Crosstalk between MUC1 and VEGF in angiogenesis and metastasis: a review highlighting roles of the MUC1 with an emphasis on metastatic and angiogenic signaling

Abstract

VEGF and its receptor family (VEGFR) members have unique signaling transduction system that play significant roles in most pathological processes, such as angiogenesis in tumor growth and metastasis. VEGF-VEGFR complex is a highly specific mitogen for endothelial cells and any de-regulation of the angiogenic balance implicates directly in endothelial cell proliferation and migration. Moreover, it has been shown that overexpressing Mucin 1 (MUC1) on the surface of many tumor cells resulting in upregulation of numerous signaling transduction cascades, such as growth and survival signaling pathways related to RTKs, loss of cell-cell and cell-matrix adhesion, and EMT. It promotes gene transcription of pro-angiogenic proteins such as HIF-1α during periods of oxygen scarcity (hypoxia) to enhance tumor growth and angiogenesis stimulation. In contrast, the cytoplasmic domain of MUC1 (MUC1-C) inhibits apoptosis, which in turn, impresses upon cell fate. Besides, it has been established that reduction in VEGF expression level correlated with silencing MUC1-C level indicating the anti-angiogenic effect of MUC1 downregulation. This review enumerates the role of MUC1-C oncoprotein and VEGF in angiogenesis and metastasis and describes several signaling pathways by which MUC1-C would mediate the pro-angiogenic activities of cancer cells.

Keywords: Angiogenesis; Cancer; MUC1; Targeted therapy; VEGF; VEGFR.

Fig. 1

Different domains and different transcription variants of MUC1. Reprinted with permission from Ref. [97]

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