Role of C3G in megakaryopoiesis, hypoxia-induced angiogenesis and melanoma metastasis.
Centro de Investigación del Cáncer (CIC-IBMCC)
C3G is a guanine nucleotide exchange factor for Rap1 that regulates platelet functions, such as activation, aggregation and release of α-granules content. C3G also participates in megakaryocytic differentiation and in platelet-mediated tumor metastasis. We have deepened into the role of C3G in physiological and pathological megakaryopoiesis. Transgenic expression of C3G (TgC3G) in megakaryocytes increases its maturation and differentiation in response to trombopoyetin (TPO), but this is not reflected in an increase in platelet production. Similarly, C3G ablation in platelets (PF4-C3G-KO mice model) did not result in differences in platelet or megakaryocyte counts in blood and bone marrow, respectively. However, megakaryocyte recovery after 5-Fluorouracil (5-FU) myelosuppression was significantly decreased in PF4-C3G-KO mice. In addition, PF4-C3G-KO mice presented an impaired downregulation of platelet levels after the recovery. Our data suggest that C3G is necessary for platelet rebound after 5-FU-induced myelosuppression, but it prevents the subsequent platelet downregulation, probably through the modulation of Cbl activity. This suggests a role of C3G in the TPO/Mpl pathway.
On the other hand, overexpression of C3G in platelets promotes angiogenesis and melanoma metastasis. Using our TgC3G and PF4-C3G-KO models we have shown that C3G promotes the recruitment hemangiocytes (BMDC, bone marrow derived cell) to the sites of hypoxia in response to tumor growth or ischemia. According to our data, C3G ablation in platelets increases the recruitment of hemangiocytes due to a higher release of VEGF and the retention of TSP1 from platelets.
Finally, further analysis of the role of platelet C3G in melanoma metastasis suggests that C3G mediates platelet-tumor cell interaction and promotes TCIPA (tumor cell-induced platelet aggregation), a crucial step in the metastasic process.