New evidence for the origin of intracranial germ cell tumours from primordial germ cells: expression of pluripotency and cell differentiation markers

Abstract

Primary intracranial germ cell tumours are rare neoplasms that occur in children and adolescents. This study examined both the biology and the origin of these tumours, as it has been hypothesized that they originate from a totipotent primordial germ cell. We applied recent knowledge from gonadal germ cell tumours and analysed expression of a wide panel of stem cell-related proteins (C-KIT, OCT-3/4 (POU5F1), AP-2gamma (TFAP2C), and NANOG) and developmentally regulated germ cell-specific proteins (including MAGE-A4, NY-ESO-1, and TSPY). Expression at the protein level was analysed in 21 children and young adults with intracranial germinomas and non-germinomas, contributing to a careful description of these unusual tumours and adding to the understanding of pathogenesis. Stem cell related proteins were highly expressed in intracranial germ cell tumours, and many similarities were detected with their gonadal equivalents, including a close similarity with primordial germ cells. A notable difference was the sex-specific expression of TSPY, a gene previously implicated in the origin of gonadoblastoma. TSPY was only detected in germ cell tumours in the central nervous system (CNS) from males, suggesting that it is not required for the initiation of malignant germ cell transformation. The expression of genes associated with embryonic stem cell pluripotency in CNS germ cell tumours strongly suggests that these tumours are derived from cells that retain, at least partially, an embryonic stem cell-like phenotype, which is a hallmark of primordial germ cells.

TSPY and its X-encoded homologue interact with cyclin B but exert contrasting functions on cyclin-dependent kinase 1 activities

“…TSPY is normally expressed in early gonocytes and prespermatogonia in fetal testis and in spermatogonia, spermatocytes and round spermatids in adult testis (Honecker et al, 2004;Kido and Lau, 2005), and has been postulated to serve normal functions in stem germ cell proliferation and meiotic division (Schnieders et al, 1996;Lau, 1999). TSPY is ectopically expressed in tumor cells in various types of germ cell tumors, including gonadoblastoma, testicular germ cell tumors and male intracranial germ cell tumors, and has been considered as a key marker that is important in the pathogenesis of these types of human tumors Kersemaekers et al, 2005;Hoei-Hansen et al, 2006;Oram et al, 2006;Li et al, 2007b). Significantly, it is also aberrantly expressed in prostate cancer and numerous somatic cancers, including hepatocellular carcinoma and melanoma of male origins (Lau and Zhang, 2000;Lau et al, 2003;Gallagher et al, 2005;Yin et al, 2005), suggesting that the TSPY tandem arrays are hot spots for epigenetic dysregulation.…”

Octamer 4 Small Interfering RNA Results in Cancer Stem Cell–Like Cell Apoptosis

“…Successfully eradicating this disease therefore requires a better understanding of how cancer initiates and progresses. Cancer stem cell-like cells (CSCLC) are now thought to play key roles in cancer initiation and development (1)(2)(3)(4)(5)(6)(7). Developing approaches to specifically target malignant stem cells by applying the principles of stem cell biology might raise hope to cure this disease.…”

The Role of Stem Cells in Pediatric Central Nervous System Malignancies

“…Nevertheless, iGCTs and gonadal GCTs share several molecular features such as chromosomal alterations, mutations in developmental genes, and epigenetic modifi cations [ 104 ]. The expression of several stem cell genes such as c-kit , Oct3/4 , and Nanog implicates an embryonic stem cell-like phenotype in these tumors, the hallmark of primordial germ cells [ 105 ]. The case for the presence of BTICs in iGCTs has been recently established with the ectopic expression of Oct4 in NSCs leading to the formation of teratomas in murine xenografts [ 98 , 106 ].…”