chemotherapy regimen. It is also well-known for presenting unique molecular features in comparison to other epithelial ovarian cancer subtypes. Here, we aim to identify potential subgroups of patients in order to (1) determine their molecular features and (2) characterize their mutational signature. Furthermore, we sought to perform the investigation based on a potentially clinically relevant setting. To that end, we assessed the mutational profile and genomic instability of 55 patients extracted from the Gynecologic Cancer Database (DGCD) by using a panel comprised of 409 cancer-associated genes and a microsatellite assay, respectively; both are currently used in our routine environment. In accordance with previous findings, ARID1A and PIK3CA were the most prevalent mutations, present in 49.1% and 41.8%, respectively. From those, the co-occurrence of ARID1A and PIK3CA mutations was observed in 36.1% of subjects, indicating that this association might be a common feature of OCCC. The microsatellite instability frequency was low across samples. An unbiased assessment of signatures identified the presence of three subgroups, where “PIK3CA” and “Double hit” (with ARID1A and PIK3CA double mutation) subgroups exhibited unique signatures, whilst “ARID1A” and “Undetermined” (no mutations on ARID1A nor PIK3CA) subgroups showed similar profiles. Those differences were further indicated by COSMIC signatures. Taken together, the current findings suggest that OCCC presents distinct mutational landscapes within its group, which may indicate different therapeutic approaches according to its subgroup. Although encouraging, it is noteworthy that the current results are limited by sample size, and further investigation on a larger group would be crucial to better elucidate them. Full article

(This article belongs to the Special Issue Next Generation Sequencing Application in Cancer Research)

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16 pages, 262 KiB

Open AccessSystematic Review

Epigenetic Modifiers as Novel Therapeutic Targets and a Systematic Review of Clinical Studies Investigating Epigenetic Inhibitors in Head and Neck Cancer

by Kyunghee Burkitt and Vassiliki Saloura

Cancers 2021, 13(20), 5241; https://doi.org/10.3390/cancers13205241 - 19 Oct 2021

Cited by 8 | Viewed by 1889

Abstract

The survival rate of head and neck squamous cell carcinoma patients with the current standard of care therapy is suboptimal and is associated with long-term side effects. Novel therapeutics that will improve survival rates while minimizing treatment-related side effects are the focus of [...] Read more.

The survival rate of head and neck squamous cell carcinoma patients with the current standard of care therapy is suboptimal and is associated with long-term side effects. Novel therapeutics that will improve survival rates while minimizing treatment-related side effects are the focus of active investigation. Epigenetic modifications have been recognized as potential therapeutic targets in various cancer types, including head and neck cancer. This review summarizes the current knowledge on the function of important epigenetic modifiers in head and neck cancer, their clinical implications and discusses results of clinical trials evaluating epigenetic interventions in past and ongoing clinical trials as monotherapy or combination therapy with either chemotherapy, radiotherapy or immunotherapy. Understanding the function of epigenetic modifiers in both preclinical and clinical settings will provide insight into a more rational design of clinical trials using epigenetic interventions and the patient subgroups that may benefit from such interventions. Full article

(This article belongs to the Special Issue Epigenetic Regulation in Human Cancers)

13 pages, 1156 KiB

Open AccessArticle

Precision Oncology of High-Grade Ovarian Cancer Defined through Targeted Sequencing

by Sandra Wessman, Beatriz Bohorquez Fuentes, Therese Törngren, Anders Kvist, Georgia Kokaraki, Hanna Menkens, Elisabet Hjerpe, Ythalo Hugo da Silva Santos, Tirzah Braz Petta, Åke Borg and Joseph W. Carlson

Cancers 2021, 13(20), 5240; https://doi.org/10.3390/cancers13205240 - 19 Oct 2021

Cited by 3 | Viewed by 2347

Abstract

Background: We examined whether molecular characterization of high-grade epithelial ovarian cancer can inform the diagnosis and/or identify potential actionable targets. Methods: All of the consecutively sequenced high-grade ovarian tumours with consent between 2014 until 2019 were included. A total of 274 tumours underwent [...] Read more.

Background: We examined whether molecular characterization of high-grade epithelial ovarian cancer can inform the diagnosis and/or identify potential actionable targets. Methods: All of the consecutively sequenced high-grade ovarian tumours with consent between 2014 until 2019 were included. A total of 274 tumours underwent next generation sequencing using a targeted panel. Results: Patients with high-grade ovarian epithelial cancer were consented to prospective molecular characterization. Clinical information was extracted from their medical record. Tumour DNA was subjected to sequencing, and selected patients received PARP inhibitor therapy. Conclusions: Tumours from 274 women were sequenced, including high-grade serous carcinoma (n = 252), clear cell carcinoma (n = 4), carcinosarcoma (n = 9), endometrioid carcinoma (n = 3), undifferentiated carcinoma (n = 1), and mixed tumours (n = 5). Genomic profiling did not influence histologic diagnosis. Mutations were identified in TP53, BRCA1, BRCA2, as well as additional homologous recombination repair pathway genes BARD1, ATR, CHEK2, PALB2, RAD51D, RAD50, SLX4, FANCA, RAD51C, and RAD54L. In addition, mutations in PTEN and CDKN2A were identified. Several somatic mutations with implications for germline testing were identified, including RMI1, STK11, and CDH1. Germline testing identified 16 previously unknown BRCA1/2 carriers. Finally, 20 patients were treated with the PARP inhibitor olaparib based on the sequencing results. Full article

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13 pages, 321 KiB

Open AccessReview

Future Perspective of Chemotherapy and Pharmacotherapy in Thymic Carcinoma

by Rui Kitadai and Yusuke Okuma

Cancers 2021, 13(20), 5239; https://doi.org/10.3390/cancers13205239 - 19 Oct 2021

Cited by 4 | Viewed by 2409

Abstract

Thymic carcinoma is a rare cancer that arises from thymic epithelial cells. Its nature and pathology differ from that of benign thymoma, presenting a poorer prognosis. If surgically resectable, surgery alone or surgery followed by chemoradiotherapy or radiotherapy is recommended by the National [...] Read more.

