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Pathogenesis and Experimental Therapeutics of Testicular Germ Cell Tumors

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 34171

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Prof. Dr. Michael J. Spinella

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1. Comparative Biosciences, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA
2. Cancer Center at Illinois, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA
3. Institute of Genomic Biology, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA
Interests: testicular cancer; cancer therapeutics; chemoresistance; epigenetics; targeted therapy

Dr. Sarah J. Freemantle

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Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Interests: mouse models of cancer; leiomyosarcoma; cyclin E; lung cancer; chemotherapy resistance

Dr. Zeeshan Fazal

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Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Interests: bioinformatics; computational genomics; epigenetics; chemotherapy resistance

Dr. Ratnakar Singh

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Guest Editor

Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Interests: cancer genetics; cell signaling; epigenetics; cancer therapeutics

Special Issue Information

Dear Colleagues,

Testicular germ cell tumors (TGCTs) have long intrigued cancer biologists. TGCTs are the most common solid tumor in young males, and are likely initiated from an early germ-like cell in utero and promoted by gonadal stimulation during adolescence and young adulthood. Several unique features of TGCTs provide a fascinating model that has the potential to illuminate targeted therapy strategies for other cancers. The molecular pathogenesis of TGCTs is poorly understood. TGCTs possess a very low tumor mutational burden and unique epigenetics, perhaps due to their germ cell origins. While highly aggressive and fatal when left untreated, metastatic TGCTs can be cured at a rate of 80% with conventional cisplatin-based chemotherapy regimens, far surpassing the success rate of any other solid tumor. However, a clinically significant number of patients are refractory and succumb to disease due to a lack of targeted therapies. The mechanisms for the exquisite sensitivity of TGCTs to therapy and mechanisms of resistance are largely unknown, but could inform better treatments for other advanced cancers. This Special Issue welcomes papers on the genetics, genomics, and epigenetics of TGCTs, especially applied to pathogenesis, chemosensitivity/resistance, and new targeted therapies.

Prof. Dr. Michael J. Spinella
Dr. Sarah J. Freemantle
Dr. Zeeshan Fazal
Dr. Ratnakar Singh
Guest Editors

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Keywords

testicular cancer
testicular germ cell tumors
cisplatin
genomics
molecular genetics
epigenetics
pathogenesis
chemoresistance
animal models
targeted therapy

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Research

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18 pages, 7457 KiB

Open AccessArticle

Expression of Intermediate Filaments in the Developing Testis and Testicular Germ Cell Cancer

by Maria E. Camacho-Moll, Leendert H. J. Looijenga, Roland Donat, Chitranjan J. Shukla, Anne Jørgensen and Rod T. Mitchell

Cancers 2022, 14(22), 5479; https://doi.org/10.3390/cancers14225479 - 8 Nov 2022

Viewed by 1636

Abstract

Cytokeratin and desmin expression have been associated with Sertoli cell maturity and the development of testicular germ cell cancer (TGCC). Thus, the present study aimed to characterize the expression of these intermediate filaments in normal testis development and TGCC. Cytokeratin and desmin were determined by immunohistochemistry and immunofluorescence in human fetal, and adult testis and tissue from patients with pre-invasive germ cell neoplasia in-situ (GCNIS) or invasive TGCC. Desmin was expressed in Sertoli cells of the human fetal testis, and the proportion of desmin expressing Sertoli cells was significantly reduced in the second trimester, compared with the first trimester (31.14% vs. 6.74%, p = 0.0016). Additionally, Desmin was expressed in the majority of Sertoli cells in the adult testis and TGCC samples. Cytokeratin was detected in Sertoli cells of human fetal testis but was not expressed in Sertoli cells of human adult testis. In patients with TGCC, cytokeratin was not expressed in Sertoli cells in tubules with active spermatogenesis but was detected in Sertoli cells in tubules containing GCNIS cells in patients with both pre-invasive and invasive TGCC. In conclusion, desmin was not associated with Sertoli cell maturation or progression to TGCC. However, cytokeratin appeared to be an indicator of impaired Sertoli cell maturation. Full article

(This article belongs to the Special Issue Pathogenesis and Experimental Therapeutics of Testicular Germ Cell Tumors)

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22 pages, 4552 KiB

Open AccessArticle

Transcriptional CDK Inhibitors as Potential Treatment Option for Testicular Germ Cell Tumors

by Kai Funke, Robert Düster, Prince De-Graft Wilson, Lena Arévalo, Matthias Geyer and Hubert Schorle

