Topical Collection "Benign and Malignant Germ Cell Tumors"

Editors

Prof. Carmen Jerónimo
Website
Collection Editor
Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar—University of Porto (ICBAS-UP), Porto, Portugal
Interests: urological tumors; molecular pathology; tumor markers; epigenetics; epitranscriptomics; epi-drugs
Prof. Leendert H.J. Looijenga

Collection Editor
Laboratory for Experimental Patho-Oncology, Department of Pathology, Erasmus MC Rotterdam & Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Interests: Germ cell tumors, fertility, disorders of sex development; (Molecular) Biomarkers; Treatment sensitivity and resistance
Prof. Rui Henrique

Collection Editor
Department of Pathology & Cancer Biology and Epigenetics Group, Portuguese Oncology Institute of Porto (IPO Porto) & Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar-University of Porto, Porto, Portugal
Interests: uropathology; cancer biomarkers; epigenetics

Topical Collection Information

Dear Colleagues,

Malignant germ cell tumors (GCTs) are among the most common cancers afflicting young adults. Despite their high curability, incidence is rising as well as disease burden, owing to chemo- and radiotherapy-induced morbidity. Moreover, a restricted, but significant, number of patients develop therapy-resistance, entailing poor prognosis, and the underlying mechanisms are mostly unknown. GCTs are archetypes of morphological heterogeneity, although the genetic background is rather similar. Hence, improved understanding of immunological signatures, molecular pathways and epigenetic alterations underlying the pathology is mandatory. Finally, the limitations of “classical” biomarkers (AFP, betaHCG) have stimulated the search for novel disease biomarkers, allowing for improved disease monitoring and refinement of therapeutic strategies, especially for the most aggressive subtypes.

Thus, in this Special Issue, we aim to cover all relevant aspects of malignant GCT encompassing basic, preclinical, and clinical research in this challenging tumor model.

Prof. Carmen Jerónimo
Prof. Leendert H.J. Looijenga
Prof. Rui Henrique
Collection Editors

Manuscript Submission Information

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Keywords

  • pathogenesis
  • similarities and differences between gonadal and extragonadal GCT
  • advances in pathological assessment of GCT
  • epigenetics and epigenomics of GCT/subtyping/molecular profiling of GCT
  • micro-environment and selection
  • GCT tumor microenvironment/GCT cancer stem cells
  • signaling pathways in GCT
  • biomarkers for detection and monitoring of GCT
  • GCT tumorigenesis, heterogeneity and metastasis
  • preclinical models
  • animal models of GCT
  • in vitro models of GCT
  • clinical aspects
  • imaging of GCT
  • drug delivery to GCT cells
  • molecular targeted therapies for GCT
  • precision medicine for GCT
  • innovative therapeutic strategies for GCT

Published Papers (8 papers)