Thymic carcinoma is a rare cancer that arises from thymic epithelial cells. Its nature and pathology differ from that of benign thymoma, presenting a poorer prognosis. If surgically resectable, surgery alone or surgery followed by chemoradiotherapy or radiotherapy is recommended by the National Comprehensive Cancer Network Guidelines. Metastatic and refractory thymic carcinomas require systemic pharmacotherapy. Combined carboplatin and paclitaxel, and cisplatin and anthracycline-based regimens have been shown a fair response rate and survival to provide a de facto standard of care when compared with other drugs employed as first-line chemotherapy. Cytotoxic agents have been pivotal for treating thymic carcinoma, as little is known regarding its tumorigenesis. In addition, genetic alterations, including driver mutations, which play an important role in treatments, have not yet been discovered. However, molecular pathways and biomarker studies assessing thymic epithelial tumors have been reported recently, resulting in the development of new agents, such as molecular targeted agents and immune checkpoint inhibitors. As treatment options are currently limited and the prognosis remains poor in metastases and recurrent thymic carcinoma, genetic alterations need to be assessed. In the present review, we focused on the current role of targeted therapies and immune checkpoint inhibitors in treating thymic carcinoma. Full article

(This article belongs to the Special Issue Thymic Carcinoma)

18 pages, 3429 KiB

Open AccessArticle

A Recurrent STAT5B^N642H Driver Mutation in Feline Alimentary T Cell Lymphoma

by Matthias Kieslinger, Alexander Swoboda, Nina Kramer, Patricia Freund, Barbara Pratscher, Heidi A. Neubauer, Ralf Steinborn, Birgitt Wolfesberger, Andrea Fuchs-Baumgartinger, Richard Moriggl and Iwan A. Burgener

Cancers 2021, 13(20), 5238; https://doi.org/10.3390/cancers13205238 - 19 Oct 2021

Cited by 4 | Viewed by 2699

Abstract

Alimentary lymphomas arising from T cells are rare and aggressive malignancies in humans. In comparison, they represent the most common anatomical form of lymphoma in cats. Due to the low prevalence in humans, the underlying pathomechanism for these diseases is poorly characterised, limiting [...] Read more.

Alimentary lymphomas arising from T cells are rare and aggressive malignancies in humans. In comparison, they represent the most common anatomical form of lymphoma in cats. Due to the low prevalence in humans, the underlying pathomechanism for these diseases is poorly characterised, limiting experimental analysis and therapeutic exploration. To date, activating mutations of the JAK/STAT core cancer pathway and particularly the STAT5B oncoprotein have been identified in human enteropathy-associated T cell lymphoma. Here, we describe a high homology of human and feline STAT3 and STAT5B proteins and strong conservation at the genomic level. Analysis of 42 samples of feline T cell alimentary lymphoma reveals broad activation of STAT3 and STAT5B. Screening for known activating mutations in STAT3 or STAT5B identifies the presence of the STAT5B^N642H driver mutation in feline enteropathy-associated T cell lymphoma in 7 out of 42 (16.67%) samples in total. Regarding lymphoma subtypes, the majority of mutations with 5 out of 17 (29.41%) cases were found in feline enteropathy-associated lymphoma type II (EATL II). This identification of an oncogenic STAT5B driver mutation in felines recapitulates the genetic situation in the corresponding human disease, thereby establishing the cat as a potential new model for a rare and incurable human T cell disease. Full article

(This article belongs to the Special Issue Feature Paper from Journal Reviewers)

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15 pages, 3646 KiB

Open AccessArticle

Evaluation of NAB2-STAT6 Fusion Variants and Other Molecular Alterations as Prognostic Biomarkers in a Case Series of 83 Solitary Fibrous Tumors

by Carmen Salguero-Aranda, Paula Martínez-Reguera, David Marcilla, Enrique de Álava and Juan Díaz-Martín

Cancers 2021, 13(20), 5237; https://doi.org/10.3390/cancers13205237 - 19 Oct 2021

Cited by 9 | Viewed by 2650

Abstract

Risk stratification of solitary fibrous tumor (SFT) patients based on clinicopathological features has limited efficacy, especially in predicting late relapse or metastasis. The hallmark alteration of SFT is the gene fusion NAB2-STAT6, whose prognostic value remains controversial. As biological knowledge of this [...] Read more.