Cancers 2022, 14(7), 1690; https://doi.org/10.3390/cancers14071690 - 26 Mar 2022

Cited by 4 | Viewed by 3125

Abstract

Type II testicular germ cell tumors (TGCT) are the most frequently diagnosed solid malignancy in young men. Up to 15% of patients with metastatic non-seminomas show cisplatin resistance and a very poor survival rate due to lacking treatment options. Transcriptional cyclin-dependent kinases (CDK) have been shown to be effective targets in the treatment of different types of cancer. Here, we investigated the effects of the CDK inhibitors dinaciclib, flavopiridol, YKL-5-124, THZ1, NVP2, SY0351 and THZ531. An XTT viability assay revealed a strong cytotoxic impact of CDK7/12/13 inhibitor SY0351 and CDK9 inhibitor NVP2 on the TGCT wild-type cell lines (2102EP, NCCIT, TCam2) and the cisplatin-resistant cell lines (2102EP-R, NCCIT-R). The CDK7 inhibitor YKL-5-124 showed a strong impact on 2102EP, 2102EP-R, NCCIT and NCCIT-R cell lines, leaving the MPAF control cell line mostly unaffected. FACS-based analysis revealed mild effects on the cell cycle of 2102EP and TCam2 cells after SY0351, YKL-5-124 or NVP2 treatment. Molecular analysis showed a cell-line-specific response for SY0351 and NVP2 inhibition while YKL-5-124 induced similar molecular changes in 2102EP, TCam2 and MPAF cells. Thus, after TGCT subtype determination, CDK inhibitors might be a potential alternative for optimized and individualized therapy independent of chemotherapy sensitivity. Full article

(This article belongs to the Special Issue Pathogenesis and Experimental Therapeutics of Testicular Germ Cell Tumors)

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9 pages, 496 KiB

Open AccessFeature PaperArticle

Very Late Recurrence in Germ Cell Tumor of the Testis: Lessons and Implications

by Joseph A. Moore, Rebecca S. Slack, Michael J. Lehner, Matthew T. Campbell, Amishi Y. Shah, Miao Zhang, Charles C. Guo, John F. Ward, Jose A. Karam, Christopher G. Wood, Louis L. Pisters and Shi-Ming Tu

Cancers 2022, 14(5), 1127; https://doi.org/10.3390/cancers14051127 - 23 Feb 2022

Cited by 12 | Viewed by 2944

Abstract

Background. Very late recurrence (LR), i.e., >5 years after initial presentation, occurs in about 1% of patients with germ cell tumors of the testis (TGCT) and is associated with poor prognosis. Methods. We retrospectively reviewed the records of patients at the M. D. Anderson Cancer Center who developed LR > 5 years after their initial diagnosis of TGCT. Results. We identified 25 patients who developed LR between July 2007 and August 2020. The median age at the time of LR was 46 years (range, 29–61). Pathology of LR: somatic transformation to carcinoma or sarcoma—11, nonseminoma with yolk sac tumor or teratoma—11, nonseminoma without yolk sac tumor or teratoma—2, not available—1. With a median follow-up of 3.5 years, 68% of patients are alive 3 years after LR. Patients with prior post-chemotherapy consolidation surgery do not have statistically significant longer survival compared to patients who did not receive post-chemotherapy consolidation surgery, 83.3% vs. 60.8% at 3 years, respectively, p = 0.50. Conclusions. Patients with LR > 5 years tend to harbor nonseminoma (with yolk sac tumor and or teratoma). Among these patients, a majority who did not undergo surgery to remove residual disease after chemotherapy developed somatic transformation and succumbed to their LR. Full article

(This article belongs to the Special Issue Pathogenesis and Experimental Therapeutics of Testicular Germ Cell Tumors)

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20 pages, 4774 KiB

Open AccessArticle

Targeting Cancer Stem Cells with Differentiation Agents as an Alternative to Genotoxic Chemotherapy for the Treatment of Malignant Testicular Germ Cell Tumors

by Amanda R. Loehr, Timothy M. Pierpont, Eric Gelsleichter, Anabella Maria D. Galang, Irma R. Fernandez, Elizabeth S. Moore, Matthew Z. Guo, Andrew D. Miller and Robert S. Weiss

