fig1

Figure 1. Non-angiogenic tumours: rational for resistance to anti-angiogenic treatment. A: Newly formed vessel. When cancer cells induce angiogenesis, new vessels sprout from the pre-existing one. These new vessels are lined up by newly formed proliferating endothelial cells. Under the influence of the angiogenic factors released by the cancer cells, like VEGF and PDEGF, the endothelial cells express higher levels of the relevant receptors. Following binding with their ligands, the intracellular portion of the receptors is phosphorylated activating the downstream intracellular pathways. A third angiogenic mechanisms is also present in this example: Angiopoietin 2 compete with Angiopoietin 1 and binds with the Tie receptor. Angiopoietin 1 maintains the endothelial cell quiescent, by taking its places Angiopoietin 2 trigger endothelial proliferation. In this situation compounds blocking VEGF or inhibitors of the Tyrosine kinases, blocking the activation of receptors like VEGFR2, can be effective; B: A co-opted pre-existing normal vessel. In non-angiogenic tumours the cells do not trigger angiogenesis but grow by exploiting the pre-existing vessels. These are lined by quiescent mature endothelial cells those few receptors for angiogenic factors remain inactive as no angiogenic stimuli are present. The Tie2 receptors remain linked to Angiopoietin 1 which maintain the vessel quiescent. Much is still to be learned about the biology of this system but is it is possible to appreciate how antibodies blocking VEGF or tyrosine kinases inhibiting angiogenesis, will not have any effects as the pathways they target are not contributing to the growth of these tumours. VEGF: vascular endothelial growth factor; PDEGF: platelets derived endothelial growth factor