Vascular endothelial growth factor receptor-1 mediates migration of human colorectal carcinoma cells by activation of Src family kinases
Identifieur interne : 002226 ( Ncbi/Merge ); précédent : 002225; suivant : 002227Vascular endothelial growth factor receptor-1 mediates migration of human colorectal carcinoma cells by activation of Src family kinases
Auteurs : D P Lesslie [États-Unis] ; J M Summy [États-Unis] ; N U Parikh [États-Unis] ; F. Fan [États-Unis] ; J G Trevino [États-Unis] ; T K Sawyer [États-Unis] ; C A Metcalf [États-Unis] ; W C Shakespeare [États-Unis] ; D J Hicklin [États-Unis] ; L M Ellis [États-Unis] ; G E Gallick [États-Unis]Source :
- British Journal of Cancer [ 0007-0920 ] ; 2006.
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.
Url:
DOI: 10.1038/sj.bjc.6603143
PubMed: 16685275
PubMed Central: 2361330
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Fan</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Cancer Biology</institution> 1515 Holcombe Boulevard, Houston, TX,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Trevino, J G" sort="Trevino, J G" uniqKey="Trevino J" first="J G" last="Trevino">J G Trevino</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center</institution> 1515 Holcombe Boulevard, Houston, TX,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Cancer Biology</institution> 1515 Holcombe Boulevard, Houston, TX,<country>USA</country></nlm:aff><country 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D P" uniqKey="Lesslie D" first="D P" last="Lesslie">D P Lesslie</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center</institution> 1515 Holcombe Boulevard, Houston, TX,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Cancer Biology</institution> 1515 Holcombe Boulevard, Houston, TX,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Summy, J M" sort="Summy, J M" uniqKey="Summy J" first="J M" last="Summy">J M Summy</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Cancer Biology</institution> 1515 Holcombe Boulevard, Houston, TX,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Parikh, N U" sort="Parikh, N U" uniqKey="Parikh N" first="N U" last="Parikh">N U Parikh</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Cancer Biology</institution> 1515 Holcombe Boulevard, Houston, TX,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Fan, F" sort="Fan, F" uniqKey="Fan F" first="F" last="Fan">F. Fan</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Cancer Biology</institution> 1515 Holcombe Boulevard, Houston, TX,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Trevino, J G" sort="Trevino, J G" uniqKey="Trevino J" first="J G" last="Trevino">J G Trevino</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center</institution> 1515 Holcombe Boulevard, Houston, TX,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Cancer Biology</institution> 1515 Holcombe Boulevard, Houston, TX,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Sawyer, T K" sort="Sawyer, T K" uniqKey="Sawyer T" first="T K" last="Sawyer">T K Sawyer</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Ariad Pharmaceuticals</institution> Cambridge, MA,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Metcalf, C A" sort="Metcalf, C A" uniqKey="Metcalf C" first="C A" last="Metcalf">C A Metcalf</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Ariad Pharmaceuticals</institution> Cambridge, MA,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Shakespeare, W C" sort="Shakespeare, W C" uniqKey="Shakespeare W" first="W C" last="Shakespeare">W C Shakespeare</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Ariad Pharmaceuticals</institution> Cambridge, MA,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hicklin, D J" sort="Hicklin, D J" uniqKey="Hicklin D" first="D J" last="Hicklin">D J Hicklin</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>ImClone Systems</institution> New York, NY,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ellis, L M" sort="Ellis, L M" uniqKey="Ellis L" first="L M" last="Ellis">L M Ellis</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center</institution> 1515 Holcombe Boulevard, Houston, TX,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Cancer Biology</institution> 1515 Holcombe Boulevard, Houston, TX,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gallick, G