Risk stratification of solitary fibrous tumor (SFT) patients based on clinicopathological features has limited efficacy, especially in predicting late relapse or metastasis. The hallmark alteration of SFT is the gene fusion NAB2-STAT6, whose prognostic value remains controversial. As biological knowledge of this entity has increased in recent years, new molecular alterations have emerged that could be helpful to refine current risk models. Here, we evaluated NAB2-STAT6 fusion variants and other molecular alterations in a series of 83 SFTs that are enriched in progressing cases. Gene fusion variants were identified by targeted RNA-seq in the whole series, whereas TERT promoter (pTERT) mutations were inspected by Sanger sequencing in a subset of 18 cases. Immunohistochemical assays were performed to assess BCOR and NTRK expression as well as P53 mutation status in 45, 44, and 44 cases, respectively. While confirming the associations of gene fusion variants with clinicopathological parameters, our results do not prove their prognostic value. Pan-TRK immunoexpresion correlated with recurrence/progression, P53 staining associated with higher mitotic counts, and pTERT mutations were enriched in cases with fatal outcome. An intriguing correlation was found for BCOR protein expression with gene fusion variants, size, and tumor location. Full article

(This article belongs to the Special Issue Diagnosis and Treatment for Bone Tumor and Sarcoma)

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19 pages, 1739 KiB

Open AccessArticle

Small Extracellular Vesicle-Derived microRNAs Stratify Prostate Cancer Patients According to Gleason Score, Race and Associate with Survival of African American and Caucasian Men

by Hamdy E. A. Ali, Mohamed S. A. Gaballah, Rofaida Gaballa, Shahenda Mahgoub, Zeinab A. Hassan, Eman A. Toraih, Bettina F. Drake and Zakaria Y. Abd Elmageed

Cancers 2021, 13(20), 5236; https://doi.org/10.3390/cancers13205236 - 19 Oct 2021

Cited by 7 | Viewed by 1920

Abstract

The utility of small extracellular vesicles (sEVs)-derived microRNAs (miRs) to segregate prostate cancer (PCa) patients according to tumor aggressiveness and ancestral background has not been fully investigated. Thus, we aimed to determine the diagnostic and prognostic utility of sEV-associated miRs in identifying aggressive [...] Read more.

The utility of small extracellular vesicles (sEVs)-derived microRNAs (miRs) to segregate prostate cancer (PCa) patients according to tumor aggressiveness and ancestral background has not been fully investigated. Thus, we aimed to determine the diagnostic and prognostic utility of sEV-associated miRs in identifying aggressive PCa in African American (AA) and Caucasian (CA) men. Using a training cohort, miR profiling was performed on sEVs isolated from plasma of PCa patients. Top-ranked sEV-associated miRs were then validated in 150 plasma samples (75 AA and 75 CA) collected from two independent cohorts; NIH (n = 90) and Washington University (n = 60) cohorts. Receiver operating characteristic (ROC) curve, Kaplan–Meier and Cox proportional hazards regression were used to assess these miRs as clinical biomarkers. Among nine top-ranked sEV-associated miRs, miR-6068 and miR-1915-3p were enriched in sEVs collected from PCa patients compared to healthy volunteers. Moreover, miR-6716-5p and miR-3692-3p segregated AA from CA men and low from high Gleason score (GS), respectively. Upregulation of sEV-associated miR-1915-3p, miR-3692-3p and miR-5001-5p was associated with improved survival time, and only miR-1915-3p was associated with longer recurrence-free survival (RFS) as an independent prognostic marker. Taken together, we identified novel sEV-associated miRs that can differentiate PCa patients from normal, AA from CA and high from low GS and predicts RFS. Full article

(This article belongs to the Collection New Discoveries and Future Trend for Prostate Cancer Research and Treatment)

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11 pages, 16299 KiB

Open AccessArticle

DARPin_9-29-Targeted Gold Nanorods Selectively Suppress HER2-Positive Tumor Growth in Mice

by Galina M. Proshkina, Elena I. Shramova, Marya V. Shilova, Ivan V. Zelepukin, Victoria O. Shipunova, Anastasia V. Ryabova, Sergey M. Deyev and Alexander B. Kotlyar

Cancers 2021, 13(20), 5235; https://doi.org/10.3390/cancers13205235 - 19 Oct 2021

Cited by 16 | Viewed by 2155

Abstract

Near-infrared phototherapy has great therapeutic potential for cancer treatment. However, for efficient application, in vivo photothermal agents should demonstrate excellent stability in blood and targeted delivery to pathological tissue. Here, we demonstrated that stable bovine serum albumin-coated gold mini nanorods conjugated to a [...] Read more.

Near-infrared phototherapy has great therapeutic potential for cancer treatment. However, for efficient application, in vivo photothermal agents should demonstrate excellent stability in blood and targeted delivery to pathological tissue. Here, we demonstrated that stable bovine serum albumin-coated gold mini nanorods conjugated to a HER2-specific designed ankyrin repeat protein, DARPin_9-29, selectively accumulate in HER2-positive xenograft tumors in mice and lead to a strong reduction in the tumor size when being illuminated with near-infrared light. The results pave the way for the development of novel DARPin-based targeted photothermal therapy of cancer. Full article

(This article belongs to the Section Cancer Therapy)

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10 pages, 25620 KiB

Open AccessArticle

Intracranial Mönckeberg’s Atherosclerosis Is Frequently Found in Autopsy Cases of Advanced Stage Malignancy with Cerebral Infarction

by Chika Shichijo, Keita Kai, Kazuki Jinnouchi, Masashi Nishihara, Hideo Hara and Shinichi Aishima

Cancers 2021, 13(20), 5234; https://doi.org/10.3390/cancers13205234 - 19 Oct 2021

Viewed by 1623

Abstract

Cerebral infarction (CI) severely affects the prognosis of patients with malignancy. The aim of the study was to compare the pathology of CI between cases with and without malignancy focusing on intracranial Mönckeberg’s atherosclerosis. Among 778 autopsy cases of craniotomy, 53 cases of [...] Read more.