2020

Jump to: 2019

Open AccessArticle
Luteinizing Hormone Receptor Is Expressed in Testicular Germ Cell Tumors: Possible Implications for Tumor Growth and Prognosis
Cancers 2020, 12(6), 1358; https://doi.org/10.3390/cancers12061358 (registering DOI) - 26 May 2020
Abstract
Luteinizing hormone/choriogonadotropin receptor (LHCGR) regulates gonadal testosterone production and recent studies have suggested a growth-regulatory role in somatic cancers. Here, we established that LHCGR is expressed in a fraction of seminoma cells and germ cell neoplasia in situ (GCNIS), and the seminoma-derived cell [...] Read more.
Luteinizing hormone/choriogonadotropin receptor (LHCGR) regulates gonadal testosterone production and recent studies have suggested a growth-regulatory role in somatic cancers. Here, we established that LHCGR is expressed in a fraction of seminoma cells and germ cell neoplasia in situ (GCNIS), and the seminoma-derived cell line TCam2 released LHCGR into the medium. LH treatment induced proliferation of TCam2 cells in vitro, while hCG treatment induced a non-significant 51% increase in volume of tumors formed in a TCam2 xenograft model. A specific ELISA was used to detect a soluble LHCGR in serum. Serum concentrations of soluble LHCGR could not distinguish 4 patients with GCNIS and 216 patients with testicular germ cell tumors (TGCTs) from 297 infertile or 148 healthy young men. Instead, serum LHCGR levels were significantly higher in 112 patients with a seminoma >5 cm or elevated serum lactate dehydrogenase (LDH) compared with men harboring smaller seminomas <2 cm or normal LDH levels. Serum LHCGR levels in TGCT patients could not predict relapse irrespective whether determined pre- or post-orchiectomy. Combined, these novel findings suggest that LHCGR may be directly involved in the progression and growth of seminomas, and our retrospective pilot study suggests that serum LHCGR may have some prognostic value in men with seminoma. Full article
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Open AccessArticle
Targeting EpCAM by a Bispecific Trifunctional Antibody Exerts Profound Cytotoxic Efficacy in Germ Cell Tumor Cell Lines
Cancers 2020, 12(5), 1279; https://doi.org/10.3390/cancers12051279 - 19 May 2020
Abstract
Outcome in high-risk patients with refractory or relapsed germ cell tumours (GCT) remains poor. Novel strategies enhancing therapeutic efficacy whilst limiting therapeutic burden are warranted, yet immunotherapy approaches geared towards activating endogenous antitumor responses have not been successful thus far. Redirection of cytotoxic [...] Read more.
Outcome in high-risk patients with refractory or relapsed germ cell tumours (GCT) remains poor. Novel strategies enhancing therapeutic efficacy whilst limiting therapeutic burden are warranted, yet immunotherapy approaches geared towards activating endogenous antitumor responses have not been successful thus far. Redirection of cytotoxic effector cells by bispecific antibodies represents a promising approach in this setting. We demonstrate that the Epithelial Cell Adhesion Molecule (EpCAM) is broadly expressed in GCT cell lines of different histologic origin including seminoma, choriocarcinoma (CHC), and embryonal carcinoma (EC). In these GCT lines of variable EpCAM surface expression, targeting T cells by the prototypic bispecific EpCAM/CD3-antibody (bAb) Catumaxomab together with natural killer (NK) cell engagement via the Fc domain promotes profound cytotoxicity across a broad range of antibody dilutions. In contrast, tumor cell lysis mediated by either immune cell subset alone is influenced by surface density of the target antigen. In the CHC line JAR, NK cell-dependent cytotoxicity dominates, which may be attributed to differential surface expression of immunomodulatory proteins such as MHC-I, CD24, and Fas receptors on CHC and EC. In view of redirecting T cell therapy mediated by bispecific antibodies, such differences in GCT immunophenotype potentially favoring immune escape are worth further investigation. Full article
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Open AccessArticle
ARID1A Regulates Transcription and the Epigenetic Landscape via POLE and DMAP1 While ARID1A Deficiency or Pharmacological Inhibition Sensitizes Germ Cell Tumor Cells to ATR Inhibition
Cancers 2020, 12(4), 905; https://doi.org/10.3390/cancers12040905 - 07 Apr 2020
Abstract
Germ cell tumors (GCTs) are the most common solid malignancies found in young men. Although they generally have high cure rates, metastases, resistance to cisplatin-based therapy, and late toxicities still represent a lethal threat, arguing for the need of new therapeutic options. In [...] Read more.
