Abstract 3441: Circulating Perivascular Progenitors, a Target of PDGFRbeta Inhibitors

Abstract Cancer blood vessels consist of two interacting types of cells: inner lining endothelial cells and surrounding perivascular cells (pericytes, vascular smooth muscle cells or mural cells). Marrow-derived PDGFRbeta(CD140b)+ progenitor perivascular cells (PPC) can differentiate into pericytes and regulate vessel stability and vascular survival in tumours (Song et al, Nature Cell Biol 2005). Similarly to what we have done with circulating endothelial cells and progenitors (Mancuso et al, Clin Cancer Res 2009), we have developed and validated a flow cytometry procedure for the enumeration of circulating PPC and the study of their viability in murine models of cancer and in cancer patients. DNA+CD45-CD31-CD140b+ cells were enumerated by six-colour flow cytometry, their perivascular nature was confirmed by electron microscopy and RT-PCR expression of CD140b, and their viability was assessed by 7AAD. PPC were found to circulate in cancer-bearing mice, and to be increased (compared to age-matched healthy controls) in patients affected by some types of cancer such as metastatic breast and kidney cancer. In murine models of cancer and in cancer patients, at variance with the kinetcs of circulating endothelial progenitors (Bertolini et al, Cancer Res 2003; Shaked et al, Cancer Cell 2008), cyclophosphamide-based chemotherapy reduced the number of viable PPC, most likely because of an increase of PPC recruitment towards vessels damaged by cyclophosphamide administration (Bertolini et al, Lancet Oncology 2001). Conversely, the administration of the tyrosine kinase inhibitor (TKI) sunitinib, known to inhibit PDGFRbeta, was associated in murine models and human cancer patients with an increase of apoptotic circulating PPC, suggesting a direct targeting of these cells. Studies are ongoing to validate PPC enumeration and viability assessment as a surrogate marker of clinical efficacy in preclinical models and in cancer patients receiving multiple TKI inhibitors including an anti-PDGFRbeta activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3441.