Cerebral infarction (CI) severely affects the prognosis of patients with malignancy. The aim of the study was to compare the pathology of CI between cases with and without malignancy focusing on intracranial Mönckeberg’s atherosclerosis. Among 778 autopsy cases of craniotomy, 53 cases of “cerebral infarction without malignancy group” (CI group), 50 cases of “malignant tumor without CI group” (MT group), and 39 cases of “cerebral infarction with malignancy group” (CM group) were identified. Mönckeberg’s atherosclerosis was mainly found in the basal ganglia and its prevalence in the CM group (38.5%) was significantly higher than in the MT group (12.0%, p = 0.005), and apparently higher than in the CI group (18.9%, p = 0.057). The CI group was significantly older, had higher BMIs, and a greater prevalence of hypertension and atrial fibrillation compared to the CM group. In addition, the prevalence of chronic renal disease was significantly lower in the CM group (2.6%, p = 0.012) than in the CI group (20.8%). Our results indicated that Mönckeberg’s atherosclerosis was often found in the basal ganglia of CM cases and that intracranial Mönckeberg’s atherosclerosis is a potential risk factor for CI in patients with advanced stage malignancy. Full article

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22 pages, 4111 KiB

Open AccessArticle

Liquid Biopsy as a Diagnostic and Prognostic Tool for Women and Female Dogs with Breast Cancer

by Jucimara Colombo, Marina Gobbe Moschetta-Pinheiro, Adriana Alonso Novais, Bruna Ribeiro Stoppe, Enrico Dumbra Bonini, Francine Moraes Gonçalves, Heidge Fukumasu, Luiz Lehmann Coutinho, Luiz Gustavo de Almeida Chuffa and Debora Aparecida Pires de Campos Zuccari

Cancers 2021, 13(20), 5233; https://doi.org/10.3390/cancers13205233 - 19 Oct 2021

Cited by 8 | Viewed by 3125

Abstract

Introduction: Breast cancer (BC) is the malignant neoplasm with the highest mortality rate in women and female dogs are good models to study BC. Objective: We investigated the efficacy of liquid biopsy to detect gene mutations in the diagnosis and follow-up of women [...] Read more.

Introduction: Breast cancer (BC) is the malignant neoplasm with the highest mortality rate in women and female dogs are good models to study BC. Objective: We investigated the efficacy of liquid biopsy to detect gene mutations in the diagnosis and follow-up of women and female dogs with BC. Materials and Methods: In this study, 57 and 37 BC samples were collected from women and female dogs, respectively. After core biopsy and plasma samples were collected, the DNA and ctDNA of the tumor fragments and plasma were processed for next generation sequencing (NGS) assay. After preprocessing of the data, they were submitted to the Genome Analysis ToolKit (GATK). Results: In women, 1788 variants were identified in tumor fragments and 221 variants in plasma; 66 variants were simultaneously detected in tumors and plasma. Conversely, in female dogs, 1430 variants were found in plasma and 695 variants in tumor fragments; 59 variants were simultaneously identified in tumors and plasma. The most frequently mutated genes in the tumor fragments of women were USH2A, ATM, and IGF2R; in female dogs, they were USH2A, BRCA2, and RRM2. Plasma of women showed the most frequent genetic variations in the MAP3K1, BRCA1, and GRB7 genes, whereas plasma from female dogs had variations in the NF1, ERBB2, and KRT17 genes. Mutations in the AKT1, PIK3CA, and BRIP genes were associated with tumor recurrence, with a highly pathogenic variant in PIK3CA being particularly prominent. We also detected a gain-of-function mutation in the GRB7, MAP3K1, and MLH1 genes. Conclusion: Liquid biopsy is useful to identify specific genetic variations at the beginning of BC manifestation and may be accompanied over the entire follow-up period, thereby supporting the clinicians in refining interventions. Full article

(This article belongs to the Special Issue Translational and Comparative Research on Innovative Anti-Cancer Therapies)

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13 pages, 62358 KiB

Open AccessArticle

Radiation-Induced Fibrotic Tumor Microenvironment Regulates Anti-Tumor Immune Response

by Jae-Kyung Nam, Ji-Hee Kim, Min-Sik Park, Eun Ho Kim, Joon Kim and Yoon-Jin Lee

Cancers 2021, 13(20), 5232; https://doi.org/10.3390/cancers13205232 - 19 Oct 2021

Cited by 3 | Viewed by 1663

Abstract

High linear energy transfer (LET) radiation, such as neutron radiation, is considered more effective for the treatment of cancer than low LET radiation, such as X-rays. We previously reported that X-ray irradiation induced endothelial-to-mesenchymal transition (EndMT) and profibrotic changes, which contributed to the [...] Read more.

