Circulating perivascular progenitors: a target of PDGFR inhibition.
Cancer blood vessels consist of two interacting types of cells: inner lining endothelial cells (ECs) and surrounding perivascular cells (pericytes, vascular smooth muscle cells or mural cells). PDGFRbeta(CD140b)+ progenitor perivascular cells (PPC) can differentiate into pericytes and regulate vessel stability and vascular survival in tumors. Similarly to what we have done with circulating ECs and progenitors, we developed a flow cytometry procedure for the enumeration of circulating PPCs 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 morphology was studied by electron microscopy, PPC specificity confirmed by reverse trascription-PCR (RT-PCR) expression of CD140b mRNA, and viability assessed by Syto16 and 7AAD. In preclinical marrow transplantation studies, 9 ± 4% of circulating PPCs were derived from the marrow donor. PPCs were increased in cancer-bearing mice and in patients affected by some types of cancer. At variance with the kinetic of circulating endothelial progenitors, high-dose cyclophosphamide reduced the number of viable PPCs. The administration of sunitinib, a drug known to inhibit PDGFR, was associated in murine models and in cancer patients with an increase of apoptotic/necrotic circulating PPC, suggesting a direct targeting of these cells. PPC enumeration might be studied as a tool for the definition of the optimal biologic dose of anti-PDGFR drugs and investigated clinically as a possible predictive/prognostic tool in patients receiving anti-PDGFR drugs.
Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy.
Patrizia
P
Mancuso
Ines
I
Martin-Padura
Angelica
A
Calleri
Paola
P
Marighetti
Jessica
J
Quarna
Cristina
C
Rabascio
Paola
P
Braidotti
Francesco
F
Bertolini
D020533:Angiogenesis Inhibitors; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002452:Cell Count; D002454:Cell Differentiation; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D009369:Neoplasms / Q000097:blood*; D020286:Pericytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D000077210:Sunitinib
D020533:Angiogenesis Inhibitors; D007211:Indoles; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011758:Pyrroles; D020797:Receptor, Platelet-Derived Growth Factor beta; D000077210:Sunitinib