The Lymphangiogenic Factor CCBE1 Promotes Angiogenesis and Tumor Growth in Colorectal Cancer

Background: Collagen and calcium-binding EGF domain-1 (CCBE1) is essential for the development of the lymphatic vasculature and colorectal cancer (CRC) lymphangiogenesis as it enhances the proteolytic process of vascular endothelial growth factor C (VEGFC) activating VEGFR3. The fully processed mature VEGFC could also activate VEGFR2, the important endothelial-specific receptor tyrosine kinase, involved in blood vascular development and tumor angiogenesis. However, the role of CCBE1 in cancer angiogenesis remains undefined. Methods: In this paper, we find that the protein expression of CCBE1 is higher in the primary CRC tissue with distant metastasis and positively correlated with blood vessel density. Results: The mRNA expression of CCBE1 is closely positively correlated with the vascular endothelial marker CD31 and VEGFR2 in CRC from TCGA datasets. The supernatant of the colorectal cancer cell line HCT116 with CCBE1 overexpression significantly promotes the tube formation ability of the human umbilical vein endothelial cells (HUVECs) in vitro and enhances angiogenesis and tumor growth in vivo. Knockdown of CCBE1 decreases the angiogenic ability of CRC. Conclusion: Our results demonstrate the angiogenic role of CCBE1 in CRC.