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[2014 Fall Life Sciences & IBB Regular Seminar]
▶Subject: Tumor associated macrophages govern the response of solid tumors to cancer therapy
▶Speaker: Martin Brown, Ph.D. (Department of Radiation Oncology, Stanford University)
▶Place: Room 401, Chemistry Building
Tumor blood vessels derive principally from two sources: From angiogenesis, the sprouting of endothelial cells from nearby blood vessels, and from vasculogenesis, the formation of blood vessels by circulating cells. For most tumors following therapy angiogenesis is the most important process for the formation of these vessels. However, in the case of irradiation, and with some chemotherapeutic drugs, anti-angiogenic or anti-vascular therapies, angiogenesis can be abrogated thereby forcing the tumor to use vasculogenesis to restore the vasculature. We and others have shown that following these vascular disruptive therapies there is a large influx of CD11b+ monocytes into the tumors, which become M2-skewed tumor associated macrophages (TAMs), and that these promote the restoration of the tumor vasculature by producing pro-angiogenic factors.
We have tested the hypothesis that the radiation response of tumors can be increased by blocking the influx of these monocytes using two human tumors (FaDu head and neck tumors and the U251 glioblastoma) transplanted into nude mice and autochthonous ENU-induced brain tumors in rats. We show that an essential contributor to vasculogenesis in irradiated tumors are CD11b+ myelomonocytic cells expressing MMP-9. These are recruited to the irradiated tumors by stromal cell derived factor 1 (SDF-1, or CXCL12) induced by increased levels of HIF-1 in the irradiated tumors. Importantly, a variety of ways of blocking this process (neutralizing antibodies to CD11b, inhibition of SDF-1, antibodies against CXCR4, and inhibition of HIF-1) render tumors less able, or unable, to recur following irradiation thereby producing a profound tumor radiosensitization. We also show that blocking vasculogenesis does not increase the radiation damage to normal skin.
Thus blocking the entry of circulating monocytes into tumors following therapy can have a major positive impact on the response of solid tumors to irradiation and other anti-vascular strategies and potentially represents a new paradigm for the treatment of such tumors.
▶Inquiry: Prof. G-One Ahn (279-2353)
* This seminar will be given in English