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

Growth-differentiation factor 3 (GDF3) belongs to the transforming growth factor (TGF)-β superfamily, and is also called Vgr-2 [1,2]. Human GDF3 was first identified during a study of cDNAs expressed in human embryonal carcinoma cells [3]. GDF3 expression is also found in primary testicular germ cell tumors, seminomas, and breast carcinomas. Despite its ubiquitous expression the role of GDF3 in cancer remains undetermined [4-6]. In normal tissues, GDF3 is expressed in embryonic stem (ES) cells and the early embryo [7-10]. Chen et al. have demonstrated that mice with null mutation on GDF3 exhibit developmental abnormalities [11].Cancers are composed of heterogeneous cell populations. The cancer stem cell (CSC) hypothesis was advocated for acute myeloid leukemia (AML) system [12] and recent studies have provided evidence that solid cancers can also originated from CSCs [13]. A previous report has shown that human melanomas also contain CSCs, and these tumor derived CSCs express ABCB5 [14]. This investigation also reported that the CSC population despite being very low could generate a tumor in human melanomas [14]. A recent work has shown that approximately 27% of human melanoma cells could initiate a tumor [15].Mouse melanoma B16-F10 cells also contain CSC-like cells, which express CD133, CD44, and CD24 [16]. The mouse melanoma CSC-like cells, when injected subcutaneously into syngenic mice display tumorigenic ability [16]. Initial reports showed that the mouse CSC-like cells are a very small population, while most cells within the B16-F10 cell line retain the ability to induce malignancy [17].The expression of ES-specific genes is observed in several human cancers. For example, the ES-specific gene, Sall4, is expressed in AML and precursor B-cell lymphoblastic leukemia [18,19]. Sall4 transgenic mice develop AML [19], but the molecular mechanism by which this occurs has not been shown yet. Another ES-specific gene, Klf4, functions as either a tumor suppressor or an o