stromal cell-derived factor-1cxcl12 contributes to mmtv-wnt1 tumor growth involving gr1+cd11b+ cells基质细胞衍生factor-1cxcl12有助于mmtv-wnt1涉及gr1一起+ cd11b +细胞的肿瘤生长.pdfVIP

Stromal Cell-Derived Factor-1/CXCL12 Contributes to MMTV-Wnt1 Tumor Growth Involving Gr1+CD11b+ Cells 1 1 1 1 2 1 Bob Y. Liu , Irina Soloviev , Peter Chang , John Lee , XiaoDong Huang , Cuiling Zhong , Napoleone 1 1 1 Ferrara , Paul Polakis , Chie Sakanaka * 1 Research Oncology, Genentech Inc, South San Francisco, California, United States of America, 2 Physiological Chemistry, Genentech Inc, South San Francisco, California, United States of America Abstract Background: Histological examinations of MMTV-Wnt1 tumors reveal drastic differences in the tumor vasculature when compared to MMTV-Her2 tumors. However, these differences have not been formally described, nor have any angiogenic factors been implicated to be involved in the Wnt1 tumors. Methodology/Principal Findings: Here, we show that MMTV-Wnt1 tumors were more vascularized than MMTV-Her2 tumors, and this correlated with significantly higher expression of a CXC chemokine, stromal cell-derived factor-1 (SDF1/ CXCL12) but not with VEGFA. Isolation of various cell types from Wnt1 tumors revealed that SDF1 was produced by both tumor myoepithelial cells and stromal cells, whereas Her2 tumors lacked myoepithelial cells and contained significantly less stroma. The growth of Wnt1 tumors, but not Her2 tumors, was inhibited by a neutralizing antibody to SDF1, but not by neutralization of VEGFA. Anti-SDF1 treatment decreased the proportion of infiltrating Gr1+ myeloid cells in the Wnt1 tumors, which correlated with a decrease in the percentage of endothelial cells. The involvement of Gr1+ cells was evident from the retardation of Wnt1 tumor growth following in vivo depletion of these cells with an a