Characterization of the effects of a small molecular weight inhibitor on IGF-I induced angiogenesis

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The IGF-IR is a transmembrane receptor tyrosine kinase that stimulates the survival and proliferation of multiple cell types. Overexpression of IGF-IR, as well as its ligands, has been documented in multiple tumour types and is positively correlated with tumour grade, disease progression and metastasis. In agreement with this, blockade of the IGF-IR is associated with inhibition of both primary tumour growth and metastatic spread in preclinical animal models. In addition to its action on tumour cells, the IGF system exerts multiple physiological effects on endothelial cells and the tumour vasculature. IGF-I treatment induces migration and morphological changes in endothelial cells, but can also act in a paracrine manner, stimulating the release of pro-angiogenic factors, such as VEGF. We have investigated the effects of a specific IGF-IR inhibitor on experimental models of angiogenesis. Using an implanted porous chamber model, IGF-I treatment led to an increase in chamber weight, blood content and Tie-2 content, a marker of vascularisation. Oral administration of an IGF-IR inhibitor effectively blocked these events. In addition, although VEGF mediated activation of its receptor, or downstream signalling pathways in endothelial cells remained unaffected, IGF-IR inhibitor treatment effectively blocked VEGF stimulated endothelial cell proliferation. Therapeutic agents that target IGF-IR kinase activity may therefore act by simultaneously inhibiting the effects IGF-I on tumour cells and the tumour vasculature.