Cancers

27 pages, 2210 KiB

Open AccessReview

The Regulatory Functions of Circular RNAs in Digestive System Cancers

by Xiao Yuan, Ya Yuan, Zhi He, Diyan Li, Bo Zeng, Qingyong Ni, Mingyao Yang and Deying Yang

Cancers 2020, 12(3), 770; https://doi.org/10.3390/cancers12030770 - 24 Mar 2020

Cited by 20 | Viewed by 4421

Abstract

Circular ribonucleic acids (circRNAs), which are a type of covalently closed circular RNA, are receiving increasing attention. An increasing amount of evidence suggests that circRNAs are involved in the biogenesis and development of multiple diseases such as digestive system cancers. Dysregulated circRNAs have [...] Read more.

Circular ribonucleic acids (circRNAs), which are a type of covalently closed circular RNA, are receiving increasing attention. An increasing amount of evidence suggests that circRNAs are involved in the biogenesis and development of multiple diseases such as digestive system cancers. Dysregulated circRNAs have been found to act as oncogenes or tumour suppressors in digestive system cancers. Moreover, circRNAs are related to ageing and a wide variety of processes in tumour cells, such as cell apoptosis, invasion, migration, and proliferation. Moreover, circRNAs can perform a remarkable multitude of biological functions, such as regulating splicing or transcription, binding RNA-binding proteins to enable function, acting as microRNA (miRNA) sponges, and undergoing translated into proteins. However, in digestive system cancers, circRNAs function mainly as miRNA sponges. Herein, we summarise the latest research progress on biological functions of circRNAs in digestive system cancers. This review serves as a synopsis of potential therapeutic targets and biological markers for digestive system cancer. Full article

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18 pages, 3883 KiB

Open AccessArticle

Accessing a New Dimension in TP53 Biology: Multiplex Long Amplicon Digital PCR to Specifically Detect and Quantitate Individual TP53 Transcripts

by Annette Lasham, Peter Tsai, Sandra J. Fitzgerald, Sunali Y. Mehta, Nicholas S. Knowlton, Antony W. Braithwaite and Cristin G. Print

Cancers 2020, 12(3), 769; https://doi.org/10.3390/cancers12030769 - 24 Mar 2020

Cited by 9 | Viewed by 4910

Abstract

TP53, the most commonly-mutated gene in cancer, undergoes complex alternative splicing. Different TP53 transcripts play different biological roles, both in normal function and in the progression of diseases such as cancer. The study of TP53’s alternative RNA splice forms and their use [...] Read more.

TP53, the most commonly-mutated gene in cancer, undergoes complex alternative splicing. Different TP53 transcripts play different biological roles, both in normal function and in the progression of diseases such as cancer. The study of TP53’s alternative RNA splice forms and their use as clinical biomarkers has been hampered by limited specificity and quantitative accuracy of current methods. TP53 RNA splice variants differ at both 5’ and 3’ ends, but because they have a common central region of 618 bp, the individual TP53 transcripts are impossible to specifically detect and precisely quantitate using standard PCR-based methods or short-read RNA sequencing. Therefore, we devised multiplex probe-based long amplicon droplet digital PCR (ddPCR) assays, which for the first time allow precise end-to-end quantitation of the seven major TP53 transcripts, with amplicons ranging from 0.85 to 1.85 kb. Multiple modifications to standard ddPCR assay procedures were required to enable specific co-amplification of these long transcripts and to overcome issues with secondary structure. Using these assays, we show that several TP53 transcripts are co-expressed in breast cancers, and illustrate the potential for this method to identify novel TP53 transcripts in tumour cells. This capability will facilitate a new level of biological and clinical understanding of the alternatively-spliced TP53 isoforms. 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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14 pages, 862 KiB

Open AccessArticle

30 Years of Experience in the Management of Stage III and IV Epithelial Ovarian Cancer: Impact of Surgical Strategies on Survival

by Berenice Delga, Jean-Marc Classe, Gilles Houvenaeghel, Guillaume Blache, Laura Sabiani, Houssein El Hajj, Nicole Andrieux and Eric Lambaudie

Cancers 2020, 12(3), 768; https://doi.org/10.3390/cancers12030768 - 24 Mar 2020

Cited by 22 | Viewed by 4089

Abstract

Objective: to analyze the evolution of surgical techniques and strategies, and to determine their influence on the survival of patients with stage III or IV epithelial ovarian cancer (EOC). Methods: a retrospective data analysis was performed in two French tertiary cancer [...] Read more.

Objective: to analyze the evolution of surgical techniques and strategies, and to determine their influence on the survival of patients with stage III or IV epithelial ovarian cancer (EOC). Methods: a retrospective data analysis was performed in two French tertiary cancer institutes. The analysis included clinical information, cytoreductive outcome (complete, optimal and suboptimal), definitive pathology, Overall Survival (OS), and Progression-Free Survival (PFS). Three surgical strategies were compared: Primary Cytoreductive Surgery (PCS), Interval Cytoreductive Surgery (ICS) after three cycles of Neo-Adjuvant Chemotherapy (NAC), and Final Cytoreductive Surgery (FCS) after at least six cycles of NAC. We analyzed four distinct time intervals: prior to 2000, between 2000 and 2004, between 2005 and 2009, and after 2009. Results: data from 1474 patients managed for International Federation of Gynecology and Obstetrics (FIGO) stages III (80%) or IV (20%) EOC were analyzed. Throughout the four time intervals, the rate of patients who were treated only medically increased significantly (10.1% vs. 22.6% p < 0.001). NAC treatment increased from 20.1% to 52.2% (p < 0.001). Complete resection rate increased from 37% to 66.2% (p < 0.001). Of our study population, 1260 patients (85.5%) underwent surgery. OS was longer in cases of complete cytoreduction (Hazard Ratio (HR) = 2.123 CI 95% [1.816–2.481] p < 0.001) but the surgical strategy itself did not affect median OS. OS was 44.9 months, 50.3 months, and 42 months for PCS, ICS, and FCS, respectively (p = 0.410). After adjusting for surgical strategies (PCS, ICS, and FCS), all patients with complete cytoreduction presented similar OS with no significant difference. However, PFS was three months shorter when FCS was compared to PCS (p < 0.001). Conclusion: In our 30 years’ experience of EOC management, complete resection rate was the only independent factor that significantly improved OS and PFS, regardless of the surgical strategy. Full article

(This article belongs to the Special Issue Preclinical and Clinical Advances in Ovarian Cancer)

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23 pages, 3142 KiB

Open AccessPerspective

Protein Expression in Metastatic Melanoma and the Link to Disease Presentation in a Range of Tumor Phenotypes

by Yonghyo Kim, Jeovanis Gil, Indira Pla, Aniel Sanchez, Lazaro Hiram Betancourt, Boram Lee, Roger Appelqvist, Christian Ingvar, Lotta Lundgren, Håkan Olsson, Bo Baldetorp, Ho Jeong Kwon, Henriett Oskolás, Melinda Rezeli, Viktoria Doma, Sarolta Kárpáti, A. Marcell Szasz, István Balázs Németh, Johan Malm and György Marko-Varga

Cancers 2020, 12(3), 767; https://doi.org/10.3390/cancers12030767 - 24 Mar 2020

Cited by 3 | Viewed by 5159

Abstract

Malignant melanoma is among the most aggressive skin cancers and it has among the highest metastatic potentials. Although surgery to remove the primary tumor is the gold standard treatment, once melanoma progresses and metastasizes to the lymph nodes and distal organs, i.e., metastatic [...] Read more.

Malignant melanoma is among the most aggressive skin cancers and it has among the highest metastatic potentials. Although surgery to remove the primary tumor is the gold standard treatment, once melanoma progresses and metastasizes to the lymph nodes and distal organs, i.e., metastatic melanoma (MM), the usual outcome is decreased survival. To improve survival rates and life span, advanced treatments have focused on the success of targeted therapies in the MAPK pathway that are based on BRAF (BRAF V600E) and MEK. The majority of patients with tumors that have higher expression of BRAF V600E show poorer prognosis than patients with a lower level of the mutated protein. Based on the molecular basis of melanoma, these findings are supported by distinct tumor phenotypes determined from differences in tumor heterogeneity and protein expression profiles. With these aspects in mind, continued challenges are to: (1) deconvolute the complexity and heterogeneity of MM; (2) identify the signaling pathways involved; and (3) determine protein expression to develop targeted therapies. Here, we provide an overview of the results from protein expression in MM and the link to disease presentation in a variety of tumor phenotypes and how these will overcome the challenges of clinical problems and suggest new promising approaches in metastatic melanoma and cancer therapy. Full article

(This article belongs to the Special Issue The Cancer Proteome)

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22 pages, 3623 KiB

Open AccessArticle

Inhibiting WNT Ligand Production for Improved Immune Recognition in the Ovarian Tumor Microenvironment

by Whitney N. Goldsberry, Selene Meza-Perez, Angelina I. Londoño, Ashwini A. Katre, Bryan T. Mott, Brandon M. Roane, Nidhi Goel, Jaclyn A. Wall, Sara J. Cooper, Lyse A. Norian, Troy D. Randall, Michael J. Birrer and Rebecca C. Arend

Cancers 2020, 12(3), 766; https://doi.org/10.3390/cancers12030766 - 24 Mar 2020

Cited by 19 | Viewed by 4928

Abstract

In ovarian cancer, upregulation of the Wnt/β–catenin pathway leads to chemoresistance and correlates with T cell exclusion from the tumor microenvironment (TME). Our objectives were to validate these findings in an independent cohort of ovarian cancer subjects and determine whether inhibiting the Wnt [...] Read more.