E" sort="Gallick, G E" uniqKey="Gallick G" first="G E" last="Gallick">G E Gallick</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Cancer Biology</institution> 1515 Holcombe Boulevard, Houston, TX,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">British Journal of Cancer</title><idno type="ISSN">0007-0920</idno><idno type="eISSN">1532-1827</idno><imprint><date when="2006">2006</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<pmc-comment> Original-type: oa</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Br J Cancer</journal-id><journal-title>British Journal of Cancer</journal-title><issn pub-type="ppub">0007-0920</issn><issn pub-type="epub">1532-1827</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">16685275</article-id><article-id pub-id-type="pmc">2361330</article-id><article-id pub-id-type="pii">6603143</article-id><article-id pub-id-type="doi">10.1038/sj.bjc.6603143</article-id><article-categories><subj-group subj-group-type="heading"><subject>Molecular Diagnostics</subject></subj-group></article-categories><title-group><article-title>Vascular endothelial growth factor receptor-1 mediates migration of human colorectal carcinoma cells by activation of Src family kinases</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Lesslie</surname><given-names>D P</given-names><suffix>III</suffix></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Summy</surname><given-names>J M</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Parikh</surname><given-names>N U</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Fan</surname><given-names>F</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Trevino</surname><given-names>J G</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Sawyer</surname><given-names>T K</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Metcalf</surname><given-names>C A</given-names><suffix>III</suffix></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Shakespeare</surname><given-names>W C</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Hicklin</surname><given-names>D J</given-names></name><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Ellis</surname><given-names>L M</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Gallick</surname><given-names>G E</given-names></name><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="corresp" rid="caf1">*</xref></contrib></contrib-group><aff id="aff1"><label>1</label><institution>Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center</institution> 1515 Holcombe Boulevard, Houston, TX,<country>USA</country></aff><aff id="aff2"><label>2</label><institution>Department of Cancer Biology</institution> 1515 Holcombe Boulevard, Houston, TX,<country>USA</country></aff><aff id="aff3"><label>3</label><institution>Ariad Pharmaceuticals</institution> Cambridge, MA,<country>USA</country></aff><aff id="aff4"><label>4</label><institution>ImClone Systems</institution> New York, NY,<country>USA</country></aff><author-notes><corresp id="caf1"><label>*</label>Author for correspondence: <email xlink:href="mailto:ggallick@mdanderson.org">ggallick@mdanderson.org</email></corresp></author-notes><pub-date pub-type="epub"><day>09</day><month>05</month><year>2006</year></pub-date><pub-date pub-type="collection"><day>30</day><month>05</month><year>2006</year></pub-date><pub-date pub-type="ppub"><day>05</day><month>06</month><year>2006</year></pub-date><volume>94</volume><issue>11</issue><fpage>1710</fpage><lpage>1717</lpage><history><date date-type="received"><day>14</day><month>10</month><year>2005</year></date><date date-type="rev-recd"><day>06</day><month>03</month><year>2006</year></date><date date-type="accepted"><day>05</day><month>04</month><year>2006</year></date></history><copyright-statement>Copyright 2006, Cancer Research UK</copyright-statement><copyright-year>2006</copyright-year><permissions><copyright-holder>Cancer Research UK</copyright-holder></permissions><abstract><p>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.