Fig. 2

VEGF signaling pathways involved in angiogenesis and its crosstalk with TA-MUC1 in cancer cells. In this proposed model, activation of VEGF signaling and several MUC1-C activities in association with cancer have been illustrated. MUC1 overexpression is existing on the surface of a majority of cancer cells. The phosphorylation of its cytoplasmic domain is capable of translocation and interacting with pro-angiogenic and proliferative regulators such as HIF-1α, β-catenin, and STAT-3 which leading to the upregulation of target-gene expression and survival of cancer cells. In the case of resistance to angiogenesis inhibitors such as TKIs, MUC1 leads to sustained downstream signaling. Activation and auto-phosphorylation of VEGF family receptor, even in the presence of therapeutic agents and aberrant activation of the PI3K/AKT/mTOR, MAPK, and JAK/STAT3 in tumor progression, leads to the elevation of pro-angiogenic gene expression and migration as well as inhibition of GSK3 and thereby blocking the apoptosis. Moreover, MUC1 induces proliferative signaling through making interaction with tyrosine kinase receptor IGF-1R and IGF-1 mediated induction of VEGF. HGF regulates VEGF expression via the tyrosine-protein kinase c-Met receptor downstream pathways, PI3K/Akt, MAPK, and STAT3 in cancer cells