High linear energy transfer (LET) radiation, such as neutron radiation, is considered more effective for the treatment of cancer than low LET radiation, such as X-rays. We previously reported that X-ray irradiation induced endothelial-to-mesenchymal transition (EndMT) and profibrotic changes, which contributed to the radioresistance of tumors. However, this effect was attenuated in tumors of endothelial-specific Trp53-knockout mice. Herein, we report that compared to X-ray irradiation, neutron radiation therapy reduced collagen deposition and suppressed EndMT in tumors. In addition to the fewer fibrotic changes, more cluster of differentiation (CD8)-positive cytotoxic T cells were observed in neutron-irradiated regrowing tumors than in X-ray-irradiated tumors. Furthermore, lower programmed death-ligand 1 (PD-L1) expression was noted in the former. Endothelial-specific Trp53 deletion suppressed fibrotic changes within the tumor environment following both X-ray and neutron radiation therapy. In particular, the upregulation in PD-L1 expression after X-ray radiation therapy was significantly dampened. Our findings suggest that compared to low LET radiation therapy, high LET radiation therapy can efficiently suppress profibrotic changes and enhance the anti-tumor immune response, resulting in delayed tumor regrowth. Full article

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25 pages, 6163 KiB

Open AccessArticle

Altered Expression of Shorter p53 Family Isoforms Can Impact Melanoma Aggressiveness

by Ana Tadijan, Francesca Precazzini, Nikolina Hanžić, Martina Radić, Nicolò Gavioli, Ignacija Vlašić, Petar Ozretić, Lia Pinto, Lidija Škreblin, Giulia Barban, Neda Slade and Yari Ciribilli

Cancers 2021, 13(20), 5231; https://doi.org/10.3390/cancers13205231 - 18 Oct 2021

Cited by 16 | Viewed by 3619

Abstract

Cutaneous melanoma is the most aggressive form of skin cancer. Despite the significant advances in the management of melanoma in recent decades, it still represents a challenge for clinicians. The TP53 gene, the guardian of the genome, which is altered in more than [...] Read more.

Cutaneous melanoma is the most aggressive form of skin cancer. Despite the significant advances in the management of melanoma in recent decades, it still represents a challenge for clinicians. The TP53 gene, the guardian of the genome, which is altered in more than 50% of human cancers, is rarely mutated in melanoma. More recently, researchers started to appreciate the importance of shorter p53 isoforms as potential modifiers of the p53-dependent responses. We analyzed the expression of p53 and p73 isoforms both at the RNA and protein level in a panel of melanoma-derived cell lines with different TP53 and BRAF status, in normal conditions or upon treatment with common anti-cancer DNA damaging agents or targeted therapy. Using lentiviral vectors, we also generated stable clones of H1299 p53 null cells over-expressing the less characterized isoforms Δ160p53α, Δ160p53β, and Δ160p53γ. Further, we obtained two melanoma-derived cell lines resistant to BRAF inhibitor vemurafenib. We observed that melanoma cell lines expressed a wide array of p53 and p73 isoforms, with Δ160p53α as the most variable one. We demonstrated for the first time that Δ160p53α, and to a lesser extent Δ160p53β, can be recruited on chromatin, and that Δ160p53γ can localize in perinuclear foci; moreover, all Δ160p53 isoforms can stimulate proliferation and in vitro migration. Lastly, vemurafenib-resistant melanoma cells showed an altered expression of p53 and p73 isoforms, namely an increased expression of potentially pro-oncogenic Δ40p53β and a decrease in tumor-suppressive TAp73β. We therefore propose that p53 family isoforms can play a role in melanoma cells’ aggressiveness. Full article

(This article belongs to the Special Issue The Isoforms of the p53 Gene Family and Their Role in Cancer and Aging：Selection Papers from International p53/p63/p73 Isoforms Workshop)

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19 pages, 3824 KiB

Open AccessArticle

Oncomine™ Comprehensive Assay v3 vs. Oncomine™ Comprehensive Assay Plus

by Lau K. Vestergaard, Douglas N. P. Oliveira, Tim S. Poulsen, Claus K. Høgdall and Estrid V. Høgdall

Cancers 2021, 13(20), 5230; https://doi.org/10.3390/cancers13205230 - 18 Oct 2021

Cited by 20 | Viewed by 4749

Abstract

The usage of next generation sequencing in combination with targeted gene panels has enforced a better understanding of tumor compositions. The identification of key genomic biomarkers underlying a disease are crucial for diagnosis, prognosis, treatment and therapeutic responses. The Oncomine™ Comprehensive Assay v3 [...] Read more.

The usage of next generation sequencing in combination with targeted gene panels has enforced a better understanding of tumor compositions. The identification of key genomic biomarkers underlying a disease are crucial for diagnosis, prognosis, treatment and therapeutic responses. The Oncomine™ Comprehensive Assay v3 (OCAv3) covers 161 cancer-associated genes and is routinely employed to support clinical decision making for a therapeutic course. An improved version, Oncomine™ Comprehensive Assay Plus (OCA-Plus), has been recently developed, covering 501 genes (144 overlapping with OCAv3) in addition to microsatellite instability (MSI) and tumor mutational burden (TMB) assays in one workflow. The validation of MSI and TMB was not addressed in the present study. However, the implementation of new assays must be validated and confirmed across multiple samples before it can be introduced into a clinical setting. Here, we report the comparison of DNA sequencing results from 50 ovarian cancer formalin-fixed, paraffin-embedded samples subjected to OCAv3 and OCA-Plus. A validation assessment of gene mutations identified using OCA-Plus was performed on the 144 overlapping genes and 313,769 intersecting nucleotide positions of the OCAv3 and the OCA-Plus. Our results showed a 91% concordance within variants classified as likely-pathogenic or pathogenic. Moreover, results showed that a region of PTEN is poorly covered by the OCA-Plus assay, hence, we implemented rescue filters for those variants. In conclusion, the OCA-Plus can reflect the mutational profile of genomic variants compared with OCAv3 of 144 overlapping genes, without compromising performance. Full article