Germ cell tumors (GCTs) are the most common solid malignancies found in young men. Although they generally have high cure rates, metastases, resistance to cisplatin-based therapy, and late toxicities still represent a lethal threat, arguing for the need of new therapeutic options. In a previous study, we identified downregulation of the chromatin-remodeling SWI/SNF complex member ARID1A as a key event in the mode of action of the histone deacetylase inhibitor romidepsin. Additionally, the loss-of-function mutations re-sensitize different tumor types to various drugs, like EZH2-, PARP-, HDAC-, HSP90- or ATR-inhibitors. Thus, ARID1A presents as a promising target for synthetic lethality and combination therapy. In this study, we deciphered the molecular function of ARID1A and screened for the potential of two pharmacological ARID1A inhibitors as a new therapeutic strategy to treat GCTs. By CRISPR/Cas9, we generated ARID1A-deficient GCT cells and demonstrate by mass spectrometry that ARID1A is putatively involved in regulating transcription, DNA repair and the epigenetic landscape via DNA Polymerase POLE and the DNA methyltransferase 1-associated protein DMAP1. Additionally, ARID1A/ARID1A deficiency or pharmacological inhibition increased the efficacy of romidepsin and considerably sensitized GCT cells, including cisplatin-resistant subclones, towards ATR inhibition. Thus, targeting ARID1A in combination with romidepsin and ATR inhibitors presents as a new putative option to treat GCTs. Full article
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Open AccessArticle
CRIPTO and miR-371a-3p Are Serum Biomarkers of Testicular Germ Cell Tumors and Are Detected in Seminal Plasma from Azoospermic Males
Cancers 2020, 12(3), 760; https://doi.org/10.3390/cancers12030760 - 23 Mar 2020
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
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Open AccessArticle
Evaluation of Circulating miRNA Biomarkers of Testicular Germ Cell Tumors during Therapy and Follow-up―A Copenhagen Experience
Cancers 2020, 12(3), 759; https://doi.org/10.3390/cancers12030759 - 23 Mar 2020
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
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Open AccessArticle
Age-Dependent Presentation and Clinical Course of 1465 Patients Aged 0 to Less than 18 Years with Ovarian or Testicular Germ Cell Tumors; Data of the MAKEI 96 Protocol Revisited in the Light of Prenatal Germ Cell Biology
Cancers 2020, 12(3), 611; https://doi.org/10.3390/cancers12030611 - 06 Mar 2020
Cited by 1
Abstract
Objective: To evaluate prognostic factors in pediatric patients with gonadal germ cell tumors (GCT). Methods: Patients <18 years with ovarian and testicular GCT (respectively OGCT and TGCT) were prospectively registered according to the guidelines of MAKEI 96. After resection of the primary tumor, [...] Read more.
Objective: To evaluate prognostic factors in pediatric patients with gonadal germ cell tumors (GCT). Methods: Patients <18 years with ovarian and testicular GCT (respectively OGCT and TGCT) were prospectively registered according to the guidelines of MAKEI 96. After resection of the primary tumor, patients staged ≥II received risk-stratified cisplatin-based combination chemotherapy. Patients were analyzed in respect to age (six age groups divided into 3-year intervals), histology, stage, and therapy. The primary end point was overall survival. Results: Between January 1996 and March 2016, the following patients were registered: 1047 OGCT, of those, 630 had ovarian teratoma (OTER) and 417 had malignant OGCT (MOGCT); and 418 TGCT, of those, 106 had testicular teratoma (TTER) and 312 had malignant TGCT (MTGCT). Only in MTGCT, older age correlated with a higher proportion of advanced tumors. All 736 teratomas and 240/415 stage I malignant gonadal GCT underwent surgery and close observation alone. In case of watchful waiting, the progression rate of OGCT was higher than that of TGCT. However, death from disease was reported in 8/417 (1.9%) MOGCT and 8/312 (2.6%) MTGCT irrespective of adjuvant chemotherapy and repeated surgery. Conclusions: The different pathogenesis and histogenesis of gonadal GCT reflects sex- and age-specific patterns that define clinically relevant risk groups. Therefore, gender and age should be considered in further research on the biology and clinical practice of pediatric gonadal GCT. Full article
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2019

