Abstract 541: TGF-β signaling in the tumor microenvironment promotes tumor formation and tumor progression

Recent studies indicated that the tumor microenvironment plays an important role in tumor growth. Both tumor cells and stromal cells produce TGF-β1, which contributes to autocrine and paracrine functions in the tumor microenvironment. During cell transformation, TGF-β induces angiogenesis, produces reactive stroma, and tumor invasiveness suggesting that crosstalk between the tumor and the stroma is very important in the progression of metastatic disease. The present study examined the effects of TGF-β1 crosstalk in the tumor microenvironment and its role in mediating tumor formation and tumor development by targeted abrogation of TGF-β expression in the tumor cells in situ. Athymic female mice were injected subcutaneously with either normal or tumor derived fibroblast, unmodified MDA-MB 435 breast cancer cells, MDA-MB 435 clones containing TGF-β siRNA either alone or in combination with fibroblasts. Implantation of the cells subcutaneously showed significant difference in tumor formation between the groups. Control animals injected with fibroblast only developed no tumors. In animals injected with TGF-β-silenced MDA-MB 435 clones there was 12.5% tumor incidence. When these same cells were injected in combination with fibroblast the tumor incidence increased to 57%. Unmodified MDA-MB 435 cells showed a tumor incidence of 85% when injected alone and 100% in the presence of fibroblasts. This data suggests that when TGF-β is inhibited in the tumor cells the surrounding stroma can provide growth factors that continue to support tumor formation. In addition to measuring the tumor incidence, tumor growth was assessed every two days over the course of 6 weeks or until tumor was removed due to necrosis. Control animals injected with fibroblasts alone showed no tumor growth. The tumors formed from TGF-β-silenced MDA-MB 435 clones display an average tumor volume of 11.2 mm 3 . When these cells were co-injected with fibroblasts, the average tumor volume increased to 76 mm 3 . Unmodified MDA-MB 435 cells produced an average tumor volume of 164.3 mm 3 but when injected with fibroblast the volume increased to 229.1 mm 3 . This data suggests that signaling from the tumor microenvironment can promote tumor progression through TGF-β signaling pathway. Thus, understanding the role of TGF-β1 expression in the tumor microenvironment will help to develop targeted therapies for cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 541.