In ovarian cancer, upregulation of the Wnt/β–catenin pathway leads to chemoresistance and correlates with T cell exclusion from the tumor microenvironment (TME). Our objectives were to validate these findings in an independent cohort of ovarian cancer subjects and determine whether inhibiting the Wnt pathway in a syngeneic ovarian cancer murine model could create a more T-cell-inflamed TME, which would lead to decreased tumor growth and improved survival. We preformed RNA sequencing in a cohort of human high grade serous ovarian carcinoma subjects. We used CGX1321, an inhibitor to the porcupine (PORCN) enzyme that is necessary for secretion of WNT ligand, in mice with established ID8 tumors, a murine ovarian cancer cell line. In order to investigate the effect of decreased Wnt/β–catenin pathway activity in the dendritic cells (DCs), we injected ID8 cells in mice that lacked β–catenin specifically in DCs. Furthermore, to understand how much the effects of blocking the Wnt/β–catenin pathway are dependent on CD8⁺ T cells, we injected ID8 cells into mice with CD8⁺ T cell depletion. We confirmed a negative correlation between Wnt activity and T cell signature in our cohort. Decreasing WNT ligand production resulted in increases in T cell, macrophage and dendritic cell functions, decreased tumor burden and improved survival. Reduced tumor growth was found in mice that lacked β–catenin specifically in DCs. When CD8⁺ T cells were depleted, CGX1321 treatment did not have the same magnitude of effect on tumor growth. Our investigation confirmed an increase in Wnt activity correlated with a decreased T-cell-inflamed environment; a relationship that was further supported in our pre-clinical model that suggests inhibiting the Wnt/β–catenin pathway was associated with decreased tumor growth and improved survival via a partial dependence on CD8⁺ T cells. Full article

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

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Graphical abstract

17 pages, 2324 KiB

Open AccessReview

Nonsense-Mediated mRNA Decay: Pathologies and the Potential for Novel Therapeutics

by Kamila Pawlicka, Umesh Kalathiya and Javier Alfaro

Cancers 2020, 12(3), 765; https://doi.org/10.3390/cancers12030765 - 24 Mar 2020

Cited by 35 | Viewed by 7928

Abstract

Nonsense-mediated messenger RNA (mRNA) decay (NMD) is a surveillance pathway used by cells to control the quality mRNAs and to fine-tune transcript abundance. NMD plays an important role in cell cycle regulation, cell viability, DNA damage response, while also serving as a barrier [...] Read more.

Nonsense-mediated messenger RNA (mRNA) decay (NMD) is a surveillance pathway used by cells to control the quality mRNAs and to fine-tune transcript abundance. NMD plays an important role in cell cycle regulation, cell viability, DNA damage response, while also serving as a barrier to virus infection. Disturbance of this control mechanism caused by genetic mutations or dys-regulation of the NMD pathway can lead to pathologies, including neurological disorders, immune diseases and cancers. The role of NMD in cancer development is complex, acting as both a promoter and a barrier to tumour progression. Cancer cells can exploit NMD for the downregulation of key tumour suppressor genes, or tumours adjust NMD activity to adapt to an aggressive immune microenvironment. The latter case might provide an avenue for therapeutic intervention as NMD inhibition has been shown to lead to the production of neoantigens that stimulate an immune system attack on tumours. For this reason, understanding the biology and co-option pathways of NMD is important for the development of novel therapeutic agents. Inhibitors, whose design can make use of the many structures available for NMD study, will play a crucial role in characterizing and providing diverse therapeutic options for this pathway in cancer and other diseases. Full article

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

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25 pages, 2612 KiB

Open AccessArticle

Global DNA Hypomethylation in Epithelial Ovarian Cancer: Passive Demethylation and Association with Genomic Instability

by Wa Zhang, David Klinkebiel, Carter J. Barger, Sanjit Pandey, Chittibabu Guda, Austin Miller, Stacey N. Akers, Kunle Odunsi and Adam R. Karpf

Cancers 2020, 12(3), 764; https://doi.org/10.3390/cancers12030764 - 24 Mar 2020

Cited by 51 | Viewed by 6758

Abstract

A hallmark of human cancer is global DNA hypomethylation (GDHO), but the mechanisms accounting for this defect and its pathological consequences have not been investigated in human epithelial ovarian cancer (EOC). In EOC, GDHO was associated with advanced disease and reduced overall and [...] Read more.

A hallmark of human cancer is global DNA hypomethylation (GDHO), but the mechanisms accounting for this defect and its pathological consequences have not been investigated in human epithelial ovarian cancer (EOC). In EOC, GDHO was associated with advanced disease and reduced overall and disease-free survival. GDHO (+) EOC tumors displayed a proliferative gene expression signature, including FOXM1 and CCNE1 overexpression. Furthermore, DNA hypomethylation in these tumors was enriched within genomic blocks (hypomethylated blocks) that overlapped late-replicating regions, lamina-associated domains, PRC2 binding sites, and the H3K27me3 histone mark. Increased proliferation coupled with hypomethylated blocks at late-replicating regions suggests a passive hypomethylation mechanism. This hypothesis was further supported by our observation that cytosine DNA methyltransferases (DNMTs) and UHRF1 showed significantly reduced expression in GDHO (+) EOC after normalization to canonical proliferation markers, including MKI67. Finally, GDHO (+) EOC tumors had elevated chromosomal instability (CIN), and copy number alterations (CNA) were enriched at the DNA hypomethylated blocks. Together, these findings implicate a passive DNA demethylation mechanism in ovarian cancer that is associated with genomic instability and poor prognosis. Full article

(This article belongs to the Special Issue Epigenomic Studies of Gynecological Cancer)

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12 pages, 2700 KiB

Open AccessArticle

Pure Large Nested Variant of Urothelial Carcinoma (LNUC) Is the Prototype of an FGFR3 Mutated Aggressive Urothelial Carcinoma with Luminal-Papillary Phenotype

by Veronika Weyerer, Markus Eckstein, Eva Compérat, Hendrik Juette, Nadine T. Gaisa, Yves Allory, Robert Stöhr, Bernd Wullich, Morgan Rouprêt, Arndt Hartmann and Simone Bertz

Cancers 2020, 12(3), 763; https://doi.org/10.3390/cancers12030763 - 24 Mar 2020

Cited by 27 | Viewed by 3938

Abstract

Since 2016, large nested urothelial carcinoma (LNUC) has been included within the WHO classification of urothelial tumors. Limited reports with mainly small case series have confirmed the malignant behavior of LNUC despite its bland morphological appearance. We evaluated, for the first time, markers [...] Read more.

