An embryo-specific expressing TGF-β family protein, growth-differentiation factor 3 (GDF3), augments progression of B16 melanoma

Nobuyuki Ehira, Hiroyuki Oshiumi, Misako Matsumoto, Takeshi Kondo, Masahiro Asaka, Tsukasa Seya

Malignant tumor cells often express embryonic antigens which share the expression with embryonic stem (ES) cells. The embryonic antigens are usually encoded by ES cell-specific genes, a number of which are associated with tumorigenesis and/or tumor progression. We examined the expression of ES cell-specific genes in the mouse B16 melanoma cell line to identify the factors promoting tumorigenesis. We found that endogenous growth-differentiation factor 3 (GDF3) expression was induced in implant B16 tumor during tumor progression in syngenic C57BL/6 mice. B16 F10, a subline with a high metastatic potential, continuously expressed GDF3 while low metastatic B16 F1 expressed comparatively decreased levels of GDF3. Overexpression of GDF3 promoted growth of implanted melanoma B16 F1 and F10 in syngenic mice. Ectopic expression of GDF3 was accompanied by an increased level of production of CD24/CD44. Such a profile was reported to be characteristic of melanoma stem cell-like cells. GDF3 expression was observed in embryonal carcinomas, primary testicular germ cell tumors, seminomas and breast carcinomas. However, the role of GDF3 in these cancers remains undetermined. Overexpression of GDF3 did not affect the growth of mouse hepatoma high or low metastatic sublines G5 or G1, both of which do not express GDF3. Since GDF3-driven CD24 acts as a receptor for endogenous innate immune ligands that modulate cell proliferation, CD24 is an effective determinant of tumorigenesis in malignant cell transformation. Finally, our results support the view that GDF3 has the ability to induce progression of CD24-inducible melanoma in mice.