(This article belongs to the Special Issue Next Generation Sequencing Application in Cancer Research)

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11 pages, 948 KiB

Open AccessReview

Metabolomic Profiling in Renal Cell Carcinoma Patients: News and Views

by Gaetano Aurilio, Matteo Santoni, Francesco Massari, Alessia Cimadamore, Alessandro Rizzo, Veronica Mollica, Elena Verri, Nicola Battelli and Rodolfo Montironi

Cancers 2021, 13(20), 5229; https://doi.org/10.3390/cancers13205229 - 18 Oct 2021

Cited by 7 | Viewed by 1867

Abstract

Background: We address novelty regarding metabolomic profiling in renal cell carcinoma (RCC) patients, in an attempt to postulate potential treatment strategies. Methods: A large-scale literature search in existing scientific websites focusing on the keywords “renal cell carcinoma”, “clear cell histology”, “papillary histology”, “metabolomic [...] Read more.

Background: We address novelty regarding metabolomic profiling in renal cell carcinoma (RCC) patients, in an attempt to postulate potential treatment strategies. Methods: A large-scale literature search in existing scientific websites focusing on the keywords “renal cell carcinoma”, “clear cell histology”, “papillary histology”, “metabolomic profiling”, and “therapeutics” was performed. Results: The PI3K/Akt signaling pathway is key in clear cell RCC metabolism and accordingly several drugs are presently available for routine use in clinical practice. Along this line, new treatment combinations against PI3K/Akt family members are currently under clinical investigation. On the other hand, new developed targets such as c-Met tyrosine kinase domain, glutathione (GSH) metabolism, and histone deacetylases enzymes (HDAC), as well as therapeutic strategies targeting them are currently being tested in clinical trials and here discussed. Conclusions: In RCC patients, the PI3K/Akt signaling is still the most effective targetable pathway. Targeting other metabolic pathways such as c-Met, GSH, and HDAC appears to be a promising approach and deserve further insights. Full article

(This article belongs to the Section Molecular Cancer Biology)

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15 pages, 20291 KiB

Open AccessArticle

Combining Hypermethylated RASSF1A Detection Using ddPCR with miR-371a-3p Testing: An Improved Panel of Liquid Biopsy Biomarkers for Testicular Germ Cell Tumor Patients

by João Lobo, Lieke M. J. van Zogchel, Mohammed G. Nuru, Ad J. M. Gillis, C. Ellen van der Schoot, Godelieve A. M. Tytgat and Leendert H. J. Looijenga

Cancers 2021, 13(20), 5228; https://doi.org/10.3390/cancers13205228 - 18 Oct 2021

Cited by 17 | Viewed by 2412

Abstract

The classical serum tumor markers used routinely in the management of testicular germ cell tumor (TGCT) patients—alpha fetoprotein (AFP) and human chorionic gonadotropin (HCG)—show important limitations. miR-371a-3p is the most recent promising biomarker for TGCTs, but it is not sufficiently informative for detection [...] Read more.

The classical serum tumor markers used routinely in the management of testicular germ cell tumor (TGCT) patients—alpha fetoprotein (AFP) and human chorionic gonadotropin (HCG)—show important limitations. miR-371a-3p is the most recent promising biomarker for TGCTs, but it is not sufficiently informative for detection of teratoma, which is therapeutically relevant. We aimed to test the feasibility of hypermethylated RASSF1A (RASSF1A_M) detected in circulating cell-free DNA as a non-invasive diagnostic marker of testicular germ cell tumors, combined with miR-371a-3p. A total of 109 serum samples of patients and 29 sera of healthy young adult males were included, along with representative cell lines and tumor tissue samples. We describe a novel droplet digital polymerase chain reaction (ddPCR) method for quantitatively assessing RASSF1A_M in liquid biopsies. Both miR-371a-3p (sensitivity = 85.7%) and RASSF1A_M (sensitivity = 86.7%) outperformed the combination of AFP and HCG (sensitivity = 65.5%) for TGCT diagnosis. RASSF1A_M detected 88% of teratomas. In this representative cohort, 14 cases were negative for miR-371a-3p, all of which were detected by RASSF1A_M, resulting in a combined sensitivity of 100%. We have described a highly sensitive and specific panel of biomarkers for TGCT patients, to be validated in the context of patient follow-up and detection of minimal residual disease. Full article

(This article belongs to the Special Issue Germ Cell Tumors)

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24 pages, 3066 KiB

Open AccessSystematic Review

Natural History and Treatment Strategies of Advanced PEComas: A Systematic Review

by Agathe Bourgmayer, Simon Nannini, Paul Bonjean, Jean-Emmanuel Kurtz, Gabriel G. Malouf and Justine Gantzer

Cancers 2021, 13(20), 5227; https://doi.org/10.3390/cancers13205227 - 18 Oct 2021

Cited by 12 | Viewed by 2739

Abstract

PEComas is a family of rare mesenchymal tumors. This systematic review aims to better understand the natural history of advanced PEComas. After a search on the PubMed database and main oncology meeting libraries according to the PRISMA guidelines, 88 articles reported in the [...] Read more.

