title: Inhibiting vasculogenesis after radiation: a new paradigm to improve local control by radiotherapy.
abstract: Tumors are supported by blood vessels, and it has long been debated whether their response to irradiation is affected by radiation damage to the vasculature. We have shown in preclinical models that, indeed, radiation is damaging to the tumor vasculature and strongly inhibits tumor angiogenesis. However, the vasculature can recover by colonization from circulating cells, primarily proangiogenenic CD11b+ monocytes or macrophages from the bone marrow. This secondary pathway of blood vessel formation, known as vasculogenesis, thus acts to restore the tumor vasculature and allows the tumor to recur following radiation. The stimulus for the influx of these CD11b+ cells into tumors following irradiation is the increased levels of hypoxia-inducible factor-1 in the tumor due to induced tumor hypoxia secondary to blood vessel loss. This increases tumor levels of the chemokine stromal cell-derived factor-1, which has chemokine receptors CXCR4 and CXCR7 on monocytes and endothelial cells thereby capturing these cells in the tumors. The increase in CD11b+ monocytes in tumors following irradiation can be prevented using antibodies or small molecules that inhibit hypoxia-inducible factor-1 or the interaction of stromal cell-derived factor-1 with its receptors. We show that the effect of inhibiting these chemokine-chemokine receptor interactions is a marked increase in the radiation response of transplanted or chemically induced tumors in mice and rats. This strategy of inhibiting vasculogenesis following tumor irradiation is a new paradigm in radiotherapy and suggests that higher levels of local control of tumors in several sites would be achievable with this strategy.
authors.affiliation: Department of Radiation Oncology, Stanford University, Stanford, CA. Electronic address: mbrown@stanford.edu.
authors.forename: Brown J
authors.initials: BJ
authors.lastname: Martin
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D039481:CD11b Antigen / Q000378:metabolism*; D015687:Cell Hypoxia / Q000528:radiation effects*; D054377:Chemokine CXCL12 / Q000378:metabolism; D018925:Chemokines / Q000037:antagonists & inhibitors; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000532:radiotherapy*
chemical_list: D039481:CD11b Antigen; D054377:Chemokine CXCL12; D018925:Chemokines; D051793:Hypoxia-Inducible Factor 1