Cancers 2021, 13(9), 2045; https://doi.org/10.3390/cancers13092045 - 23 Apr 2021

Cited by 6 | Viewed by 4834

Abstract

Testicular germ cell tumors (TGCTs) are exceptionally sensitive to genotoxic chemotherapy, resulting in a high cure rate for the young men presenting with these malignancies. However, this treatment is associated with significant toxicity, and a subset of malignant TGCTs demonstrate chemoresistance. Mixed nonseminomas often contain pluripotent embryonal carcinoma (EC) cells, the cancer stem cells (CSCs) of these tumors. We hypothesized that differentiation therapy, a treatment strategy which aims to induce differentiation of tumor-propagating CSCs to slow tumor growth, could effectively treat mixed nonseminomas without significant toxicity. The FDA-approved antipsychotic thioridazine and the agricultural antibiotic salinomycin are two drugs previously found to selectively target CSCs, and here we report that these agents differentiate EC cells in vitro and greatly reduce their tumorigenic potential in vivo. Using a novel transformed induced pluripotent stem cell allograft model and a human xenograft model, we show that thioridazine extends the survival of tumor-bearing mice and can reduce the number of pluripotent EC cells within tumors. These results suggest that thioridazine could be repurposed as an alternative TGCT treatment that avoids the toxicity of conventional chemotherapeutics. Full article

(This article belongs to the Special Issue Pathogenesis and Experimental Therapeutics of Testicular Germ Cell Tumors)

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15 pages, 2588 KiB

Open AccessArticle

The Potential of Artificial Intelligence to Detect Lymphovascular Invasion in Testicular Cancer

by Abhisek Ghosh, Korsuk Sirinukunwattana, Nasullah Khalid Alham, Lisa Browning, Richard Colling, Andrew Protheroe, Emily Protheroe, Stephanie Jones, Alan Aberdeen, Jens Rittscher and Clare Verrill

Cancers 2021, 13(6), 1325; https://doi.org/10.3390/cancers13061325 - 16 Mar 2021

Cited by 16 | Viewed by 3641

Abstract

Testicular cancer is the most common cancer in men aged from 15 to 34 years. Lymphovascular invasion refers to the presence of tumours within endothelial-lined lymphatic or vascular channels, and has been shown to have prognostic significance in testicular germ cell tumours. In non-seminomatous tumours, lymphovascular invasion is the most powerful prognostic factor for stage 1 disease. For the pathologist, searching multiple slides for lymphovascular invasion can be highly time-consuming. The aim of this retrospective study was to develop and assess an artificial intelligence algorithm that can identify areas suspicious for lymphovascular invasion in histological digital whole slide images. Areas of possible lymphovascular invasion were annotated in a total of 184 whole slide images of haematoxylin and eosin (H&E) stained tissue from 19 patients with testicular germ cell tumours, including a mixture of seminoma and non-seminomatous cases. Following consensus review by specialist uropathologists, we trained a deep learning classifier for automatic segmentation of areas suspicious for lymphovascular invasion. The classifier identified 34 areas within a validation set of 118 whole slide images from 10 patients, each of which was reviewed by three expert pathologists to form a majority consensus. The precision was 0.68 for areas which were considered to be appropriate to flag, and 0.56 for areas considered to be definite lymphovascular invasion. An artificial intelligence tool which highlights areas of possible lymphovascular invasion to reporting pathologists, who then make a final judgement on its presence or absence, has been demonstrated as feasible in this proof-of-concept study. Further development is required before clinical deployment. Full article

(This article belongs to the Special Issue Pathogenesis and Experimental Therapeutics of Testicular Germ Cell Tumors)

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17 pages, 4373 KiB

Open AccessArticle

Prognostic Value of Apoptosis-Inducing Factor (AIF) in Germ Cell Tumors

by Katarina Letkovska, Pavel Babal, Zuzana Cierna, Silvia Schmidtova, Veronika Liskova, Katarína Kalavska, Vera Miskovska, Samuel Horak, Katarina Rejlekova, Michal Chovanec, Jozef Mardiak, Pavel Janega and Michal Mego

