title: Human tumor xenografts recurring after radiotherapy are more sensitive to anti-vascular endothelial growth factor receptor-2 treatment than treatment-naive tumors.
abstract: The effects of antiangiogenic therapy on tumors relapsing after irradiation are not known. To this end, we irradiated human tumors growing s.c. in nude mice with a single dose of 20 or 30 Gy. Compared with primary (treatment-naive) xenografts, the growth rate of recurrent tumors was 1.6-fold slower, which is consistent with the known "tumor bed effect." For similar size tumors, recurrences had fewer functional vessels, a reduced vessel coverage by perivascular cells, and were more necrotic. Placenta growth factor concentration was significantly lower in relapses, whereas vascular endothelial growth factor (VEGF) levels were similar between primary and recurrent tumors. On the other hand, fibrillar collagen deposition was significantly increased in recurrent tumors. This radiation-induced fibrosis was partially responsible for the slower growth of recurrences; the i.t. injection of collagenase increased the growth rate of tumor relapses without affecting primary tumor growth. The mouse-specific VEGF receptor 2-blocking antibody DC101 induced a 2.2-fold longer growth delay in recurrent tumors compared with treatment-naive tumors. DC101 significantly decreased the interstitial fluid pressure and did not change the functional vessel density and perivascular cell coverage in both tumor variants. Interestingly, DC101 induced a rapid (2 days after treatment initiation) and significant decrease in tumor cell proliferation in recurrent but not in primary tumors. Thus, our results show that the stromal compartment and the response to antiangionenic therapy of primary and in-field recurrent tumors are significantly different. Our findings suggest that antiangiogenic agents could be effective in the treatment of patients with relapses after radiotherapy.
authors.affiliation: Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Kozin
authors.forename: Frank
authors.initials: F
authors.lastname: Winkler
authors.forename: Igor
authors.initials: I
authors.lastname: Garkavtsev
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.forename: Yves
authors.initials: Y
authors.lastname: Boucher
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism; D017364:Collagenases / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000532:radiotherapy*; D051379:Mice; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local / Q000098:blood supply* / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D024042:Collagen Type I; C511761:DC101 monoclonal antibody; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; D017364:Collagenases