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Intracrine VEGF Signalling Mediates Colorectal Cancer Cell Migration and Invasion

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Intracrine VEGF Signalling Mediates Colorectal Cancer Cell Migration and Invasion FULL PAPER British Journal of Cancer (2017) 117, 848–855 | doi: 10.1038/bjc.2017.238 Keywords: colorectal cancer; VEGF; VEGFR1; intracrine signalling; migration; EMT Intracrine VEGF signalling mediates colorectal cancer cell migration and invasion Rajat Bhattacharya*,1, Fan Fan1, Rui Wang1, Xiangcang Ye1, Ling Xia1, Delphine Boulbes1 and Lee M Ellis*,1,2 1Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA and 2Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 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 (VEGF) is a key regulator of function remains poorly understood. Lee et al (2007b) showed that angiogenesis and vascular function. Vascular endothelial growth an intracrine pathway might mediate cell survival in breast cancer factor promotes angiogenesis in numerous pathologic conditions, cells. Work from our laboratory has demonstrated that VEGF plays including cancer and ocular diseases (Connolly et al, 1989; Leung et al, an important role in tumour cell survival and modulates the 1989; Plouet et al, 1989). Its importance in development and sensitivity of tumour cells to chemotherapy (Samuel et al, 2011). physiology is demonstrated by embryonic lethality in mice with Our studies utilising depletion of VEGF by somatic knockout of deletion of a single VEGF allele (Ferrara et al, 1996; Gerber et al, 1999). the VEGF gene (Samuel et al, 2011) or by siRNA knockdown in Vascular endothelial growth factor is also the most prominent growth human colorectal cancer (CRC) cell lines (Bhattacharya et al, 2016) factor to mediate endothelial cell proliferation and survival (Gerber have demonstrated that loss of VEGF expression significantly et al, 1998a,b). These effects are attributed to well-studied canonical decreased cell proliferation, increased apoptosis, and enhanced paracrine and autocrine VEGF signalling effects on endothelial cells chemo-sensitivity of CRC cells (Samuel et al, 2011; Bhattacharya (Lee et al, 2007a). The mechanisms of VEGF signalling in angiogenesis et al, 2016). Importantly, these effects were not mediated in an have been extensively studied (Ferrara et al, 2003). autocrine or paracrine fashion, as neutralisation of extracellular Although the effects of VEGF and its receptors have been well VEGF with a monoclonal antibody or inhibition of VEGF receptor characterised in endothelial cells, the role of VEGF in tumour cell (VEGFR) kinase activity did not alter cell survival. These findings *Correspondence: Dr R Bhattacharya; E-mail: [email protected] or Professor LM Ellis; E-mail: [email protected] Received 11 April 2017; revised 19 June 2017; accepted 30 June 2017; published online 25 July 2017 r 2017 Cancer Research UK. All rights reserved 0007 – 0920/17 848 www.bjcancer.com | DOI:10.1038/bjc.2017.238 Intracrine VEGF mediates cancer cell migration BRITISH JOURNAL OF CANCER suggest that the intracellular effects of VEGF were independent of (diluted in blocking buffer or 2% bovine serum albumin in TBST) canonical VEGF-VEGFR activity (Samuel et al, 2011; Bhattacharya overnight. Membranes were then washed three times in TBST and et al, 2016). Cumulatively, these studies demonstrated that VEGF re-incubated with horseradish peroxidase-labelled secondary anti- functions in CRC cells via a novel intracrine mechanism that is bodies for 1 h, washed three times in TBST, and exposed to distinct from the established paracrine or autocrine roles of VEGF autoradiography films. Signals were detected by chemilumines- in angiogenesis. These intracrine effects were mediated through cence (Thermo Fisher Scientific). Antibodies for N-cadherin, VEGF by regulation of the activity of multiple receptor tyrosine E-cadherin, pcMET Y1234/Y1235, pEGFR Y1068, pFAK Y925, kinases (RTKs; e.g., EGFR and cMET) and downstream AKT pSRC Y416, vimentin, Snail, and Twist were from Cell Signaling signalling (Bhattacharya