Cancers 2021, 13(4), 776; https://doi.org/10.3390/cancers13040776 - 13 Feb 2021

Cited by 1 | Viewed by 2152

Abstract

Apoptosis is a strictly regulated process essential for preservation of tissue homeostasis. This study aimed to evaluate expression of apoptosis inducing factor (AIF) in testicular germ cell tumors (GCTs) and to correlate expression patterns with clinicopathological variables. Formalin-fixed and paraffin-embedded specimens of non-neoplastic testicular tissue and GCTs obtained from 216 patients were included in the study. AIF expression was detected by immunohistochemistry, scored by the multiplicative quickscore method (QS). Normal testicular tissue exhibits higher cytoplasmic granular expression of AIF compared to GCTs (mean QS = 12.77 vs. 4.80, p < 0.0001). Among invasive GCTs, mean QS was the highest in embryonal carcinoma, yolk sac tumor and seminoma, lower in teratoma and the lowest in choriocarcinoma. No nuclear translocation of AIF was observed. Nonpulmonary visceral metastases were associated with lower AIF expression. Metastatic GCTs patients with high AIF expression had better overall survival compared to patients with low AIF expression (HR = 0.26, 95% CI 0.11–0.62, p = 0.048). We observed significantly lower AIF expression in GCTs compared to normal testicular tissue, which is an uncommon finding in malignant tumors. AIF downregulation might represent one of the mechanisms of inhibition of apoptosis and promotion of cell survival in GCTs. Full article

(This article belongs to the Special Issue Pathogenesis and Experimental Therapeutics of Testicular Germ Cell Tumors)

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23 pages, 4680 KiB

Open AccessArticle

Teratoma Growth Retardation by HDACi Treatment of the Tumor Embryonal Source

by Jure Krasic, Lucija Skara, Monika Ulamec, Ana Katusic Bojanac, Sanja Dabelic, Floriana Bulic-Jakus, Davor Jezek and Nino Sincic

Cancers 2020, 12(11), 3416; https://doi.org/10.3390/cancers12113416 - 18 Nov 2020

Cited by 6 | Viewed by 2909

Abstract

Among testicular germ cell tumors, teratomas may often be very aggressive and therapy-resistant. Our aim was to investigate the impact of histone deacetylase inhibitors (HDACi) on the in vitro growth of experimental mouse teratoma by treating their embryonic source, the embryo-proper, composed only of the three germ layers. The growth of teratomas was measured for seven days, and histopathological analysis, IHC/morphometry quantification, gene enrichment analysis, and qPCR analysis on a selected panel of pluripotency and early differentiation genes followed. For the first time, within teratomas, we histopathologically assessed the undifferentiated component containing cancer stem cell-like cells (CSCLCs) and differentiated components containing numerous lymphocytes. Mitotic indices were higher than apoptotic indices in both components. Both HDACi treatments of the embryos-proper significantly reduced teratoma growth, although this could be related neither to apoptosis nor proliferation. Trichostatin A increased the amount of CSCLCs, and upregulated the mRNA expression of pluripotency/stemness genes as well as differentiation genes, e.g., T and Eomes. Valproate decreased the amount of CSCLCs, and downregulated the expressions of pluripotency/stemness and differentiation genes. In conclusion, both HDACi treatments diminished the inherent tumorigenic growth potential of the tumor embryonal source, although Trichostatin A did not diminish the potentially dangerous expression of cancer-related genes and the amount of CSCLC. Full article

(This article belongs to the Special Issue Pathogenesis and Experimental Therapeutics of Testicular Germ Cell Tumors)

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19 pages, 2439 KiB

Open AccessArticle

Efficacy of HDAC Inhibitors Belinostat and Panobinostat against Cisplatin-Sensitive and Cisplatin-Resistant Testicular Germ Cell Tumors

by João Lobo, Catarina Guimarães-Teixeira, Daniela Barros-Silva, Vera Miranda-Gonçalves, Vânia Camilo, Rita Guimarães, Mariana Cantante, Isaac Braga, Joaquina Maurício, Christoph Oing, Friedemann Honecker, Daniel Nettersheim, Leendert H. J. Looijenga, Rui Henrique and Carmen Jerónimo

Cancers 2020, 12(10), 2903; https://doi.org/10.3390/cancers12102903 - 10 Oct 2020