PEComas is a family of rare mesenchymal tumors. This systematic review aims to better understand the natural history of advanced PEComas. After a search on the PubMed database and main oncology meeting libraries according to the PRISMA guidelines, 88 articles reported in the English literature were included. Data on clinical and histological features, treatments and outcomes were collected. To identify risk factors, univariate and multivariate analyses were performed. Seven cohorts of patients and 124 individual patients were identified. Focusing on case reports, most patients were metastatic, and the median overall survival (OS) of the entire cohort was 60 months (95%CI 33; NA). Risk factors significantly associated with OS in the multivariate analysis were the presence of metastasis at diagnosis (HR: 2.59, 95%CI 1.06; 6.33, p = 0.036) and the grouped-Bleeker’s risk category (HR: 4.66; 95%CI 1.07; 20.19; p = 0.039). In the metastatic population, only the presence of lymph node metastasis was associated with OS (HR: 3.11; 95%CI 1.13; 8.60, p < 0.05). Due to a lack of events, it was not possible to conclude on other factors. This review of the literature highlights the heterogeneity of literature data and shows the great diversity of clinical management strategies. Full article

(This article belongs to the Special Issue Metastatic Soft-Tissue Sarcomas)

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14 pages, 2623 KiB

Open AccessArticle

Characterization of Microtubule Destabilizing Drugs: A Quantitative Cell-Based Assay That Bridges the Gap between Tubulin Based- and Cytotoxicity Assays

by Marie-Catherine Laisne, Sophie Michallet and Laurence Lafanechère

Cancers 2021, 13(20), 5226; https://doi.org/10.3390/cancers13205226 - 18 Oct 2021

Cited by 7 | Viewed by 2601

Abstract

(1) Background: Microtubule depolymerizing agents (MDAs) are commonly used for cancer treatment. However, the therapeutic use of such microtubule inhibitors is limited by their toxicity and the emergence of resistance. Thus, there is still a sustained effort to develop new MDAs. During the [...] Read more.

(1) Background: Microtubule depolymerizing agents (MDAs) are commonly used for cancer treatment. However, the therapeutic use of such microtubule inhibitors is limited by their toxicity and the emergence of resistance. Thus, there is still a sustained effort to develop new MDAs. During the characterization of such agents, mainly through in vitro analyses using purified tubulin and cytotoxicity assays, quantitative comparisons are mandatory. The relationship between the effect of the drugs on purified tubulin and on cell viability are not always direct. (2) Methods: We have recently developed a cell-based assay that quantifies the cellular microtubule content. In this study, we have conducted a systematic comparative analysis of the effect of four well-characterized MDAs on the kinetics of in vitro tubulin assembly, on the cellular microtubule content (using our recently developed assay) and on cell viability. (3) Conclusions: These assays gave complementary results. Additionally, we found that the drugs’ effect on in vitro tubulin polymerization is not completely predictive of their relative cytotoxicity. Their effect on the cellular microtubule content, however, is closely related to their effect on cell viability. In conclusion, the assay we have recently developed can bridge the gap between in vitro tubulin assays and cell viability assays. Full article

(This article belongs to the Special Issue Microtubule Dynamics and Cancer)

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27 pages, 4446 KiB

Open AccessReview

Currently Used Laboratory Methodologies for Assays Detecting PD-1, PD-L1, PD-L2 and Soluble PD-L1 in Patients with Metastatic Breast Cancer

by Seri Jeong, Nuri Lee, Min-Jeong Park, Kibum Jeon and Wonkeun Song

Cancers 2021, 13(20), 5225; https://doi.org/10.3390/cancers13205225 - 18 Oct 2021

Cited by 10 | Viewed by 2460

Abstract

Approximately 20% of breast cancer (BC) patients suffer from distant metastasis. The incidence and prevalence rates of metastatic BC have increased annually. Immune checkpoint inhibitors are an emerging area of treatment, especially for metastatic patients with poor outcomes. Several antibody drugs have been [...] Read more.

Approximately 20% of breast cancer (BC) patients suffer from distant metastasis. The incidence and prevalence rates of metastatic BC have increased annually. Immune checkpoint inhibitors are an emerging area of treatment, especially for metastatic patients with poor outcomes. Several antibody drugs have been developed and approved for companion testing of the programmed death protine-1 (PD-1) axis. We reviewed currently used laboratory methodologies for assays determining PD-1 axis to provide a comprehensive understanding of principles, advantages, and drawbacks involved in their implementation. The most commonly used method is immunohistochemistry (92.9%) for PD-L1 expression using tissue samples (96.4%). The commonly used anti-PD-L1 antibody clone were commercially available 22C3 (30.8%), SP142 (19.2%), SP263 (15.4%), and E1L3N (11.5%). Enzyme-linked immunosorbent assay and electrochemiluminescent immunoassay that target soluble PD-ligand (L)1 were developed and popularized in 2019–2021, in contrast to 2016–2018. Easy accessibility and non-invasiveness due to the use of blood samples, quantitative outputs, and relatively rapid turnaround times make them more preferable. Regarding scoring methods, a combination of tumor and immune cells (45.5% in 2016–2018 to 57.1% in 2019–2021) rather than each cell alone became more popular. Information about antibody clones, platforms, scoring methods, and related companion drugs is recommended for reporting PD-L1 expression. Full article