</p></abstract><kwd-group><kwd>VEGFR-1</kwd><kwd>VEGF</kwd><kwd>Src kinase</kwd><kwd>colorectal cancer</kwd></kwd-group></article-meta></front><floats-wrap><fig id="fig1"><label>Figure 1</label><caption><p>Effect of VEGF on SFK activity in human CRC cell lines. (<bold>A</bold>) Serum-starved HT29 cells at 50% confluency were untreated (0) or stimulated with VEGF-A for 5, 10 and 15 min. Cell lysates were immunoprecipitated with anti-Src or anti-Yes antibodies and subjected to immune complex kinase assays (top two panels) or Western blotting with the phospho-specific anti-Src Y416 antibody. Western blotting (following immunoprecipitation) with anti-Src antibody demonstrates equivalent total Src expression (bottom panel). (<bold>B</bold>) Serum-starved HT29 cells at 50% confluency were untreated (0) or stimulated with indicated concentrations of VEGF-A for 15 min. Cell lysates were immunoprecipitated with anti-Src or anti-Yes antibodies and subjected to immune complex kinase assay. (<bold>C</bold>) KM12L4 cell lysates were prepared and immunoblotted with SrcY416 antibodies and stripped and reprobed with total Src antibodies as described above.</p></caption><graphic mime-subtype="jpeg" xlink:href="94-6603143f1"></graphic></fig><fig id="fig2"><label>Figure 2</label><caption><p>Requirement for VEGFR-1 for Src activation by VEGF-A and VEGF-B. (<bold>A</bold>) Lysates from VEGF-treated cells in the presence or absence of the VEGFR-1 blocking antibody, IMC-18F1, following immunodepletion with anti-VEGFR-1 antibody (first lane) or nonspecific IgG (second and third lanes) were prepared, and the resultant supernatants were subjected to Western blotting with anti-phosphotyrosine antibody or anti-VEGFR-1 antibody. (<bold>B</bold>, <bold>C</bold>) Serum-starved HT29 cells at 50% confluency were pretreated with IMC-18F1 or PBS control for 1 h and were untreated (0) or stimulated with VEGF-A or VEGF-B for 10, 15 and 30 min. Cell lysates were immunoprecipitated with anti-Src or anti-Yes antibodies and subjected to immune complex kinase assay or subjected to Western blotting with anti-Src, anti-Yes or anti-VEGFR-1 antibodies to demonstrate the lack of effect on expression of these proteins. (<bold>D</bold>) Lysates from VEGF-A-treated cells in the presence or absence or IMC-18F1 were immunoprecipitated with anti-VEGFR-1 antibody. The resultant immunoprecipitates were run on SDS–PAGE and subjected to Western blotting with antibodies to Src, Yes or VEGFR-1.</p></caption><graphic mime-subtype="jpeg" xlink:href="94-6603143f2"></graphic></fig><fig id="fig3"><label>Figure 3</label><caption><p>Effects of VEGF-mediated SFK activation on CRC migration. HT29 and KM12L4 CRC cells were pretreated with IMC-18F1 (20 <italic>μ</italic>g ml<sup>−1</sup>), the novel, potent Src kinase inhibitor, AP23464 (1 <italic>μ</italic><sc>M</sc>), a commercially available Src inhibitor, PP2 (10 <italic>μ</italic><sc>M</sc>) or PBS control for 1 h and allowed to migrate in a modified Boyden chamber containing VEGF-A (10 ng ml<sup>−1</sup>) or 10% FBS for 72 h. (<bold>A</bold>, <bold>B</bold>) Representative photos of migrated cells ( × 100 magnification). (<bold>C</bold>, <bold>D</bold>) Quantitation of migrated cells. <sup>*</sup><italic>P</italic><0.001 <italic>vs</italic> control cells. <sup>**</sup><italic>P</italic><0.001 <italic>vs</italic> cells treated with VEGF alone. Bars represent s.e.m.</p></caption><graphic mime-subtype="jpeg" xlink:href="94-6603143f3"></graphic></fig><fig id="fig4"><label>Figure 4</label><caption><p>Effects of Src-targeted siRNA on VEGF-induced CRC migration. (<bold>A</bold>) HT29 parental cells and stable G418-resistant clones expressing either empty vector (siRNA control) or Src-targeted siRNA were subjected to Western blot analysis with antibodies to total Src. Membranes were stripped and reprobed with anti-vinculin antibody as a loading control. Parental HT29, siRNA control, siRNA cl. 18 and siRNA cl. 23 cells were placed in a modified Boyden chamber containing VEGF-A (10 ng ml<sup>−1</sup>) or 10% FBS for 72 h. (<bold>B</bold>) Representative photos of VEGF-A-treated cells ( × 100 magnification). (<bold>C</bold>) Quantitation of migrated cells. <sup>*</sup><italic>P</italic><0.001 <italic>vs</italic> VEGF-treated siRNA control.