Vascular endothelial growth factor receptor-1 mediates migration of human colorectal carcinoma cells by activation of Src family kinases

Abstract

Vascular endothelial growth factor (VEGF) is the predominant pro-angiogenic cytokine in human malignancy, and its expression correlates with disease recurrence and poor outcomes in patients with colorectal cancer. Recently, expression of vascular endothelial growth factor receptors (VEGFRs) has been observed on tumours of epithelial origin, including those arising in the colon, but the molecular mechanisms governing potential VEGF-driven biologic functioning in these tumours are not well characterised. In this report, we investigated the role of Src family kinases (SFKs) in VEGF-mediated signalling in human colorectal carcinoma (CRC) cell lines. Vascular endothelial growth factor specifically activated SFKs in HT29 and KM12L4 CRC cell lines. Further, VEGF stimulation resulted in enhanced cellular migration, which was effectively blocked by pharmacologic inhibition of VEGFR-1 or Src kinase. Correspondingly, migration studies using siRNA clones with reduced Src expression confirmed the requirement for Src in VEGF-induced migration in these cells. Furthermore, VEGF treatment enhanced VEGFR-1/SFK complex formation and increased tyrosine phosphorylation of focal adhesion kinase, p130 cas and paxillin. Finally, we demonstrate that VEGF-induced migration is not due, at least in part, to VEGF acting as a mitogen. These results suggest that VEGFR-1 promotes migration of tumour cells through a Src-dependent pathway linked to activation of focal adhesion components that regulate this process.

The Lysine 831 of Vascular Endothelial Growth Factor Receptor 1 Is a Novel Target of Methylation by SMYD3

“…VEGFR1 is expressed in a wide range of human tissues, including colon (22)(23)(24)(25), breast (26,27), pancreatic (28,29), prostate (30), renal (31,32), and ovarian (33,34) cancer tissues and cancer cell lines (23,24,27,30,35,36). Reportedly, VEGFR1 expression was faint in primary colon cancer specimen, but its expression was clearly detected in liver metastasis (23).…”

Inhibition of VEGF-A prevents the angiogenic switch and results in increased survival of Apc +/min mice

“…Recent studies have raised the possibility that VEGF-A also may have direct effects on intestinal epithelial cells through VEGFR-1 (39,40). Future studies are required to determine whether such a mechanism plays a role in the growth of Apc ϩ/min adenomas.…”

Multiple receptor tyrosine kinases regulate HIF-1α and HIF-2α in normoxia and hypoxia in neuroblastoma: implications for antiangiogenic mechanisms of multikinase inhibitors

“…VEGFR-1 was initially identified as a facilitator of monocyte migration, but has since been shown to promote migration of colorectal and pancreatic cancer cells (Wey et al, 2005;Lesslie et al, 2006). VEGFR-1 is elevated in advanced-stage neuroblastoma (Fakhari et al, 2002).…”