(This article belongs to the Special Issue Metastatic Breast Cancers)

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17 pages, 2618 KiB

Open AccessReview

Role of Pancreatic Stellate Cell-Derived Exosomes in Pancreatic Cancer-Related Diabetes: A Novel Hypothesis

by Chamini J. Perera, Marco Falasca, Suresh T. Chari, Jerry R. Greenfield, Zhihong Xu, Romano C. Pirola, Jeremy S. Wilson and Minoti V. Apte

Cancers 2021, 13(20), 5224; https://doi.org/10.3390/cancers13205224 - 18 Oct 2021

Cited by 11 | Viewed by 3098

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating condition characterised by vague symptomatology and delayed diagnosis. About 30% of PDAC patients report a history of new onset diabetes, usually diagnosed within 3 years prior to the diagnosis of cancer. Thus, new onset diabetes, which [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating condition characterised by vague symptomatology and delayed diagnosis. About 30% of PDAC patients report a history of new onset diabetes, usually diagnosed within 3 years prior to the diagnosis of cancer. Thus, new onset diabetes, which is also known as pancreatic cancer-related diabetes (PCRD), could be a harbinger of PDAC. Diabetes is driven by progressive β cell loss/dysfunction and insulin resistance, two key features that are also found in PCRD. Experimental studies suggest that PDAC cell-derived exosomes carry factors that are detrimental to β cell function and insulin sensitivity. However, the role of stromal cells, particularly pancreatic stellate cells (PSCs), in the pathogenesis of PCRD is not known. PSCs are present around the earliest neoplastic lesions and around islets. Given that PSCs interact closely with cancer cells to drive cancer progression, it is possible that exosomal cargo from both cancer cells and PSCs plays a role in modulating β cell function and peripheral insulin resistance. Identification of such mediators may help elucidate the mechanisms of PCRD and aid early detection of PDAC. This paper discusses the concept of a novel role of PSCs in the pathogenesis of PCRD. Full article

(This article belongs to the Special Issue Pancreatic Cancer: Pathogenesis, Early Diagnosis, and Management for Improved Survival)

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13 pages, 767 KiB

Open AccessReview

Primary Mediastinal and Testicular Germ Cell Tumors in Adolescents and Adults: A Comparison of Genomic Alterations and Clinical Implications

by Milena Urbini, Giuseppe Schepisi, Sara Bleve, Alessandra Virga, Caterina Gianni, Giorgia Gurioli, Paola Ulivi and Ugo De Giorgi

Cancers 2021, 13(20), 5223; https://doi.org/10.3390/cancers13205223 - 18 Oct 2021

Cited by 8 | Viewed by 2493

Abstract

Mediastinal germ cell tumors (MGCTs) share histologic, molecular and biomarkers features with testicular GCTs; however, nonseminomatous MGCTs are usually more aggressive and have poorer prognosis than nonseminomatous TGCTs. Most nonseminomatous MGCT cases show early resistance to platinum-based therapies and seldom have been associated [...] Read more.

Mediastinal germ cell tumors (MGCTs) share histologic, molecular and biomarkers features with testicular GCTs; however, nonseminomatous MGCTs are usually more aggressive and have poorer prognosis than nonseminomatous TGCTs. Most nonseminomatous MGCT cases show early resistance to platinum-based therapies and seldom have been associated with the onset of one or more concomitant somatic malignancies, in particular myeloid neoplasms with recent findings supporting a common, shared genetic precursor with the primary MGCT. Genomic, transcriptomic and epigenetic features of testicular GCTs have been extensively studied, allowing for the understanding of GCT development and transformation of seminomatous and nonseminomatous histologies. However, MGCTs are still lacking proper multi-omics analysis and only few data are reported in the literature. Understanding of the mechanism involved in the development, in the progression and in their higher resistance to common therapies is still poorly understood. With this review, we aim to collect all molecular findings reported in this rare disease, resuming the similarities and disparities with the gonadal counterparts. Full article

(This article belongs to the Special Issue Mediastinal and Central Nervous System Germ Cell Tumors)

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19 pages, 1138 KiB

Open AccessPerspective

FDG-PET/CT in Lymphoma: Where Do We Go Now?

by Yassine Al Tabaa, Clement Bailly and Salim Kanoun

Cancers 2021, 13(20), 5222; https://doi.org/10.3390/cancers13205222 - 18 Oct 2021

Cited by 13 | Viewed by 3887

Abstract

18F-fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG-PET/CT) is an essential part of the management of patients with lymphoma at staging and response evaluation. Efforts to standardize PET acquisition and reporting, including the 5-point Deauville scale, have enabled PET to become a [...] Read more.

18F-fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG-PET/CT) is an essential part of the management of patients with lymphoma at staging and response evaluation. Efforts to standardize PET acquisition and reporting, including the 5-point Deauville scale, have enabled PET to become a surrogate for treatment success or failure in common lymphoma subtypes. This review summarizes the key clinical-trial evidence that supports PET-directed personalized approaches in lymphoma but also points out the potential place of innovative PET/CT metrics or new radiopharmaceuticals in the future. Full article

(This article belongs to the Section Cancer Survivorship and Quality of Life)

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