Abstract
Abstract Among the mechanisms of resistance to cancer treatment is the recruitment by tumors of inflammatory myeloid (CD11b+, Gr-1+) suppressor cells, promoting angiogenesis and tumor progression. Here, we report the effects of tissue inhibitor of metalloproteases(TIMP)-2 on the recruitment of CD11b+, Gr-1+ cells and subsequent suppression of tumor angiogenesis. Previously, we showed that xenografts of A549 cells with up-regulated TIMP-2 demonstrated significant reduction in the number of CD11b+, Gr-1+ cells, expression of VEGF-R2, and αvβ3 as well as reduced angiogenesis. Here, the effect of TIMP-2 on the growth of Luciferase-tagged-A549 cells was tested in vivo using the direct in vivo angiogenesis (DIVA) assay implanted subcutaneously containing 400 nM TIMP-2 or PBS. TIMP-2 decreased A549-cell proliferation in vivo as determined by quantitating bioluminescence emission. Immuno-histochemistry analysis of the tissue in TIMP-2 treated DIVAs demonstrated a drastic reduction in inflammation, fewer CD11b+, Gr-1+ cells were recruited into the TIMP-2 DIVA compared with untreated DIVA controls, as well as significant lower number of angiogenic vessels and invading endothelial cells were seen. Moreover, bone marrow from mice carrying DIVA with TIMP-2-treated A549 cells demonstrated a relative decrease in cell progenitors as compared with PBS treated tumor cells, suggesting that TIMP-2 blocked the release of tumor factors affecting the mobilization of bone marrow progenitors. These findings support TIMP-2 as anti-angiogenesis and anti-inflammatory factor. By targeting tumor-myeloid suppressors cells, TIMP-2 may have a therapeutic utility in the resistance of tumors to angiogenesis inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1376. doi:1538-7445.AM2012-1376
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