et al, 2016) in CRC cells. Similar effects in Technology (Danvers, MA, USA). The antibody against pVEGFR1 these cells were observed upon depletion of VEGFR1, supporting (Y1213) was purchased from R&D Systems Inc.. Antibodies for the role of a novel intracellular VEGF-VEGFR1 complex in CRC VEGF, vinculin, a-tubulin, Zeb1, and actin were from Santa Cruz cell survival (Bhattacharya et al, 2016). Biotechnology (Dallas, TX, USA). All antibodies were used Apart from its pro-survival effects, VEGF signalling also according to manufacturers’ specifications. All cell lysates were mediates migration in numerous cell types. Previous studies have prepared in radioimmunoprecipitation assay buffer with protease shown that VEGF signalling induces migration of endothelial cells and phosphatase inhibitors. in normal physiologic processes and in tumours (Koch and Claesson-Welsh, 2012). Inhibition of paracrine VEGF signalling siRNA knockdown. A mixture of three different siRNAs targeting has been shown to inhibit endothelial cell motility (Podar et al, all isoforms of human VEGF were used to deplete VEGF in CRC 2006; Costa et al, 2009). Our studies and studies from other groups cells (Bhattacharya et al, 2016). Similarly, VEGFR1 was depleted have also shown that paracrine/autocrine VEGF signalling, using a mixture of two different siRNAs targeting the N-terminus through its receptors, mediates migration of various tumour cells of VEGFR1 as previously described (Bhattacharya et al, 2016). A (Fan et al, 2005; Lu et al, 2012; Sennino et al, 2012). Since VEGF validated non-targeting siRNA obtained from Sigma-Aldrich (St. signalling has been shown to mediate migration of endothelial cells Louis, MO, USA) was used as a control. Lipofectamine 2000 siRNA and various tumour cells and since our prior studies demonstrated transfection reagent was used according to the manufacturer’s the presence of an intracrine signalling pathway in CRC cells, we instructions (Thermo Fisher Scientific). The siRNA knockdown sought to determine whether inhibition of intracrine VEGF experiments were performed in six-well dishes in regular cell signalling affects CRC cell motility. In this study, we show that culture medium containing 5% FBS and without antibiotics. inhibition of intracrine VEGF signalling strongly reduces CRC cell Twenty-four hours after transfections, cells were washed with migration and invasion. Our study also indicates that these changes phosphate-buffered saline (PBS) and cultured with MEM supple- in migration are not due to epithelial-mesenchymal transition mented with 1% FBS and antibiotics. Forty-eight hours later, (EMT)-like changes in CRC cells but, rather, are due to a decrease supernatant media were collected and assayed for VEGF depletion, in the activity of proteins associated with cell motility. or cells were lysed and assayed for various proteins. For cMET depletion, siRNAs targeting cMET (Silencer Select siRNA #4390824; Thermo Fisher Scientific) were used according to MATERIALS AND METHODS the manufacturer’s protocol. Migration and invasion assays. Cell migration in response to Cell culture. The human CRC cell lines HCT116, SW480, SW620, increased serum concentrations was assessed using modified and HT29 were purchased from American Type Culture Collection Boyden chambers according to the manufacturer’s protocol (ATCC; Manassas, VA, USA). The CRC cells were cultured in (Corning, Bedford, MA, USA). In brief, CRC cells were transfected minimum essential medium (MEM) supplemented with 10% foetal with control-siRNA, VEGF- siRNA, or VEGFR1-siRNA. Approxi- bovine serum (FBS; Atlanta Biologicals, Flowery Branch, GA, USA) mately 48 h after transfection, HCT116 (50 000 cells), SW480 cells and the recommended concentrations of vitamins, nonessential (100 000 cells), SW620 (100 000 cells), or HT29 (100 000 cells) in amino acids, penicillin/streptomycin, sodium pyruvate, and 1% MEM-FBS were incubated on membrane inserts with 8.0-mm L-glutamine (Thermo Fisher Scientific, Waltham, MA, USA). All pores in 24-well plates. Chemo-attractants (10% MEM-FBS)
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