Cited by 22 | Viewed by 3077

Abstract

Novel treatment options are needed for testicular germ cell tumor (TGCT) patients, particularly important for those showing or developing cisplatin resistance, the major cause of cancer-related deaths. As TGCTs pathobiology is highly related to epigenetic (de)regulation, epidrugs are potentially effective therapies. Hence, we sought to explore, for the first time, the effect of the two most recently FDA-approved HDAC inhibitors (HDACis), belinostat and panobinostat, in (T)GCT cell lines including those resistant to cisplatin. In silico results were validated in 261 patient samples and differential expression of HDACs was also observed across cell lines. Belinostat and panobinostat reduced cell viability in both cisplatin-sensitive cells (NCCIT-P, 2102Ep-P, and NT2-P) and, importantly, also in matched cisplatin-resistant subclones (NCCIT-R, 2102Ep-R, and NT2-R), with IC50s in the low nanomolar range for all cell lines. Treatment of NCCIT-R with both drugs increased acetylation, induced cell cycle arrest, reduced proliferation, decreased Ki67 index, and increased p21, while increasing cell death by apoptosis, with upregulation of cleaved caspase 3. These findings support the effectiveness of HDACis for treating TGCT patients in general, including those developing cisplatin resistance. Future studies should explore them as single or combination agents. Full article

(This article belongs to the Special Issue Pathogenesis and Experimental Therapeutics of Testicular Germ Cell Tumors)

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17 pages, 1413 KiB

Open AccessReview

Molecular Biology of Pediatric and Adult Male Germ Cell Tumors

by Mariana Tomazini Pinto, Flavio Mavignier Cárcano, Ana Glenda Santarosa Vieira, Eduardo Ramos Martins Cabral and Luiz Fernando Lopes

Cancers 2021, 13(10), 2349; https://doi.org/10.3390/cancers13102349 - 13 May 2021

Cited by 12 | Viewed by 3850

Abstract

Cancer is a leading cause of death by disease in children and the second most prevalent of all causes in adults. Testicular germ cell tumors (TGCTs) make up 0.5% of pediatric malignancies, 14% of adolescent malignancies, and are the most common of malignancies in young adult men. Although the biology and clinical presentation of adult TGCTs share a significant overlap with those of the pediatric group, molecular evidence suggests that TGCTs in young children likely represent a distinct group compared to older adolescents and adults. The rarity of this cancer among pediatric ages is consistent with our current understanding, and few studies have analyzed and compared the molecular basis in childhood and adult cancers. Here, we review the major similarities and differences in cancer genetics, cytogenetics, epigenetics, and chemotherapy resistance between pediatric and adult TGCTs. Understanding the biological and molecular processes underlying TGCTs may help improve patient outcomes, and fuel further investigation and clinical research in childhood and adult TGCTs. Full article

(This article belongs to the Special Issue Pathogenesis and Experimental Therapeutics of Testicular Germ Cell Tumors)

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17 pages, 1302 KiB

Open AccessReview

Between a Rock and a Hard Place: An Epigenetic-Centric View of Testicular Germ Cell Tumors

by Ratnakar Singh, Zeeshan Fazal, Sarah J. Freemantle and Michael J. Spinella

Cancers 2021, 13(7), 1506; https://doi.org/10.3390/cancers13071506 - 25 Mar 2021

Cited by 21 | Viewed by 4600

Abstract

Compared to many common solid tumors, the main genetic drivers of most testicular germ cell tumors (TGCTs) are unknown. Decades of focus on genomic alterations in TGCTs including awareness of a near universal increase in copies of chromosome 12p have failed to uncover exceptional driver genes, especially in genes that can be targeted therapeutically. Thus far, TGCT patients have missed out on the benefits of targeted therapies available to treat most other malignancies. In the past decade there has been a greater appreciation that epigenetics may play an especially prominent role in TGCT etiology, progression, and hypersensitivity to conventional chemotherapy. While genetics undoubtedly plays a role in TGCT biology, this mini-review will focus on the epigenetic “states” or features of testicular cancer, with an emphasis on DNA methylation, histone modifications, and miRNAs associated with TGCT susceptibility, initiation, progression, and response to chemotherapy. In addition, we comment on the current status of epigenetic-based therapy and epigenetic biomarker development for TGCTs. Finally, we suggest a unifying “rock and a hard place” or “differentiate or die” model where the tumorigenicity and curability of TGCTs are both dependent on common but still ill-defined epigenetic states. Full article

(This article belongs to the Special Issue Pathogenesis and Experimental Therapeutics of Testicular Germ Cell Tumors)

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