An oncofetal and developmental perspective on testicular germ cell cancer

Germ cell tumors (GCTs) represent a diverse group of tumors presumably originating from (early fetal) developing germ cells. Most frequent are the testicular germ cell cancers (TGCC). Overall, TGCC is the most frequent malignancy in Caucasian males (20-40 years) and remains an important cause of (treatment related) mortality in these young men. The strong association between the phenotype of TGCC stem cell components and their totipotent ancestor (fetal primordial germ cell or gonocyte) makes these tumors highly relevant from an onco-fetal point of view. This review subsequently discusses the evidence for the early embryonic origin of TGCCs, followed by an overview of the crucial association between TGCC pathogenesis, genetics, environmental exposure and the (fetal) testicular micro-environment (genvironment). This culminates in an evaluation of three genvironmentally modulated hallmarks of TGCC directly related to the oncofetal pathogenesis of TGCC: (1) maintenance of pluripotency, (2) cell cycle control/cisplatin sensitivity and (3) regulation of proliferation/migration/apoptosis by KIT-KITL mediated receptor tyrosine kinase signaling. Briefly, TGCC exhibit identifiable stem cell components (seminoma and embryonal carcinoma) and progenitors that show large and consistent similarities to primordial/embryonic germ cells, their presumed totipotent cells of origin. TGCC pathogenesis depends crucially on a complex interaction of genetic and (micro-)environmental, i.e. genvironmental risk factors that have only been partly elucidated despite significant effort. TGCC stem cell components also show a high degree of similarity with embryonic stem/germ cells (ES) in the regulation of pluripotency and cell cycle control, directly related to their exquisite sensitivity to DNA damaging agents (e.g. cisplatin). Of note, (ES specific) micro-RNAs play a pivotal role in the crossover between cell cycle control, pluripotency and chemosensitivity. Moreover, multiple consistent observations reported TGCC to be associated with KIT-KITL mediated receptor tyrosine kinase signaling, a pathway crucially implicated in proliferation, migration and survival during embryogenesis including germ cell development. In conclusion, TGCCs are a fascinating model for onco-fetal developmental processes especially with regard to studying cell cycle control, pluripotency maintenance and KIT-KITL signaling. The knowledge presented here contributes to better understanding of the molecular characteristics of TGCC pathogenesis, translating to identification of at risk individuals and enhanced quality of care for TGCC patients (diagnosis, treatment and follow-up).