Since 2016, large nested urothelial carcinoma (LNUC) has been included within the WHO classification of urothelial tumors. Limited reports with mainly small case series have confirmed the malignant behavior of LNUC despite its bland morphological appearance. We evaluated, for the first time, markers for new immunooncological or targeted therapies including FGFR3 mutational status and PD-L1 status, the frequency of TERT-promoter mutations and the molecular subtype in a cohort of 25 LNUC using SNaPshot analysis and immunohistochemistry. Of the 25 cases, 17 were pure LNUC, with 13 showing an additional exophytic papillary/papillary-like component. Seven mixed LNUCs presented areas of classical nested variant urothelial carcinoma (NVUC) and one showed a component of conventional urothelial carcinoma. Of the 17 evaluable pure LNUCs, 16 were FGFR3-mutated with identical mutations in their concomitant papillary/papillary-like components. An FGFR3 mutation was found in 1/7 evaluable mixed LNUCs combined with NVUC. TERT-promoter mutations were detected in 86.7% pure and 83.3% mixed tumors. Immunohistochemistry revealed a luminal phenotype; PD-L1 was negative in the majority of tumor cells and tumor-associated immune cells. Pure LNUC is a prime example of a luminal, FGFR3-mutated, mostly PD-L1-negative tumor. In contrast, FGFR3 mutations seem to be rare in mixed LNUC, which may indicate a different pathway of tumor development. Full article

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

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15 pages, 725 KiB

Open AccessArticle

Proposed Modification of Staging for Distal Cholangiocarcinoma Based on the Lymph Node Ratio Using Korean Multicenter Database

by Yunghun You, Yong Chan Shin, Dong Wook Choi, Jin Seok Heo, Sang Hyun Shin, Naru Kim, Kee-Taek Jang, Hongbeom Kim, Chang-Sup Lim, Sun Hee Chang, Kang Min Han and In Woong Han

Cancers 2020, 12(3), 762; https://doi.org/10.3390/cancers12030762 - 24 Mar 2020

Cited by 11 | Viewed by 2894

Abstract

The 8th American Joint Committee on Cancer (AJCC) staging system for distal cholangiocarcinoma (DCC) included a positive lymph node count (PLNC), but a comparison of the prognostic predictive power of PLNC and lymph node ratio (LNR) is still under debate. This study aimed [...] Read more.

The 8th American Joint Committee on Cancer (AJCC) staging system for distal cholangiocarcinoma (DCC) included a positive lymph node count (PLNC), but a comparison of the prognostic predictive power of PLNC and lymph node ratio (LNR) is still under debate. This study aimed to compare various staging models made by combining the abovementioned factors, identify the model with the best predictive power, and propose a modified staging system. We retrospectively reviewed 251 patients who underwent surgery for DCC at four centers. To determine the superiority of various staging models for predicting overall OSR, Akaike information criterion (AIC), Bayesian information criterion (BIC), AIC correction (AICc), and Harrell’s C-statistic were calculated. In multivariate analysis, age (p = 0.003), total lymph node count (p = 0.033), and revised T(LNR)M staging (p < 0.001) were identified as independent factors for overall survival rate. The predictive performance of revised T (LNR) M staging (AIC: 1288.925, BIC: 1303.377, AICc: 1291.52, and Harrell’s C statics: 0.667) was superior to other staging system. A modified staging system consisting of revised T category and LNR predicted better overall survival of DCC than AJCC 7th and AJCC 8th editions. In the future, external validation of the proposed new system using a larger cohort will be required. Full article

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11 pages, 2305 KiB

Open AccessArticle

Extended Texture Analysis of Non-Enhanced Whole-Body MRI Image Data for Response Assessment in Multiple Myeloma Patients Undergoing Systemic Therapy

by Kaspar Ekert, Clemens Hinterleitner, Karolin Baumgartner, Jan Fritz and Marius Horger

Cancers 2020, 12(3), 761; https://doi.org/10.3390/cancers12030761 - 24 Mar 2020

Cited by 39 | Viewed by 4018

Abstract

Identifying MRI-based radiomics features capable to assess response to systemic treatment in multiple myeloma (MM) patients. Retrospective analysis of whole-body MR-image data in 67 consecutive stage III MM patients (40 men; mean age, 60.4 years). Bone marrow involvement was evaluated using a standardized [...] Read more.

Identifying MRI-based radiomics features capable to assess response to systemic treatment in multiple myeloma (MM) patients. Retrospective analysis of whole-body MR-image data in 67 consecutive stage III MM patients (40 men; mean age, 60.4 years). Bone marrow involvement was evaluated using a standardized MR-imaging protocol consisting of T1w-, short-tau inversion recovery- (STIR-) and diffusion-weighted-imaging (DWI) sequences. Ninety-two radiomics features were evaluated, both in focally and diffusely involved bone marrow. Volumes of interest (VOI) were used. Response to treatment was classified according to International Myeloma Working Group (IMWG) criteria in complete response (CR), very-good and/or partial response (VGPR + PR), and non-response (stable disease (SD) and progressive disease (PD)). According to the IMWG-criteria, response categories were CR (n = 35), VGPR + PR (n = 19), and non-responders (n = 13). On apparent diffusion coefficient (ADC)-maps, gray-level small size matrix small area emphasis (Gray Level Size Zone (GLSZM) small area emphasis (SAE)) significantly correlated with CR (p < 0.001), whereas GLSZM non-uniformity normalized (NUN) significantly (p < 0.008) with VGPR/PR in focal medullary lesions (FL), whereas in diffuse involvement, 1st order root mean squared significantly (p < 0.001) correlated with CR, whereas for VGPR/PR Log (gray-level run-length matrix (GLRLM) Short Run High Gray Level Emphasis) proved significant (p < 0.003). On T1w, GLRLM NUN significantly (p < 0.002) correlated with CR in FL, whereas gray-level co-occurrence matric (GLCM) informational measure of correlation (Imc1) significantly (p < 0.04) correlated with VGPR/PR. For diffuse myeloma involvement, neighboring gray-tone difference matrix (NGTDM) contrast and 1st order skewness were significantly associated with CR and VGPR/PR (p < 0.001 for both). On STIR-images, CR correlated with gray-level co-occurrence matrix (GLCM) Informational Measure of Correlation (IMC) 1 (p < 0.001) in FL and 1st order mean absolute deviation in diffusely involved bone marrow (p < 0.001). VGPR/PR correlated at best in FL with GSZLM size zone NUN (p < 0.019) and in all other involved medullary areas with GLSZM large area low gray level emphasis (p < 0.001). GLSZM large area low gray level emphasis also significantly correlated with the degree of bone marrow infiltration assessed histologically (p = 0.006). GLCM IMC 1 proved significant throughout T1w/STIR sequences, whereas GLSZM NUN in STIR and ADC. MRI-based texture features proved significant to assess clinical and hematological response (CR, VPGR, and PR) in multiple myeloma patients undergoing systemic treatment. Full article

(This article belongs to the Special Issue Radiomics and Cancers)

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18 pages, 2752 KiB

Open AccessArticle

CRIPTO and miR-371a-3p Are Serum Biomarkers of Testicular Germ Cell Tumors and Are Detected in Seminal Plasma from Azoospermic Males

by Cassy M. Spiller, João Lobo, Willem P. A. Boellaard, Ad J. M. Gillis, Josephine Bowles and Leendert H. J. Looijenga

Cancers 2020, 12(3), 760; https://doi.org/10.3390/cancers12030760 - 23 Mar 2020

Cited by 7 | Viewed by 3118

Abstract

miR-371a-3p is currently the most informative reported biomarker for germ cell tumors (GCTs). Another developmental-related biomarker, CRIPTO, is involved in the regulation of pluripotency and germ cell fate commitment. We aimed to assess the value of CRIPTO as a diagnostic and prognostic biomarker [...] Read more.

miR-371a-3p is currently the most informative reported biomarker for germ cell tumors (GCTs). Another developmental-related biomarker, CRIPTO, is involved in the regulation of pluripotency and germ cell fate commitment. We aimed to assess the value of CRIPTO as a diagnostic and prognostic biomarker of testicular GCTs (TGCTs) and also to assess its presence in seminal plasma samples, compared with miR-371a-3p. In total, 217 and 94 serum/seminal plasma samples were analyzed. CRIPTO was quantified using ELISA and miR-371a-3p using bead-based isolation followed by RT-qPCR. Methylation profiling (EPIC array) for the CRIPTO promoter region was undertaken in 35 TGCT tissues plus four (T)GCT cell lines. Significantly higher CRIPTO concentration was found in sera of non-seminomas compared to controls (p = 0.0297), and in stage II/III disease compared to stage I (p = 0.0052, p = 0.0097). CRIPTO concentration was significantly positively correlated with miR-371a-3p levels in serum (r = 0.16) and seminal plasma (r = 0.40). CRIPTO/miR-371a-3p levels were significantly higher in seminal plasma controls when compared to serum controls (p = 0.0001, p < 0.0001). CRIPTO/miR-371a-3p were detected both in normospermic and azoospermic males, and levels were higher in TGCTs compared to GCNIS-only. We have provided the largest dataset of evaluation of CRIPTO in serum and seminal plasma of GCTs, showing its potential value as a biomarker of the disease. Full article

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

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Graphical abstract

16 pages, 1716 KiB

Open AccessArticle

Evaluation of Circulating miRNA Biomarkers of Testicular Germ Cell Tumors during Therapy and Follow-up―A Copenhagen Experience

by Nina Mørup, Ewa Rajpert-De Meyts, Anders Juul, Gedske Daugaard and Kristian Almstrup

Cancers 2020, 12(3), 759; https://doi.org/10.3390/cancers12030759 - 23 Mar 2020

Cited by 19 | Viewed by 3528

Abstract

New microRNA-based serum biomarkers (miRNA-367-3p, -371a-3p, -372-3p, and -373-3p) have shown great potential for the detection of testicular germ cell tumors (TGCTs), but few studies have investigated the clinical utility and performance of these tests in treatment monitoring. In this study, circulating miRNA [...] Read more.

