EXPRESSION OF TERATOCARCINOMA-DERIVED GROWTH-FACTOR-I (TDGF-1) IN TESTIS GERM-CELL TUMORS AND ITS EFFECTS ON GROWTH AND DIFFERENTIATION OF EMBRYONAL CARCINOMA CELL-LINE NTERA2 D1/

The teratocarcinoma-derived growth factor-1 (TDGF-1) gene codes for a 188-aminoacid glycoprotein that shares structural homology with the ep idermal growth factor (EGF) family of growth factors, TDGF-1 is highly expressed in the undifferentiated embryonal carcinoma stem cell line NTERA2 clone D1 (NT2/D1) and its expression is downregulated in respon se to differentiating agents such as retinoic acid (RA) and hexamethyl en-bisacetamide (HMBA), To assess the role of TDGF-1 in the onset and/ or progression of human germ cell tumors, we analysed TDGF-1 expressio n by Northern blot and immunostaining in a panel of 59 human germ cell tumors of different histological origins, We show that TDGF-1 express ion is markedly elevated in a subset of human testicular germ cell tum ors as compared to normal testes, TDGF-1 overexpression occurs in abou t 100% of tumors with non-seminomatous phenotype, such as embryonal ca rcinomas and malignant undifferentiated teratocarcinomas, To address t he questions of how TDGF-1 (previously called CRIPTO) may affect the g rowth and/or the differentiation of embryonal carcinoma cells, we have characterized the effects of exogenous recombinant TDGF-1 protein on the proliferation rate and differentiation potential of NT2/D1, Exogen ous TDGF-1 protein stimulated DNA synthesis and cell proliferation in both undifferentiated and differentiated NT2/D1 cells, However, TDGF-1 protein treatment was unable to block differentiation induced by both RA and HMBA, These results suggest that TDGF-1 growth factor may repr esent an autocrine growth factor that may be involved in the process o f development of testicular neoplasms.