Jump to: 2020

Open AccessFeature PaperArticle
Detailed Characterization of Immune Cell Infiltrate and Expression of Immune Checkpoint Molecules PD-L1/CTLA-4 and MMR Proteins in Testicular Germ Cell Tumors Disclose Novel Disease Biomarkers
Cancers 2019, 11(10), 1535; https://doi.org/10.3390/cancers11101535 - 11 Oct 2019
Cited by 2
Abstract
Background: The immune infiltrate plays an important part in testicular germ cell tumors, but it remains scarcely studied. We aimed at thoroughly characterizing the immune infiltrate and expression of immune checkpoints PD-L1/CTLA-4 and mismatch repair (MMR) proteins in these neoplasms, seeking for associations [...] Read more.
Background: The immune infiltrate plays an important part in testicular germ cell tumors, but it remains scarcely studied. We aimed at thoroughly characterizing the immune infiltrate and expression of immune checkpoints PD-L1/CTLA-4 and mismatch repair (MMR) proteins in these neoplasms, seeking for associations with patient outcome. Methods: A total of 162 consecutively diagnosed patients (2005–2018) were included. Immunostaining for PD-L1, CTLA-4 and MMR proteins was independently assessed both in immune cells (ICs) and tumor cells (TCs) of primary tumors and metastases, and characterization of IC populations was pursued. Results: PD-L1 and CTLA-4 positivity in ICs was frequent (85.5% and 96.3%). Patients with absent PD-L1 positive ICs exhibited significantly worse relapse-free survival (hazard ratio = 4.481, 95% CI 1.366–14.697, p = 0.013), both in univariable and multivariable analysis. Lower CD20 and CD3 IC infiltration in seminomas associated with higher disease stage (p = 0.0216, p = 0.0291). CTLA-4 TC intensity was significantly higher in yolk sac tumor, choriocarcinoma and teratoma, while PD-L1 TC positivity was significantly more frequent in choriocarcinoma. Both PD-L1 and CTLA-4 immunoexpression in ICs of metastatic samples was frequent (100% and 88.2%). MMR proteins were differentially expressed among the different tumor subtypes. Conclusions: Immune infiltrate/checkpoints associate with patients’ outcome, constituting novel (potentially targetable) disease biomarkers. Full article
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Open AccessArticle
XIST-Promoter Demethylation as Tissue Biomarker for Testicular Germ Cell Tumors and Spermatogenesis Quality
Cancers 2019, 11(9), 1385; https://doi.org/10.3390/cancers11091385 - 17 Sep 2019
Cited by 4
Abstract
Background: The event of X chromosome inactivation induced by XIST, which is physiologically observed in females, is retained in testicular germ cell tumors (TGCTs), as a result of a supernumerary X chromosome constitution. X chromosome inactivation also occurs in male germline, specifically [...] Read more.
Background: The event of X chromosome inactivation induced by XIST, which is physiologically observed in females, is retained in testicular germ cell tumors (TGCTs), as a result of a supernumerary X chromosome constitution. X chromosome inactivation also occurs in male germline, specifically during spermatogenesis. We aimed to analyze the promoter methylation status of XIST in a series of TGCT tissues, representative cell lines, and testicular parenchyma. Methods: Two independent cohorts were included, comprising a total of 413 TGCT samples, four (T)GCT cell lines, and 86 testicular parenchyma samples. The relative amount of methylated and demethylated XIST promoter fragments was assessed by quantitative methylation-specific PCR (qMSP) and more sensitive high-resolution melting (HRM) methylation analyses. Results: Seminomas showed a lower amount of methylated XIST fragments as compared to non-seminomas or normal testis (p < 0.0001), allowing for a good discrimination among these groups (area under the curve 0.83 and 0.81, respectively). Seminomas showed a significantly higher content of demethylated XIST as compared to non-seminomas. The percentage of demethylated XIST fragment in cell lines reflected their chromosomal constitution (number of extra X chromosomes). A novel and strong positive correlation between the Johnsen’s score and XIST demethylation was identified (r = 0.75, p < 0.0001). Conclusions: The X chromosome inactivation event and demethylated XIST promoter are promising biomarkers for TGCTs and for assessing spermatogenesis quality. Full article
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