</p></caption><graphic mime-subtype="jpeg" xlink:href="94-6603143f4"></graphic></fig><fig id="fig5"><label>Figure 5</label><caption><p>Effects of VEGF on phosphorylation of FAK, p130<sup>cas</sup> and paxillin in CRC. Serum-starved HT29 cells at 50% confluency were pretreated with the VEGFR-1 blocking antibody (IMC-18F1) or PBS control for 1 h and were untreated (0) or stimulated with VEGF-A for 10, 15 and 30 min. Cell lysates were immunoprecipitated with anti-FAK antibody and subjected to immune complex kinase assay with enolase as an exogenous substrate or subjected to Western blotting with anti-phospho-FAK Y861, anti-phospho-FAK Y397 or anti-FAK antibodies as indicated (<bold>A</bold>), run on SDS–PAGE and subjected to Western blotting with anti-phospho-p130<sup>cas</sup> or anti-p130<sup>cas</sup> antibodies (<bold>B</bold>) or subjected to Western blotting with anti-phospho-paxillin or anti-paxillin antibodies (<bold>C</bold>). Western blot for vinculin is included to demonstrate equivalent protein loading.</p></caption><graphic mime-subtype="jpeg" xlink:href="94-6603143f5"></graphic></fig><fig id="fig6"><label>Figure 6</label><caption><p>Effects of VEGF on CRC proliferation. HT29 cells (2 × 10<sup>3</sup>) in 96-well plates in serum-free media were untreated or treated with VEGF-A (10 ng ml<sup>−1</sup>) in the presence of AP23464 (1 <italic>μ</italic><sc>M</sc>) or IMC-18F1 (20 <italic>μ</italic>g ml<sup>−1</sup>) and proliferation was determined by MTT assay as described in Materials and Methods. Bars represent standard error of the mean. Results are representative of three independent experiments.</p></caption><graphic mime-subtype="gif" xlink:href="94-6603143f6"></graphic></fig><fig id="fig7"><label>Figure 7</label><caption><p>Model by which Src and VEGF contribute to tumour progression and metastasis through activities in both tumour and tumour-associated endothelial cells. In tumour cells (left) Src activation is frequent, resulting from overexpression of growth factor receptors, FAK and deregulated transcription (<bold>A</bold>). Src activation increases VEGF expression from tumour cells (<bold>B</bold>), leading to binding of VEGFR-1 (<bold>C</bold>), association with and further activation of Src (<bold>D</bold>), and the subsequent autocrine loop contributes to tumour cell migration through FAK activation (<bold>E</bold>). Vascular endothelial growth factor produced by tumour cells also binds VEGF receptors on endothelial cells (<bold>F</bold>), leading to association and activation of Src in these cells (<bold>G</bold>) and leading to increased permeability through VE cadherin phosphorylation affecting tumour cell extravasation (<bold>H</bold>), a process critical for permeability and tumour cell extravasation (<bold>I</bold>). Thus, inhibitors of VEGF, VEGFR-1 and Src may have therapeutic efficacy due to their effects in both normal and tumour cells.</p></caption><graphic mime-subtype="jpeg" xlink:href="94-6603143f7"></graphic></fig></floats-wrap></pmc><affiliations><list><country><li>États-Unis</li></country></list><tree><country name="États-Unis"><noRegion><name sortKey="Lesslie, D P" sort="Lesslie, D P" uniqKey="Lesslie D" first="D P" last="Lesslie">D P Lesslie</name></noRegion><name sortKey="Ellis, L M" sort="Ellis, L M" uniqKey="Ellis L" first="L M" last="Ellis">L M Ellis</name><name sortKey="Ellis, L M" sort="Ellis, L M" uniqKey="Ellis L" first="L M" last="Ellis">L M Ellis</name><name sortKey="Fan, F" sort="Fan, F" uniqKey="Fan F" first="F" last="Fan">F. Fan</name><name sortKey="Gallick, G E" sort="Gallick, G E" uniqKey="Gallick G" first="G E" last="Gallick">G E Gallick</name><name sortKey="Hicklin, D J" sort="Hicklin, D J" uniqKey="Hicklin D" first="D J" last="Hicklin">D J Hicklin</name><name sortKey="Lesslie, D P" sort="Lesslie, D P" uniqKey="Lesslie D" first="D P" last="Lesslie">D P Lesslie</name><name sortKey="Metcalf, C A" sort="Metcalf, C A" uniqKey="Metcalf C" first="C A" last="Metcalf">C A Metcalf</name><name sortKey="Parikh, N U" sort="Parikh, N U" uniqKey="Parikh N" first="N U" last="Parikh">N U Parikh</name><name sortKey="Sawyer, T K" sort="Sawyer, T K" uniqKey="Sawyer T" first="T K" last="Sawyer">T K Sawyer</name><name sortKey="Shakespeare, W C" sort="Shakespeare, W C" uniqKey="Shakespeare W" first="W C" last="Shakespeare">W C Shakespeare</name><name sortKey="Summy, J M" sort="Summy, J M" uniqKey="Summy J" first="J M" last="Summy">J M Summy</name><name sortKey="Trevino, J G" sort="Trevino, J G" uniqKey="Trevino J" first="J G" last="Trevino">J G Trevino</name><name sortKey="Trevino, J G" sort="Trevino, J G" uniqKey="Trevino J" first="J G" last="Trevino">J G Trevino</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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