Intracrine VEGF signalling mediates colorectal cancer cell migration and invasion

Abstract

Background:Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) are key regulators of angiogenesis, affecting endothelial cell survival and function. However, the effect of VEGF-VEGFR signalling on tumour cell function is not well understood. Our previous studies in colorectal cancer (CRC) cells have demonstrated an intracrine VEGF/VEGFR1 signalling mechanism that mediates CRC cell survival and chemo-sensitivity. Since extracellular VEGF signalling regulates migration of endothelial cells and various tumour cells, we attempted to determine whether intracrine VEGF signalling affects CRC cell motility.Methods:Migration and invasion of CRC cells, with and without VEGF or VEGFR1 depletion, were assayed using transwell migration chambers. Changes in cell morphology, epithelial-mesenchymal transition (EMT) markers, and markers of cell motility were assessed by immunostaining and western blot.Results:Depletion of intracellular VEGF and VEGFR1 in multiple CRC cell lines led to strong inhibition of migration and invasion of CRC cells. Except for Twist, there were no significant differences in markers of EMT between control and VEGF/VEGFR1-depleted CRC cells. However, VEGF/VEGFR1-depleted CRC cells demonstrated a significant reduction in levels of phosphorylated focal adhesion kinase and its upstream regulators pcMET and pEGFR.Conclusions:Inhibition of intracrine VEGF signalling strongly inhibits CRC cell migration and invasion by regulating proteins involved in cell motility.

Vascular endothelial growth factor A/Vascular endothelial growth factor receptor 2 axis promotes human dental pulp stem cell migration via the FAK/PI3K/Akt and p38 MAPK signalling pathways

“…VEGFA induces the migration of endothelial cells and lymphatic endothelium through activation of VEGFR2 (Suzuki et al 2008, Dellinger & Brekken 2011. Bhattacharya et al (2017) suggested that VEGF regulates colorectal cancer cell invasion and migration via intracrine VEGF signalling mediated by VEGFR1. Bhattacharya et al (2017) suggested that VEGF regulates colorectal cancer cell invasion and migration via intracrine VEGF signalling mediated by VEGFR1.…”

“…Notably, to eliminate the influence of gravity on transwell assay, hDPSCs was seeded on the back of chambers and VEGFA was placed in the upper chambers, and the results were consistent with those of conventional experiments (data not shown). Previous studies have revealed that VEGF regulates cell migration via several signalling pathways (Simons et al 2016, Bhattacharya et al 2017. VEGF promotes human MSC migration via an ERK MAPK-and FAK-dependent mechanism.…”

“…As a chemokine and mitogen, VEGF binds with its prime receptor VEGFR2 to play a key role in endothelial cell survival and angiogenesis (Karali et al 2014). On the other hand, VEGFR1 participates in migration, invasion and survival of human colorectal cancer cells via a novel intracrine mechanism that is diverse from the canonical autocrine or paracrine roles of VEGF (Bhattacharya et al 2016(Bhattacharya et al , 2017. On the other hand, VEGFR1 participates in migration, invasion and survival of human colorectal cancer cells via a novel intracrine mechanism that is diverse from the canonical autocrine or paracrine roles of VEGF (Bhattacharya et al 2016(Bhattacharya et al , 2017.…”

“…The binding of VEGF to VEGFR2 brings receptor autophosphorylation and initiates a string of signalling cascades, resulting in cell proliferation, migration and survival (Simons et al 2016). On the other hand, VEGFR1 participates in migration, invasion and survival of human colorectal cancer cells via a novel intracrine mechanism that is diverse from the canonical autocrine or paracrine roles of VEGF (Bhattacharya et al 2016(Bhattacharya et al , 2017. Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) are activated by VEGF in endothelial cells to enhance cell migration (Chiu et al 2013).…”

Lysine‐specific demethylase 1 activation by vitamin B2 attenuates efficacy of apatinib for proliferation and migration of gastric cancer cell MGC‐803

“…Recent studies have implicated that VEGFR activation led to an increase in expression of the EMT-associated transcription factors Snail, Twist, and Slug which regulated the expression of epithelial markers E-cadherin to induce cell migration and invasion in cancer cells. [48][49][50] As the important roles of vascular endothelial growth factor VEGF and VEGFR in carcinogenesis, therapeutic strategies against these targets have been widely studied. 51,52 Gastric cancer is one of the indications for VEGF/VEGFR-targeted therapy based on the angiogenic evidence.…”