New microRNA-based serum biomarkers (miRNA-367-3p, -371a-3p, -372-3p, and -373-3p) have shown great potential for the detection of testicular germ cell tumors (TGCTs), but few studies have investigated the clinical utility and performance of these tests in treatment monitoring. In this study, circulating miRNA levels were measured, together with serum tumor markers alpha-fetoprotein (AFP), β-subunit of human chorionic gonadotropin (β-HCG) and lactate dehydrogenase (LDH) in 406 consecutive blood samples obtained during the treatment and follow-up of 52 TGCT patients at the Copenhagen University Hospital. After testing three different methods of RNA isolation from peripheral blood and PCR quantification in a subset of samples (n = 15), the best performing setup of targeted isolation of miRNAs inside and outside exosomes was selected to analyze all samples. At primary diagnosis, the miRNAs significantly outperformed the serum tumor markers, with a sensitivity and specificity of 78% and 100% (based on 40 patients), respectively. The picture was not as clear when patient trajectories were investigated, with both positive and negative signals for miRNAs and serum tumor markers. To establish whether measuring miRNAs adds value beyond the primary diagnosis, large prospective clinical trials comparing miRNAs and classical tumor markers during the treatment and follow-up of TGCT patients are needed. Full article

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

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18 pages, 4338 KiB

Open AccessArticle

MeCP2 Promotes Colorectal Cancer Metastasis by Modulating ZEB1 Transcription

by Dan Luo and Wei Ge

Cancers 2020, 12(3), 758; https://doi.org/10.3390/cancers12030758 - 23 Mar 2020

Cited by 23 | Viewed by 4160

Abstract

Background: Recurrence and distant organ metastasis is a major cause of death in colorectal cancer (CRC); however, the underlying molecular mechanisms regulating this phenomenon are poorly understood. MeCP2 is a key epigenetic regulator and is amplified in many types of cancer. Its [...] Read more.

Background: Recurrence and distant organ metastasis is a major cause of death in colorectal cancer (CRC); however, the underlying molecular mechanisms regulating this phenomenon are poorly understood. MeCP2 is a key epigenetic regulator and is amplified in many types of cancer. Its role in CRC and the molecular mechanisms underlying its action remain unknown. Methods: We used western blot and immunohistochemistry to detect MeCP2 expression in CRC tissues, and then investigated its biological functions in vitro and in vivo. Chromatin immunoprecipitation, co-immunoprecipitation, and electrophoretic mobility shift assays were used to detect the associations among MeCP2 (Methyl-CpG binding protein 2), SPI1 (Spi-1 Proto-Oncogene), and ZEB1 (Zinc Finger E-Box Binding Homeobox 1). Results: Using the Cancer Genome Atlas and Oncomine databases, we found MeCP2 expression was upregulated in CRC tissues and this upregulation was related to poor prognosis. Meanwhile, MeCP2 depletion (KO/KD) in CRC cells significantly inhibited stem cell frequency, and invasion and migration ability in vitro, and suppressed CRC metastasis in vivo. Mechanistically, we show MeCP2 binds to the transcription factor SPI1, and aids its recruitment to the ZEB1 promoter. SPI1 then facilitates ZEB1 expression at the transcription level. In turn, ZEB1 induces the expression of MMP14, CD133, and SOX2, thereby maintaining CRC stemness and metastasis. Conclusions: MeCP2 is a novel regulator of CRC metastasis. MeCP2 suppression may be a promising therapeutic strategy in CRC. Full article

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9 pages, 1383 KiB

Open AccessArticle

LRRC15 Targeting in Soft-Tissue Sarcomas: Biological and Clinical Implications

by Eytan Ben-Ami, Raul Perret, Ying Huang, Félicie Courgeon, Prafulla C. Gokhale, Audrey Laroche-Clary, Benjamin K. Eschle, Valérie Velasco, François Le Loarer, Marie-Paule Algeo, James Purcell, George D. Demetri and Antoine Italiano

Cancers 2020, 12(3), 757; https://doi.org/10.3390/cancers12030757 - 23 Mar 2020

Cited by 17 | Viewed by 6624

Abstract

Background: LRRC15 is a member of the LRR (leucine-rich repeat) superfamily present on tumor-associated fibroblasts (CAFs) and stromal cells. The expression of LRRC15 is upregulated by the pro-inflammatory cytokine TGFβ. ABBV-085 is a monomethyl auristatin E (MMAE)-containing antibody-drug conjugate (ADC) designed to target [...] Read more.

Background: LRRC15 is a member of the LRR (leucine-rich repeat) superfamily present on tumor-associated fibroblasts (CAFs) and stromal cells. The expression of LRRC15 is upregulated by the pro-inflammatory cytokine TGFβ. ABBV-085 is a monomethyl auristatin E (MMAE)-containing antibody-drug conjugate (ADC) designed to target LRRC15, and which has shown significant anti-tumor activity in several tumor models. This is the first focused examination of LRRC15 expression and ABBV-085 activity in soft-tissue sarcomas (STS). Methods: We analyzed the LRRC15 expression profile by immunohistochemistry in 711 STS cases, covering a broad spectrum of STS histologies and sub-classifications. In vivo experiments were carried out by using LRRC15-positive and LRRC15-negative patient-derived xenograft (PDX) models of STS. Results: In contrast to patterns observed in epithelial tumors, LRRC15 was expressed not only by stromal cells but also by cancer cells in multiple subsets of STS with significant variations noted between histological subtypes. Overexpression of LRRC15 is positively correlated with grade and independently associated with adverse outcome. ABBV-085 has robust preclinical efficacy against LRRC15 positive STS patient-derived xenograft (PDX) models. Conclusion: We provide the first preclinical evidence that LRRC15 targeting with an antibody-drug conjugate is a promising strategy in LRRC15-positive STS. ABBV-085 is being evaluated in an ongoing clinical trial in STS and other malignancies. Full article

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25 pages, 3566 KiB

Open AccessArticle

Analysis of Dual Class I Histone Deacetylase and Lysine Demethylase Inhibitor Domatinostat (4SC-202) on Growth and Cellular and Genomic Landscape of Atypical Teratoid/Rhabdoid

by Mariah M. Hoffman, Jessica S. Zylla, Somshuvra Bhattacharya, Kristin Calar, Timothy W. Hartman, Ratan D. Bhardwaj, W. Keith Miskimins, Pilar de la Puente, Etienne Z. Gnimpieba and Shanta M. Messerli

Cancers 2020, 12(3), 756; https://doi.org/10.3390/cancers12030756 - 23 Mar 2020

Cited by 27 | Viewed by 5268

Abstract

Central nervous system atypical teratoid/rhabdoid tumors (ATRTs) are rare and aggressive tumors with a very poor prognosis. Current treatments for ATRT include resection of the tumor, followed by systemic chemotherapy and radiation therapy, which have toxic side effects for young children. Gene expression [...] Read more.

Central nervous system atypical teratoid/rhabdoid tumors (ATRTs) are rare and aggressive tumors with a very poor prognosis. Current treatments for ATRT include resection of the tumor, followed by systemic chemotherapy and radiation therapy, which have toxic side effects for young children. Gene expression analyses of human ATRTs and normal brain samples indicate that ATRTs have aberrant expression of epigenetic markers including class I histone deacetylases (HDAC’s) and lysine demethylase (LSD1). Here, we investigate the effect of a small molecule epigenetic modulator known as Domatinostat (4SC-202), which inhibits both class I HDAC’s and Lysine Demethylase (LSD1), on ATRT cell survival and single cell heterogeneity. Our findings suggest that 4SC-202 is both cytotoxic and cytostatic to ATRT in 2D and 3D scaffold cell culture models and may target cancer stem cells. Single-cell RNA sequencing data from ATRT-06 spheroids treated with 4SC-202 have a reduced population of cells overexpressing stem cell-related genes, including SOX2. Flow cytometry and immunofluorescence on 3D ATRT-06 scaffold models support these results suggesting that 4SC-202 reduces expression of cancer stem cell markers SOX2, CD133, and FOXM1. Drug-induced changes to the systems biology landscape are also explored by multi-omics enrichment analyses. In summary, our data indicate that 4SC-202 has both cytotoxic and cytostatic effects on ATRT, targets specific cell sub-populations, including those with cancer stem-like features, and is an important potential cancer therapeutic to be investigated in vivo. Full article

