M. Gourlaouen

Publications (2)6.37 Total impact

• Article: Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib.

  J C Welti, M Gourlaouen, T Powles, S C Kudahetti, P Wilson, D M Berney, A R Reynolds
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  ABSTRACT: The vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor sunitinib has been approved for first-line treatment of patients with metastatic renal cancer and is currently being trialled in other cancers. However, the effectiveness of this anti-angiogenic agent is limited by the presence of innate and acquired drug resistance. By screening a panel of candidate growth factors we identified fibroblast growth factor 2 (FGF2) as a potent regulator of endothelial cell sensitivity to sunitinib. We show that FGF2 supports endothelial proliferation and de novo tubule formation in the presence of sunitinib and that FGF2 can suppress sunitinib-induced retraction of tubules. Importantly, these effects of FGF2 were ablated by PD173074, a small molecule inhibitor of FGF receptor signalling. We also show that FGF2 can stimulate pro-angiogenic signalling pathways in endothelial cells despite the presence of sunitinib. Finally, analysis of clinical renal-cancer samples demonstrates that a large proportion of renal cancers strongly express FGF2. We suggest that therapeutic strategies designed to simultaneously target both VEGF and FGF2 signalling may prove more efficacious than sunitinib in renal cancer patients whose tumours express FGF2.
  Oncogene 11/2010; 30(10):1183-93. · 6.37 Impact Factor
• Article: Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors

  A.R. Reynolds, I.R. Hart, A.R. Watson, J.C. Welti, R.G. Silva, S.D. Robinson, G. Da Violante, M. Gourlaouen, M. Salih, M.C. Jones, D.T. Jones, G. Saunders, V. Kostourou, F. Perron-Sierra, J.C. Norman, G.C. Tucker, K.M. Hodivala-Dilke
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  ABSTRACT: Inhibitors of alpha(v)beta(3) and alpha(v)beta(5) integrin have entered clinical trials as antiangiogenic agents for cancer treatment but generally have been unsuccessful. Here we present in vivo evidence that low (nanomolar) concentrations of RGD-mimetic alpha(v)beta(3) and alpha(v)beta(5) inhibitors can paradoxically stimulate tumor growth and tumor angiogenesis. We show that low concentrations of these inhibitors promote VEGF-mediated angiogenesis by altering alpha(v)beta(3) integrin and vascular endothelial growth factor receptor-2 trafficking, thereby promoting endothelial cell migration to VEGF. The proangiogenic effects of low concentrations of RGD-mimetic integrin inhibitors could compromise their efficacy as anticancer agents and have major implications for the use of RGD-mimetic compounds in humans.