On the origin of germ cell neoplasia in situ: Dedifferentiation of human adult Sertoli cells in cross talk with seminoma cells in vitro

Abstract

Germ cell neoplasia in situ (GCNIS) is the noninvasive precursor of testicular germ cell tumors type II, the most common cancer in young men, which originates from embryonic germ cells blocked in their maturation. GCNIS is associated with impaired Sertoli cells (SCs) that express fetal keratin 18 (KRT18) and the pluripotency factor SRY-Box transcription factor 2 (SOX2). According to the current theory concerning the origin of GCNIS, these SCs are prepubertal cells arrested in their maturation due to (epi)genetic anomalies and/or environmental antiandrogens. Thus, they are unable to support the development of germ cells, which leads to their maturational block and further progresses into GCNIS. Alternatively, these SCs are hypothesized to be adult cells dedifferentiating secondarily under the influence of GCNIS. To examine whether tumor cells can dedifferentiate SCs, we established a coculture model of adult human SCs (FS1) and a seminoma cell line similar to GCNIS (TCam-2). After 2 wk of coculture, FS1 cells showed progressive expression of KRT18 and SOX2, mimicking the in vivo changes. TCam-2 cells showed SOX2 expression and upregulation of further pluripotency- and reprogramming-associated genes, suggesting a seminoma to embryonal carcinoma transition. Thus, our FS1/TCam-2 coculture model is a valuable tool for investigating interactions between SCs and seminoma cells. Our immunohistochemical and ultrastructural studies of human testicular biopsies with varying degrees of GCNIS compared to biopsies from fetuses, patients with androgen insensitivity syndrome, and patients showing normal spermatogenesis further suggest that GCNIS-associated SCs represent adult cells undergoing progressive dedifferentiation.

Analysis of connexin 43, connexin 45 and N-cadherin in the human sertoli cell line FS1 and the human seminoma-like cell line TCam-2 in comparison with human testicular biopsies

“…The cells exhibit morphological features typical for adult SCs. They further express classical SC markers and pubertal differentiation markers but not pluripotency markers or prepubertal differentiation markers, suggesting that these SCs are differentiated [50,51]. However, a detailed investigation of cell contacts is still pending.…”

“…Primary cells were obtained from a 35-year-old man with a classic and pure seminoma [52]. TCam-2 cells express several markers and show morphological features that are typical for seminoma [51][52][53][54][55][56][57]. Only very few studies have addressed junctions until now, thus many questions are still open regarding the formation of cell contacts and the related intercellular communication.…”

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

“…Thus, suggesting that either (1) Sertoli cells are only partially differentiated in TGCC patients and retain some immature features or (2) the loss of normal germ cells could have led to partial de-differentiation of Sertoli cells. In a study involving the co-culture of adult Sertoli cells with seminoma tumour cells, Sertoli cells begin to express cytokeratin after 2 weeks of co-culture [ 23 ], suggesting that the interaction between Sertoli cells and a tumour microenvironment can lead to dedifferentiation of Sertoli cells.…”

The Role of microRNAs in the Gonocyte Theory as Target of Malignancy: Looking for Potential Diagnostic Biomarkers

“…It is considered to be the precursor lesion for TGCT. GCNIS cells can be dormant and later transform into cancer cells, arresting the process of spermatogenesis [81,82]. To date, the cause for the malignant transformation of cells to GCNIS is unknown.…”