(This article belongs to the Special Issue Pediatric Brain Tumor)

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17 pages, 4654 KiB

Open AccessArticle

Landscape of Mitochondria Genome and Clinical Outcomes in Stage 1 Lung Adenocarcinoma

by Lovely Raghav, Ya-Hsuan Chang, Yi-Chiung Hsu, Yu-Cheng Li, Chih-Yi Chen, Tsung-Ying Yang, Kun-Chieh Chen, Kuo-Hsuan Hsu, Jeng-Sen Tseng, Cheng-Yen Chuang, Mei-Hsuan Lee, Chih-Liang Wang, Huei-Wen Chen, Sung-Liang Yu, Sheng-Fang Su, Shin-Sheng Yuan, Jeremy J.W. Chen, Shinn-Ying Ho, Ker-Chau Li, Pan-Chyr Yang, Gee-Chen Chang and Hsuan-Yu Chen Show full author list Hide full author list

Cancers 2020, 12(3), 755; https://doi.org/10.3390/cancers12030755 - 23 Mar 2020

Cited by 11 | Viewed by 4340

Abstract

Risk factors including genetic effects are still being investigated in lung adenocarcinoma (LUAD). Mitochondria play an important role in controlling imperative cellular parameters, and anomalies in mitochondrial function might be crucial for cancer development. The mitochondrial genomic aberrations found in lung adenocarcinoma and [...] Read more.

Risk factors including genetic effects are still being investigated in lung adenocarcinoma (LUAD). Mitochondria play an important role in controlling imperative cellular parameters, and anomalies in mitochondrial function might be crucial for cancer development. The mitochondrial genomic aberrations found in lung adenocarcinoma and their associations with cancer development and progression are not yet clearly characterized. Here, we identified a spectrum of mitochondrial genome mutations in early-stage lung adenocarcinoma and explored their association with prognosis and clinical outcomes. Next-generation sequencing was used to reveal the mitochondrial genomes of tumor and conditionally normal adjacent tissues from 61 Stage 1 LUADs. Mitochondrial somatic mutations and clinical outcomes including relapse-free survival (RFS) were analyzed. Patients with somatic mutations in the D-loop region had longer RFS (adjusted hazard ratio, adjHR = 0.18, p = 0.027), whereas somatic mutations in mitochondrial Complex IV and Complex V genes were associated with shorter RFS (adjHR = 3.69, p = 0.012, and adjHR = 6.63, p = 0.002, respectively). The risk scores derived from mitochondrial somatic mutations were predictive of RFS (adjHR = 9.10, 95%CI: 2.93–28.32, p < 0.001). Our findings demonstrated the vulnerability of the mitochondrial genome to mutations and the potential prediction ability of somatic mutations. This research may contribute to improving molecular guidance for patient treatment in precision medicine. Full article

(This article belongs to the Special Issue Mitochondrial function and dysfunction in cancer and their potential as anti-cancer targets)

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12 pages, 932 KiB

Open AccessArticle

Early Tumor Shrinkage as a Predictive Factor for Outcomes in Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Analysis

by Aya Takahashi, Michihisa Moriguchi, Yuya Seko, Toshihide Shima, Yasuhide Mitsumoto, Hidetaka Takashima, Hiroyuki Kimura, Hideki Fujii, Hiroki Ishikawa, Takaharu Yo, Hiroshi Ishiba, Atsuhiro Morita, Masayasu Jo, Yasuyuki Nagao, Masahiro Arai, Tasuku Hara, Akira Okajima, Akira Muramatsu, Naomi Yoshinami, Tomoki Nakajima, Hironori Mitsuyoshi, Atsushi Umemura, Taichiro Nishikawa, Kanji Yamaguchi, Takeshi Okanoue and Yoshito Itoh Show full author list Hide full author list

Cancers 2020, 12(3), 754; https://doi.org/10.3390/cancers12030754 - 23 Mar 2020

Cited by 18 | Viewed by 4041

Abstract

We investigated the association between early tumor shrinkage (ETS) and treatment outcome in patients with hepatocellular carcinoma treated with lenvatinib (LEN). A retrospective analysis was performed in 104 patients. ETS was defined as tumor shrinkage at the first evaluation in the sum of [...] Read more.

We investigated the association between early tumor shrinkage (ETS) and treatment outcome in patients with hepatocellular carcinoma treated with lenvatinib (LEN). A retrospective analysis was performed in 104 patients. ETS was defined as tumor shrinkage at the first evaluation in the sum of target lesions’ longest diameters from baseline according to the Response Evaluation Criteria in Solid Tumors (RECIST). The median overall survival (OS) was not reached, whereas the median progression-free survival (PFS) was 5.0 months. The receiver operating characteristic curve analysis in differentiating long-term responders (PFS ≥ 5.0 months) from short-term responders (PFS < 5.0 months) revealed an ETS cut-off value of 10%. ETS ≥ 10% was significantly correlated with better PFS and OS compared with ETS < 10%. Additionally, ETS ≥ 10% showed a better discrimination ability on prognosis compared with modified RECIST-based objective response at the first evaluation. Multivariate analysis confirmed ETS ≥ 10% as an independent predictor of better OS, as well as a Child–Pugh score of 5 and macrovascular invasion. In conclusion, ETS ≥ 10% was strongly associated with outcome in patients treated with LEN. This biomarker could allow earlier assessment of the treatment response and guide treatment decision-making for HCC. Full article

(This article belongs to the Special Issue Hepatocellular Carcinoma)

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18 pages, 1894 KiB

Open AccessArticle

Molecular Profiling for Predictors of Radiosensitivity in Patients with Breast or Head-and-Neck Cancer

by Kimi Drobin, Michal Marczyk, Martin Halle, Daniel Danielsson, Anna Papiez, Traimate Sangsuwan, Annika Bendes, Mun-Gwan Hong, Ulrika Qundos, Mats Harms-Ringdahl, Peter Wersäll, Joanna Polanska, Jochen M. Schwenk and Siamak Haghdoost

Cancers 2020, 12(3), 753; https://doi.org/10.3390/cancers12030753 - 22 Mar 2020

Cited by 22 | Viewed by 6314

Abstract

Nearly half of all cancers are treated with radiotherapy alone or in combination with other treatments, where damage to normal tissues is a limiting factor for the treatment. Radiotherapy-induced adverse health effects, mostly of importance for cancer patients with long-term survival, may appear [...] Read more.

Nearly half of all cancers are treated with radiotherapy alone or in combination with other treatments, where damage to normal tissues is a limiting factor for the treatment. Radiotherapy-induced adverse health effects, mostly of importance for cancer patients with long-term survival, may appear during or long time after finishing radiotherapy and depend on the patient’s radiosensitivity. Currently, there is no assay available that can reliably predict the individual’s response to radiotherapy. We profiled two study sets from breast (n = 29) and head-and-neck cancer patients (n = 74) that included radiosensitive patients and matched radioresistant controls.. We studied 55 single nucleotide polymorphisms (SNPs) in 33 genes by DNA genotyping and 130 circulating proteins by affinity-based plasma proteomics. In both study sets, we discovered several plasma proteins with the predictive power to find radiosensitive patients (adjusted p < 0.05) and validated the two most predictive proteins (THPO and STIM1) by sandwich immunoassays. By integrating genotypic and proteomic data into an analysis model, it was found that the proteins CHIT1, PDGFB, PNKD, RP2, SERPINC1, SLC4A, STIM1, and THPO, as well as the VEGFA gene variant rs69947, predicted radiosensitivity of our breast cancer (AUC = 0.76) and head-and-neck cancer (AUC = 0.89) patients. In conclusion, circulating proteins and a SNP variant of VEGFA suggest that processes such as vascular growth capacity, immune response, DNA repair and oxidative stress/hypoxia may be involved in an individual’s risk of experiencing radiation-induced toxicity. Full article

(This article belongs to the Special Issue Plasma Proteins and Cancer)

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20 pages, 3498 KiB

Open AccessArticle

Upregulation of Protein Synthesis and Proteasome Degradation Confers Sensitivity to Proteasome Inhibitor Bortezomib in Myc-Atypical Teratoid/Rhabdoid Tumors

by Huy Minh Tran, Kuo-Sheng Wu, Shian-Ying Sung, Chun Austin Changou, Tsung-Han Hsieh, Yun-Ru Liu, Yen-Lin Liu, Min-Lan Tsai, Hsin-Lun Lee, Kevin Li-Chun Hsieh, Wen-Chang Huang, Muh-Lii Liang, Hsin-Hung Chen, Yi-Yen Lee, Shih-Chieh Lin, Donald Ming-Tak Ho, Feng-Chi Chang, Meng-En Chao, Wan Chen, Shing-Shung Chu, Alice L. Yu, Yun Yen, Che-Chang Chang and Tai-Tong Wong Show full author list Hide full author list

Cancers 2020, 12(3), 752; https://doi.org/10.3390/cancers12030752 - 22 Mar 2020

Cited by 8 | Viewed by 5191

Abstract

Atypical teratoid rhabdoid tumors (ATRTs) are among the most malignant brain tumors in early childhood and remain incurable. Myc-ATRT is driven by the Myc oncogene, which directly controls the intracellular protein synthesis rate. Proteasome inhibitor bortezomib (BTZ) was approved by the Food and [...] Read more.

