Nancy Dumont

Stromal cells can have a significant impact on the carcinogenic process in adjacent epithelia. The role of transforming growth factor-beta (TGF-beta) signaling in such epithelial-mesenchymal interactions was determined by conditional inactivation of the TGF-beta type II receptor gene in mouse fibroblasts (Tgfbr2fspKO). The loss of TGF-beta responsiveness in fibroblasts resulted in intraepithelial neoplasia in prostate and invasive squamous cell carcinoma of the forestomach, both 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. Thus, TGF-beta signaling in fibroblasts modulates the growth and oncogenic potential of adjacent epithelia in selected tissues.

TGF-betas are potent inhibitors of epithelial cell proliferation. However, in established carcinomas, autocrine/paracrine TGF-beta interactions can enhance tumor cell viability and progression. Thus, we studied the effect of a soluble Fc:TGF-beta type II receptor fusion protein (Fc:TbetaRII) on transgenic and transplantable models of breast cancer metastases. Systemic administration of Fc:TbetaRII did not alter primary mammary tumor latency in MMTV-Polyomavirus middle T antigen transgenic mice. However, Fc:TbetaRII increased apoptosis in primary tumors, while reducing tumor cell motility, intravasation, and lung metastases. These effects correlated with inhibition of Akt activity and FKHRL1 phosphorylation. Fc:TbetaRII also inhibited metastases from transplanted 4T1 and EMT-6 mammary tumors in syngeneic BALB/c mice. Tumor microvessel density in a mouse dorsal skin window chamber was unaffected by Fc:TbetaRII. Therefore, blockade of TGF-beta signaling may reduce tumor cell viability and migratory potential and represents a testable therapeutic approach against metastatic carcinomas.

TGF-s are potent inhibitors of epithelial cell proliferation.However, in established carcinomas, autocrine/paracrine TGF- interactions can enhance tumor cell viability and progression.Thus, we studied the effect of a soluble Fc:TGF- type II receptor fusion protein (Fc:TRII) on transgenic and transplantable models of breast cancer metastases.Systemic administration of Fc:TRII did not alter primary mammary tumor latency in MMTV-Polyomavirus middle T antigen transgenic mice.However, Fc:TRII increased apoptosis in primary tumors, while reducing tumor cell motility, intravasation, and lung metastases.These effects correlated with inhibition of Akt activity and FKHRL1 phosphorylation.Fc:TRII also inhibited metastases from transplanted 4T1 and EMT-6 mammary tumors in syngeneic BALB/c mice.Tumor microvessel density in a mouse dorsal skin window chamber was unaffected by Fc:TRII.Therefore, blockade of TGF- signaling may reduce tumor cell viability and migratory potential and represents a testable therapeutic approach against metastatic carcinomas.