Molecular characteristics of testicular germ cell tumors: pathogenesis and mechanisms of therapy resistance

Al‐Obaidy, Khaleel I; Chovanec, Michal; Cheng, Liang

doi:10.1080/14737140.2020.1717337

Cited by 11 publications

(11 citation statements)

References 27 publications

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Section: Introductionmentioning

confidence: 99%

“…Despite intense research efforts directed towards a better understanding of cisplatin sensitivity and resistance in this tumor model, a major unifying mechanism is still lacking which may be therapeutically targeted [ 10 , 11 , 12 , 13 ]. Most likely, the biology of cisplatin resistance is multifactorial [ 12 , 14 ]. Importantly, epigenetic (de)regulation has been implicated as contributing to resistance by interfering with several candidate mechanisms and pathways [ 15 , 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

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

Lobo

Guimarães‐Teixeira

Barros‐Silva

et al. 2020

Cancers

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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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Lobo

Guimarães‐Teixeira

Barros‐Silva

et al. 2020

Cancers

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“…Their incidence increases after puberty, following a bell-shaped age distribution with a mean age of 25 and 35 years for nonseminomas and seminoma, respectively. 1 The development of these tumors is multifactorial, and interaction between genetic and environmental factors is considered essential, and is supported by the differences in incidence observed between different ethnic and geographic populations. 2 According to the cell of origin, and molecular characteristics, human germ cell tumors have been divided into 5 subtypes, 3 of which occur in the testis.…”

Section: Testicular Germ Cell Tumorsmentioning

confidence: 99%

Testicular Tumors: A Contemporary Update on Morphologic, Immunohistochemical and Molecular Features

Al‐Obaidy

Idrees

2021

Advances in Anatomic Pathology

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Testicular tumors are incredibly diverse and one of the most challenging areas in surgical pathology. Because of the rarity and overlapping features with numerous entities occurring in the testis and paratestis, these tumors pose a diagnostic challenge even to the most experienced general pathologists. In 2016, the latest "World Health Organization (WHO) classification of testicular tumors" was released, which incorporated several updates to the previous 2004 classification system. These updates involved several entities, including germ cell tumors, sex cord-stromal tumors, tumors containing both germ cells and sex-cord stromal cells, a miscellaneous group of testicular tumors and paratesticular tumors. In addition, significant changes were also introduced in the 2018 AJCC TNM staging (8th edition) regarding testicular tumors. The germ cell tumors are divided into 2 major groups; tumors derived from germ cell neoplasia in situ (GCNIS) and those unrelated to GCNIS. The GCNIS associated tumors include seminomatous and nonseminomatous germ cell tumors, which constitute a heterogeneous group of tumors. Non-GCNIS-associated tumors include prepubertal-type teratoma, prepubertal yolk sac tumor, mixed prepubertal-type teratoma and yolk sac tumor and spermatocytic seminoma. In the sex cord-stromal category, the tumors are classified based on their cells of origin. Most are Leydig cell tumors and Sertoli cell tumors; however, several mixed and diverse entities based on cell types are included in this group. Gonadoblastoma is the only tumor in the mixed germ cell and sex cord-stromal tumor category. Because of recent advances in molecular techniques, abundant new genetic information has emerged which helped classify the tumors based on the molecular alterations and provided insights into the tumor pathogenesis. This review focused on the updates related to testicular germ cell tumors and sex cord-stromal tumors and described the morphologic, immunohistochemical and molecular characteristics with an aim to provide a practical diagnostic approach and an update on relevant recent molecular advances.

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“…Genetic and environmental factors contribute to the development of testicular germ cell tumors, supported by ethical and geographic evidence ( Al-Obaidy et al, 2020 ). It is also reported that isochromosome 12p alternation is especially associated with the progression and invasiveness of the tumors; and it can be related to abnormalities in malignant transformation, oxidative damage, and DNA repairing ( Reuter, 2005 ; Cheng et al, 2017 ; Al-Obaidy et al, 2020 ). Globally, testicular cancer affected about 74,458 new cases in 2020, which resulted in 9,334 deaths in 2020.…”

Section: Introductionmentioning

confidence: 99%

“…Overall, reproductive cancers comprised 28.11% of incidence, 17.34% of mortality, and 38.05% of prevalence (5 years) of all cancers in the world in 2020, demonstrating its relevance as a public health problem ( Table 1 ). The molecular mechanism of reproductive related cancers had been extensively reviewed, which is a complex carcinogenesis process accompanied by related pathophysiology ( Zheng et al, 2017 ; Gupta and Mania-Pramanik, 2019 ; Testa et al, 2019 ; Al-Obaidy et al, 2020 ; Horowitz et al, 2020 ; Terzic et al, 2021 ). These include enhanced growth factors and oncogenes but resisting apoptotic factors and tumor suppressors, as a result of enhanced invasiveness and metastasis.…”

Section: Introductionmentioning

confidence: 99%

Green Tea Epigallocatechin-3-Gallate Regulates Autophagy in Male and Female Reproductive Cancer

Hung

Chen

et al. 2022

Front. Pharmacol.

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With a rich abundance of natural polyphenols, green tea has become one of the most popular and healthiest nonalcoholic beverages being consumed worldwide. Epigallocatechin-3-gallate (EGCG) is the predominant catechin found in green tea, which has been shown to promote numerous health benefits, including metabolic regulation, antioxidant, anti-inflammatory, and anticancer. Clinical studies have also shown the inhibitory effects of EGCG on cancers of the male and female reproductive system, including ovarian, cervical, endometrial, breast, testicular, and prostate cancers. Autophagy is a natural, self-degradation process that serves important functions in both tumor suppression and tumor cell survival. Naturally derived products have the potential to be an effective and safe alternative in balancing autophagy and maintaining homeostasis during tumor development. Although EGCG has been shown to play a critical role in the suppression of multiple cancers, its role as autophagy modulator in cancers of the male and female reproductive system remains to be fully discussed. Herein, we aim to provide an overview of the current knowledge of EGCG in targeting autophagy and its related signaling mechanism in reproductive cancers. Effects of EGCG on regulating autophagy toward reproductive cancers as a single therapy or cotreatment with other chemotherapies will be reviewed and compared. Additionally, the underlying mechanisms and crosstalk of EGCG between autophagy and other cellular processes, such as reactive oxidative stress, ER stress, angiogenesis, and apoptosis, will be summarized. The present review will help to shed light on the significance of green tea as a potential therapeutic treatment for reproductive cancers through regulating autophagy.

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Molecular characteristics of testicular germ cell tumors: pathogenesis and mechanisms of therapy resistance

Cited by 11 publications

References 27 publications

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

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

Testicular Tumors: A Contemporary Update on Morphologic, Immunohistochemical and Molecular Features

Green Tea Epigallocatechin-3-Gallate Regulates Autophagy in Male and Female Reproductive Cancer

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