Atypical teratoid rhabdoid tumors (ATRTs) are among the most malignant brain tumors in early childhood and remain incurable. Myc-ATRT is driven by the Myc oncogene, which directly controls the intracellular protein synthesis rate. Proteasome inhibitor bortezomib (BTZ) was approved by the Food and Drug Administration as a primary treatment for multiple myeloma. This study aimed to determine whether the upregulation of protein synthesis and proteasome degradation in Myc-ATRTs increases tumor cell sensitivity to BTZ. We performed differential gene expression and gene set enrichment analysis on matched primary and recurrent patient-derived xenograft (PDX) samples from an infant with ATRT. Concomitant upregulation of the Myc pathway, protein synthesis and proteasome degradation were identified in recurrent ATRTs. Additionally, we found the proteasome-encoding genes were highly expressed in ATRTs compared with in normal brain tissues, correlated with the malignancy of tumor cells and were essential for tumor cell survival. BTZ inhibited proliferation and induced apoptosis through the accumulation of p53 in three human Myc-ATRT cell lines (PDX-derived tumor cell line Re1-P6, BT-12 and CHLA-266). Furthermore, BTZ inhibited tumor growth and prolonged survival in Myc-ATRT orthotopic xenograft mice. Our findings suggest that BTZ may be a promising targeted therapy for Myc-ATRTs. Full article

(This article belongs to the Special Issue Pediatric Brain Tumor)

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20 pages, 687 KiB

Open AccessPerspective

Immunotherapy in Glioblastoma: Current Shortcomings and Future Perspectives

by Bas Weenink, Pim J. French, Peter A.E. Sillevis Smitt, Reno Debets and Marjolein Geurts

Cancers 2020, 12(3), 751; https://doi.org/10.3390/cancers12030751 - 22 Mar 2020

Cited by 69 | Viewed by 6310

Abstract

Glioblastomas are aggressive, fast-growing primary brain tumors. After standard-of-care treatment with radiation in combination with temozolomide, the overall prognosis of newly diagnosed patients remains poor, with a 2-year survival rate of less than 20%. The remarkable survival benefit gained with immunotherapy in several [...] Read more.

Glioblastomas are aggressive, fast-growing primary brain tumors. After standard-of-care treatment with radiation in combination with temozolomide, the overall prognosis of newly diagnosed patients remains poor, with a 2-year survival rate of less than 20%. The remarkable survival benefit gained with immunotherapy in several extracranial tumor types spurred a variety of experimental intervention studies in glioblastoma patients. These ranged from immune checkpoint inhibition to vaccinations and adoptive T cell therapies. Unfortunately, almost all clinical outcomes were universally disappointing. In this perspective, we provide an overview of immune interventions performed to date in glioblastoma patients and re-evaluate their performance. We argue that shortcomings of current immune therapies in glioblastoma are related to three major determinants of resistance, namely: low immunogenicity; immune privilege of the central nervous system; and immunosuppressive micro-environment. In this perspective, we propose strategies that are guided by exact shortcomings to sensitize glioblastoma prior to treatment with therapies that enhance numbers and/or activation state of CD8 T cells. Full article

(This article belongs to the Special Issue Personalized Medicine: Recent Progress in Cancer Therapy)

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15 pages, 2895 KiB

Open AccessArticle

Calcium Release-Activated Calcium (CRAC) Channel Inhibition Suppresses Pancreatic Ductal Adenocarcinoma Cell Proliferation and Patient-Derived Tumor Growth

by Husain Yar Khan, Gabriel B. Mpilla, Rachel Sexton, Srikant Viswanadha, Kumar V. Penmetsa, Amro Aboukameel, Maria Diab, Mandana Kamgar, Mohammed Najeeb Al-Hallak, Mark Szlaczky, Anteneh Tesfaye, Steve Kim, Philip A. Philip, Ramzi M. Mohammad and Asfar S. Azmi

Cancers 2020, 12(3), 750; https://doi.org/10.3390/cancers12030750 - 22 Mar 2020

Cited by 27 | Viewed by 4048

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains an unmet clinical problem in urgent need of newer molecularly driven treatment modalities. Calcium signals, particularly those associated with calcium release-activated calcium (CRAC) channels, are known to influence the development, growth, and metastasis of many cancers. This is [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) remains an unmet clinical problem in urgent need of newer molecularly driven treatment modalities. Calcium signals, particularly those associated with calcium release-activated calcium (CRAC) channels, are known to influence the development, growth, and metastasis of many cancers. This is the first study investigating the impact of CRAC channel inhibition on PDAC cell lines and patient-derived tumor models. PDAC cell lines were exposed to a novel CRAC channel inhibitor, RP4010, in the presence or absence of standard of care drugs such as gemcitabine and nab-paclitaxel. The in vivo efficacy of RP4010 was evaluated in a hyaluronan-positive PDAC patient-derived xenograft (PDx) in the presence or absence of chemotherapeutic agents. Treatment of PDAC cell lines with single-agent RP4010 decreased cell growth, while the combination with gemcitabine/nab-paclitaxel exhibited synergy at certain dose combinations. Molecular analysis showed that RP4010 modulated the levels of markers associated with CRAC channel signaling pathways. Further, the combination treatment was observed to accentuate the effect of RP4010 on molecular markers of CRAC signaling. Anti-tumor activity of RP4010 was enhanced in the presence of gemcitabine/nab-paclitaxel in a PDAC PDx model. Our study indicates that targeting CRAC channel could be a viable therapeutic option in PDAC that warrants further clinical evaluation. Full article

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

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16 pages, 612 KiB

Open AccessReview

Non-Coding microRNAs as Novel Potential Tumor Markers in Testicular Cancer

by Manuel Regouc, Gazanfer Belge, Anja Lorch, Klaus-Peter Dieckmann and Martin Pichler

Cancers 2020, 12(3), 749; https://doi.org/10.3390/cancers12030749 - 22 Mar 2020

Cited by 41 | Viewed by 7709

Abstract

Testicular cancer is an important disease with increasing incidence and a high burden of morbidity and mortality in young men worldwide. Histological examination of the testicular tissue after orchiectomy plays an important role alongside patient history, imaging, clinical presentation and laboratory parameters. Surgical [...] Read more.

Testicular cancer is an important disease with increasing incidence and a high burden of morbidity and mortality in young men worldwide. Histological examination of the testicular tissue after orchiectomy plays an important role alongside patient history, imaging, clinical presentation and laboratory parameters. Surgical procedures and chemotherapeutic treatment provide a high chance of cure in early stages, though some patients in advanced stages belonging to a poor risk group experience cancer-related death. Though conventional serum-based tumor markers, including α-fetoprotein (AFP), the β-subunit of human chorionic gonadotropin (β-hCG), and lactate dehydrogenase (LDH), are useful as prognostic and diagnostic biomarkers, unfortunately, these tumor markers only have a sensitivity of about 60%, and in pure seminoma even lower with about 20%. Therefore, the development of new tumor markers is an important and intensively ongoing issue. The analysis of epigenetic modification and non-coding RNA microRNAs (miRNAs) are carrying most promising potential as tumor markers in future. miRNAs are small RNAs secreted by testicular tumor cells and circulate and be measurable in body fluids. In recent years, miRNAs of the miR-371-373 cluster in particular have been identified as potentially superior tumor markers in testicular cancer patients. Studies showed that miR-371a-3p and miR-302/367 expression significantly differ between testicular tumors and healthy testicular tissue. Several studies including high prospective multi-center trials clearly demonstrated that these miRNAs significantly exceed the sensitivity and specificity of conventional tumor markers and may help to facilitate the diagnosis, follow-up, and early detection of recurrences in testicular cancer patients. In addition, other miRNAs such as miR-223-3p, miR-449, miR-383, miR-514a-3p, miR-199a-3p, and miR-214 will be discussed in this review. However, further studies are needed to identify the value of these novel markers in additional clinical scenarios, including the monitoring in active surveillance or after adjuvant chemotherapy, but also to show the limitations of these tumor markers. The aim of this review is to give an overview on the current knowledge regarding the relevance of non-coding miRNAs as biomarkers in testicular cancer. Full article

