Taxanes Induce a Rapid Mobilization of Different Populations of Circulating Endothelial Progenitors by SDF-1 Modulation in Cancer Patients.

There is increasing clinical evidence that the addition of certain anti-angiogenic drugs can enhance the anti-cancer activity of many different chemotherapeutic drugs. Hypotheses to explain how anti-angiogenic drugs act as chemosensitizing agents include the “cancer vessel normalization” scenario and the ability of anti-angiogenic drugs to slow down tumor regrowth and thus increase the degree and durability of the tumor response. We have previously observed in preclinical studies a mobilization of circulating endothelial progenitors (CEPs) several days after the administration of maximum tolerable dose (MTD) cyclophosphamide (Bertolini et al, 2003), and suggested that such a CEP mobilization may facilitate tumor cell repopulation during the subsequent drug-free break that is necessary to allow recovery from the toxic side effects of such therapy. We report here preclinical and clinical evidence that several chemotherapeutics, and in particular taxanes, induce a rapid CEP increase. In previous mouse studies (Shaked et al, Cancer Cell, in press 2008), 4–24 hours after MTD administration of taxanes we observed a 3–8 fold CEP increase (depending on the mice strain, drug and dose administered). A similarly rapid CEP mobilization was observed (albeit at a less relevant level) after 5-FU administration, but not after the administration of drugs such as gemcitabine, anthracycline derivates or topo-isomerase inhibitors. The rapid mobilization induced by taxanes resulted in a colonization of treated tumors by CEPs, that was abrogated by the previous administration of anti-angiogenic drugs blocking VEGF or VEGFR2. A rapid increase in circulating SDF-1 levels was similarly observed after taxane administration, and inhibition of the CXCR4-SDF-1 axis by monoclonal antibodies blocked CEP mobilization and significantly enhanced the anti-tumor activity of taxanes. In clinical studies in cancer patients in Milan and Utrecht (n=54), we observed that MTD taxanes induced a rapid (by 4 hours) increase in circulating SDF-1 levels and a parallel 2–4 fold increase in a variety of different CEP populations (evaluated by six-colour flow cytometry as viable CD45- CD34+VEGFR2+ cells, CD133+ cells, CD45-CD133+ cells, CD45-CD34+CD133+ cells and CD45-CD34+CD133+CXCR4+ cells). Circulating levels of G-CSF, VEGF, VEGFR1 and VEGFR2 were not significantly modulated 4–24 hours after taxane administration. Taken together, our data indicate a novel SDF-1-related mechanism explaining the chemosensitizing activity of anti-angiogenic drugs and suggest that VEGF/VEGFR and SDF-1 inhibition can increase the anti-cancer efficacy of taxanes. Further investigations about chemotherapy-induced CEP mobilization might have a clinical impact in cancer and vascular medicine.