Stromal and epithelial TGF-β signaling in mammary tumorigenesis

The importance of stromal-epithelial interactions in mammary gland development and tumorigenesis is well established. These interactions probably involve autocrine and paracrine action of multiple growth factors, including members of the TGF-β family, which are expressed in both stroma and epithelium. Again, to accomplish complete knockout of the type II TGF-β receptor gene in mammary stromal cells, FSP1-Cre and Tgfbr2flox/flox mice were crossed to attain Tgfbr2fspKO mice. The loss of TGF-β responsiveness in fibroblasts resulted in intraepithelial neoplasia in prostate and invasive squamous cell carcinoma of the forestomach with high penetrance by 6 weeks of age. Both epithelial lesions were associated with an increased abundance of stromal cells. Activation of paracrine hepatocyte growth factor (HGF) signaling was identified as one possible mechanism for stimulation of epithelial proliferation. TGF-β signaling in fibroblasts thus modulates the growth and oncogenic potential of adjacent epithelia in selected tissues.More recently, we have examined the effects of Tgfbr2fspKO fibroblasts on normal and transformed mammary epithelium. We analyzed the role of TGF-β signaling by stromal cells in mammary tumor progression. To avoid the possibility of endogenous wild-type fibroblasts masking potential effects of Tgfbr2fspKO cells on tumor progression, we implanted PyVmT mammary carcinoma cells with Tgfbr2fspKO or wild-type fibroblasts in the subrenal capsule of nude mice. Mammary tumor cells implanted with Tgfbr2fspKO cells exhibited an increase in tumor growth and intravasation associated with an increase in tumor cell survival, proliferation and an increase in tumor angiogenesis compared with tumor cells implanted with control fibroblasts. We demonstrated increased expression of several growth factors by Tgfbr2fspKO fibroblasts compared with control fibroblasts in primary culture. These included HGF, MSP and TGF-α. There was an increase in tumor cell activating phosphoryl