(This article belongs to the Special Issue Non-Coding RNAs as Emerging Regulators of Signalling Pathways and Novel Therapeutic Targets in Human Cancers)

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19 pages, 7137 KiB

Open AccessArticle

KLF5 Is Crucial for Androgen-AR Signaling to Transactivate Genes and Promote Cell Proliferation in Prostate Cancer Cells

by Juan Li, Baotong Zhang, Mingcheng Liu, Xing Fu, Xinpei Ci, Jun A, Changying Fu, Ge Dong, Rui Wu, Zhiqian Zhang, Liya Fu and Jin-Tang Dong

Cancers 2020, 12(3), 748; https://doi.org/10.3390/cancers12030748 - 21 Mar 2020

Cited by 16 | Viewed by 4416

Abstract

Androgen/androgen receptor (AR) signaling drives both the normal prostate development and prostatic carcinogenesis, and patients with advanced prostate cancer often develop resistance to androgen deprivation therapy. The transcription factor Krüppel-like factor 5 (KLF5) also regulates both normal and cancerous development of the prostate. [...] Read more.

Androgen/androgen receptor (AR) signaling drives both the normal prostate development and prostatic carcinogenesis, and patients with advanced prostate cancer often develop resistance to androgen deprivation therapy. The transcription factor Krüppel-like factor 5 (KLF5) also regulates both normal and cancerous development of the prostate. In this study, we tested whether and how KLF5 plays a role in the function of AR signaling in prostate cancer cells. We found that KLF5 is upregulated by androgen depending on AR in LNCaP and C4-2B cells. Silencing KLF5, in turn, reduced AR transcriptional activity and inhibited androgen-induced cell proliferation and tumor growth in vitro and in vivo. Mechanistically, KLF5 occupied the promoter of AR, and silencing KLF5 repressed AR transcription. In addition, KLF5 and AR physically interacted with each other to regulate the expression of multiple genes (e.g., MYC, CCND1 and PSA) to promote cell proliferation. These findings indicate that, while transcriptionally upregulated by AR signaling, KLF5 also regulates the expression and transcriptional activity of AR in androgen-sensitive prostate cancer cells. The KLF5-AR interaction could provide a therapeutic opportunity for the treatment of prostate cancer. Full article

(This article belongs to the Special Issue Urological Cancer 2020)

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10 pages, 379 KiB

Open AccessArticle

Association between Angiotensin-Converting Enzyme Inhibitors and Lung Cancer—A Nationwide, Population-Based, Propensity Score-Matched Cohort Study

by Shih-Yi Lin, Cheng-Li Lin, Cheng-Chieh Lin, Wu-Huei Hsu, Chia-Der Lin, I.-Kuan Wang, Chung-Y. Hsu and Chia-Hung Kao

Cancers 2020, 12(3), 747; https://doi.org/10.3390/cancers12030747 - 21 Mar 2020

Cited by 38 | Viewed by 5410

Abstract

Background: Direct evidence of lung cancer risk in Asian users of angiotensin-converting enzyme inhibitors (ACEIs) is lacking. Methods: The ACEI cohort comprised 22,384 patients aged ≥ 18 years with a first prescription of ACEI. The comparison angiotensin receptor blocker (ARB) cohort consisted of [...] Read more.

Background: Direct evidence of lung cancer risk in Asian users of angiotensin-converting enzyme inhibitors (ACEIs) is lacking. Methods: The ACEI cohort comprised 22,384 patients aged ≥ 18 years with a first prescription of ACEI. The comparison angiotensin receptor blocker (ARB) cohort consisted of age-, sex- and comorbidity-matched patients at a ratio of 1:1. The primary outcome was the incidence of lung cancer, which was evaluated using a proportional hazard model. Results: The overall incidence rates of lung cancer in the ACEI and ARB cohorts were 16.6 and 12.2 per 10,000 person-years, respectively. The ACEI cohort had a significantly higher risk of lung cancer than the ARB cohort (adjusted hazard ratio [aHR]. = 1.36; 95% confidence interval [CI]. = 1.11–1.67). Duration–response and dose–response analyses revealed that compared with patients who did not receive ACEIs, patients who received ACEIs for more than 45 days per year (aHR = 1.87; 95% CI = 1.48–2.36) and patients who received more than 540 defined daily doses of ACEIs per year (aHR =1.80; 95% CI = 1.43–-2.27) had a significantly higher risk of lung cancer. The cumulative incidence of lung cancer was also significantly higher in the ACEI cohort than in the ARB cohort (log-rank test, p = 0.002). Conclusions: ACEI use is associated with an increased risk of lung cancer compared with ARB use. Patients using ARBs have a significantly lower risk of lung cancer than non-ARB users. Full article

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14 pages, 3866 KiB

Open AccessArticle

Immune-Complexome Analysis Identifies Immunoglobulin-Bound Biomarkers That Predict the Response to Chemotherapy of Pancreatic Cancer Patients

by Giorgia Mandili, Laura Follia, Giulio Ferrero, Hiroyuki Katayama, Wang Hong, Amin A. Momin, Michela Capello, Daniele Giordano, Rosella Spadi, Maria Antonietta Satolli, Andrea Evangelista, Samir M. Hanash, Francesca Cordero and Francesco Novelli

Cancers 2020, 12(3), 746; https://doi.org/10.3390/cancers12030746 - 21 Mar 2020

Cited by 8 | Viewed by 3442

Abstract

Pancreatic Ductal Adenocarcinoma (PDA) is an aggressive malignancy with a very poor outcome. Although chemotherapy (CT) treatment has poor efficacy, it can enhance tumor immunogenicity. Tumor-Associated Antigens (TAA) are self-proteins that are overexpressed in tumors that may induce antibody production and can be [...] Read more.

Pancreatic Ductal Adenocarcinoma (PDA) is an aggressive malignancy with a very poor outcome. Although chemotherapy (CT) treatment has poor efficacy, it can enhance tumor immunogenicity. Tumor-Associated Antigens (TAA) are self-proteins that are overexpressed in tumors that may induce antibody production and can be PDA theranostic targets. However, the prognostic value of TAA-antibody association as Circulating Immune Complexes (CIC) has not yet been elucidated, mainly due to the lack of techniques that lead to their identification. In this study, we show a novel method to separate IgG, IgM, and IgA CIC from sera to use them as prognostic biomarkers of CT response. The PDA Immune-Complexome (IC) was identified using a LTQ-Orbitrap mass spectrometer followed by computational analysis. The analysis of the IC of 37 PDA patients before and after CT revealed differential associated antigens (DAA) for each immunoglobulin class. Our method identified different PDA-specific CIC in patients that were associated with poor prognosis patients. Finally, CIC levels were significantly modified by CT suggesting that they can be used as effective prognostic biomarkers to follow CT response in PDA patients. Full article

(This article belongs to the Special Issue The Cancer Proteome)

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16 pages, 1779 KiB

Open AccessArticle

A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy

by Sooyeon Oh, YoungJoon Park, Hyun-Jung Lee, Jooho Lee, Soo-Hyeon Lee, Young-Seok Baek, Su-Kyung Chun, Seung-Min Lee, Mina Kim, Young-Eun Chon, Yeonjung Ha, Yuri Cho, Gi Jin Kim, Seong-Gyu Hwang and KyuBum Kwack

Cancers 2020, 12(3), 745; https://doi.org/10.3390/cancers12030745 - 21 Mar 2020

Cited by 25 | Viewed by 4392

Abstract

The chemotherapeutics sorafenib and regorafenib inhibit shedding of MHC class I-related chain A (MICA) from hepatocellular carcinoma (HCC) cells by suppressing a disintegrin and metalloprotease 9 (ADAM9). MICA is a ligand for natural killer (NK) group 2 member D (NKG2D) and is expressed [...] Read more.

