The EGFR inhibitor gefitinib suppresses recruitment of pericytes and bone marrow-derived perivascular cells into tumor vessels.
Drugs that target EGFR have established anti-tumor effect and are used in the clinic. Here we addressed whether inhibition of EGFR tyrosine kinase activity by gefitinib in tumor microenvironment affected tumor angiogenesis or vasculogenesis. A syngeneic tumor model of mice with grafted GFP-labeled bone marrow cells was used to analyze the effects of gefitinib on different cellular components of tumor vasculature. To characterize tumor cell-independent stromal effects of EGFR targeting, the mice were injected with B16 melanoma cells not expressing significant quantities of EGFR, and treated with gefitinib for seven days, a period not sufficient for significant reduction in total tumor volume. Numbers of vessels as well as cell surface areas covered by markers of endothelial, pericyte and bone marrow-derived progenitor cells were quantified by image analysis of tumor sections. Quantitative analysis of immunohistochemical data demonstrated that gefitinib decreased the coverage of small CD31-positive vessels with NG2-positive pericytes, as well as reduced the recruitment of perivascular GFP-positive bone marrow-derived progenitor cells within the tumor tissue. These results suggest that inhibition of EGFR activity in tumors has vascular effects in the absence of direct effect on tumor cells. EGFR targeting may lead to suppressed mobilization of pericytes needed for vessel stabilization, as well as of bone marrow-derived perivascular progenitor cells. These findings introduce novel cellular mechanisms by which EGFR targeted drugs may suppress tumor growth.
Iivanainen
Erika
E
Department of Medical Biochemistry and Genetics, University of Turku, FIN-20520 Turku, Finland.
Lauttia
Susanna
S
Zhang
Na
N
Tvorogov
Denis
D
Kulmala
Jarmo
J
Grenman
Reidar
R
Salven
Petri
P
Elenius
Klaus
K
D000818:Animals; D000941:Antigens / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000077156:Gefitinib; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020286:Pericytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000098:blood supply / Q000188:drug therapy; D000099216:Chondroitin Sulfate Proteoglycan 4
D000941:Antigens; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077156:Gefitinib; D047428:Protein Kinase Inhibitors; D011509:Proteoglycans; D011799:Quinazolines; D000099216:Chondroitin Sulfate Proteoglycan 4