The chemotherapeutics sorafenib and regorafenib inhibit shedding of MHC class I-related chain A (MICA) from hepatocellular carcinoma (HCC) cells by suppressing a disintegrin and metalloprotease 9 (ADAM9). MICA is a ligand for natural killer (NK) group 2 member D (NKG2D) and is expressed on tumor cells to elicit attack by NK cells. This study measured ADAM9 mRNA levels in blood samples of advanced HCC patients (n = 10). In newly diagnosed patients (n = 5), the plasma ADAM9 mRNA level was significantly higher than that in healthy controls (3.001 versus 1.00, p < 0.05). Among four patients treated with nivolumab therapy, two patients with clinical response to nivolumab showed significant decreases in fold changes of serum ADAM9 mRNA level from 573.98 to 262.58 and from 323.88 to 85.52 (p < 0.05); however, two patients with no response to nivolumab did not. Using the Cancer Genome Atlas database, we found that higher expression of ADAM9 in tumor tissues was associated with poorer survival of HCC patients (log-rank p = 0.00039), while ADAM10 and ADAM17 exhibited no such association. In addition, ADAM9 expression showed a positive correlation with the expression of inhibitory checkpoint molecules. This study, though small in sample size, clearly suggested that ADAM9 mRNA might serve as biomarker predicting clinical response and that the ADAM9-MICA-NKG2D system can be a good therapeutic target for HCC immunotherapy. Future studies are warranted to validate these findings. Full article

(This article belongs to the Special Issue Immunotherapy in Hepatocellular Carcinoma)

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21 pages, 6192 KiB

Open AccessArticle

Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety

by Yanming Wang, Lianqi Liu, Shiyong Fan, Dian Xiao, Fei Xie, Wei Li, Wu Zhong and Xinbo Zhou

Cancers 2020, 12(3), 744; https://doi.org/10.3390/cancers12030744 - 21 Mar 2020

Cited by 25 | Viewed by 10456

Abstract

Monomethyl auristatin E (MMAE) is the most popular and widely used cytotoxin in the development of antibody-drug conjugates (ADCs). However, current MMAE-based ADCs are all constructed using cleavable linkers, and this design concept still has insurmountable drawbacks. Their potential instabilities and lipophilic MMAE-induced [...] Read more.

Monomethyl auristatin E (MMAE) is the most popular and widely used cytotoxin in the development of antibody-drug conjugates (ADCs). However, current MMAE-based ADCs are all constructed using cleavable linkers, and this design concept still has insurmountable drawbacks. Their potential instabilities and lipophilic MMAE-induced “bystander effect” inevitably increase the toxicity to normal tissues. Herein, we overturn previous negative views of MMAE-based ADCs with non-cleavable linkers and propose using ionized L-Cysteine (Cys)-linker-MMAE as a novel payload, which can ingeniously enrich and enter tumor cells through receptor-mediated endocytosis of antibodies while its lower permeability helps to avoid further off-target toxicity. We demonstrate that Cys-linker-MMAE maintains high potency similar to free MMAE at the tubulin molecular level and can also be efficiently released in target cells. As a result, the preferred ADC (mil40-15) not only exhibits ideal plasma stability and maintains potent cytotoxicity as MMAE (IC₅₀: 10⁻¹¹ M), but also shows improved safety with lower bystander toxicity (IC₅₀: 10⁻⁹ M), its maximum tolerated dose approaching the level of the naked antibody (160 mg/kg). This study indicated that Cys-linker-MMAE has the potential as a potent payload for ADCs, which is expected to provide novel strategies for the development of MMAE-based ADCs. Full article

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20 pages, 1155 KiB

Open AccessReview

Gauging the Impact of Cancer Treatment Modalities on Circulating Tumor Cells (CTCs)

by Trevor J. Mathias, Katarina T. Chang, Stuart S. Martin and Michele I. Vitolo

Cancers 2020, 12(3), 743; https://doi.org/10.3390/cancers12030743 - 21 Mar 2020

Cited by 11 | Viewed by 4378

Abstract

The metastatic cascade consists of multiple complex steps, but the belief that it is a linear process is diminishing. In order to metastasize, cells must enter the blood vessels or body cavities (depending on the cancer type) via active or passive mechanisms. Once [...] Read more.

The metastatic cascade consists of multiple complex steps, but the belief that it is a linear process is diminishing. In order to metastasize, cells must enter the blood vessels or body cavities (depending on the cancer type) via active or passive mechanisms. Once in the bloodstream and/or lymphatics, these cancer cells are now termed circulating tumor cells (CTCs). CTC numbers as well as CTC clusters have been used as a prognostic marker with higher numbers of CTCs and/or CTC clusters correlating with an unfavorable prognosis. However, we have very limited knowledge about CTC biology, including which of these cells are ultimately responsible for overt metastatic growth, but due to the fact that higher numbers of CTCs correlate with a worse prognosis; it would seem appropriate to either limit CTCs and/or their dissemination. Here, we will discuss the different cancer treatments which may inadvertently promote the mobilization of CTCs and potential CTC therapies to decrease metastasis. Full article

(This article belongs to the Special Issue Liquid Biopsy: Latest Advances and Future Challenges)

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13 pages, 3998 KiB

Open AccessArticle

The Role of PTEN Loss in Immune Escape, Melanoma Prognosis and Therapy Response

by Rita Cabrita, Shamik Mitra, Adriana Sanna, Henrik Ekedahl, Kristina Lövgren, Håkan Olsson, Christian Ingvar, Karolin Isaksson, Martin Lauss, Ana Carneiro and Göran Jönsson

Cancers 2020, 12(3), 742; https://doi.org/10.3390/cancers12030742 - 21 Mar 2020

Cited by 39 | Viewed by 5139

Abstract

Checkpoint blockade therapies have changed the clinical management of metastatic melanoma patients considerably, showing survival benefits. Despite the clinical success, not all patients respond to treatment or they develop resistance. Although there are several treatment predictive biomarkers, understanding therapy resistance and the mechanisms [...] Read more.

Checkpoint blockade therapies have changed the clinical management of metastatic melanoma patients considerably, showing survival benefits. Despite the clinical success, not all patients respond to treatment or they develop resistance. Although there are several treatment predictive biomarkers, understanding therapy resistance and the mechanisms of tumor immune evasion is crucial to increase the frequency of patients benefiting from treatment. The PTEN gene is thought to promote immune evasion and is frequently mutated in cancer and melanoma. Another feature of melanoma tumors that may affect the capacity of escaping T-cell recognition is melanoma cell dedifferentiation characterized by decreased expression of the microphtalmia-associated transcription factor (MITF) gene. In this study, we have explored the role of PTEN in prognosis, therapy response, and immune escape in the context of MITF expression using immunostaining and genomic data from a large cohort of metastatic melanoma. We confirmed in our cohort that PTEN alterations promote immune evasion highlighted by decreased frequency of T-cell infiltration in such tumors, resulting in a worse patient survival. More importantly, our results suggest that dedifferentiated PTEN negative melanoma tumors have poor patient outcome, no T-cell infiltration, and transcriptional properties rendering them resistant to targeted- and immuno-therapy. Full article

(This article belongs to the Special Issue Advanced Melanoma)

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Open AccessArticle

Molecular Engineering Strategies Tailoring the Apoptotic Response to a MET Therapeutic Antibody

by Chiara Modica, Simona Gallo, Cristina Chiriaco, Martina Spilinga, Paolo Maria Comoglio, Tiziana Crepaldi, Cristina Basilico and Elisa Vigna

Cancers 2020, 12(3), 741; https://doi.org/10.3390/cancers12030741 - 21 Mar 2020

Cited by 3 | Viewed by 3005

Abstract

The MET oncogene encodes a tyrosine kinase receptor involved in the control of a complex network of biological responses that include protection from apoptosis and stimulation of cell growth during embryogenesis, tissue regeneration, and cancer progression. We previously developed an antagonist antibody (DN30) [...] Read more.

The MET oncogene encodes a tyrosine kinase receptor involved in the control of a complex network of biological responses that include protection from apoptosis and stimulation of cell growth during embryogenesis, tissue regeneration, and cancer progression. We previously developed an antagonist antibody (DN30) inducing the physical removal of the receptor from the cell surface and resulting in suppression of the biological responses to MET. In its bivalent form, the antibody displayed a residual agonist activity, due to dimerization of the lingering receptors, and partial activation of the downstream signaling cascade. The balance between the two opposing activities is variable in different biological systems and is hardly predictable. In this study, we generated and characterized two single-chain antibody fragments derived from DN30, sharing the same variable regions but including linkers different in length and composition. The two engineered molecules bind MET with high affinity but induce different biological responses. One behaves as a MET-antagonist, promoting programmed cell death in MET “addicted” cancer cells. The other acts as a hepatocyte growth factor (HGF)-mimetic, protecting normal cells from doxorubicin-induced apoptosis. Thus, by engineering the same receptor antibody, it is possible to generate molecules enhancing or inhibiting apoptosis either to kill cancer cells or to protect healthy tissues from the injuries of chemotherapy. Full article

(This article belongs to the Special Issue Cell Death in Cancer)

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Cancers, Volume 12, Issue 3 (March 2020) – 246 articles

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