Emerging data indicate that TGF-ss signaling in both epithelial cells and fibroblasts, in addition to controlling cell proliferation, also regulates the microenvironment by modulating the expression of growth factors, chemokines and cytokines. Loss of TGF-ss signaling in both mammary epithelial cells and stromal fibroblasts can result in increased production of chemokines that recruit bone marrow-derived cells (BMDCs), which then influence the initiation and progression of carcinomas. By conditional knockout of the type II TGFss receptor gene (Tgfbr2) in a subset of tissue fibroblasts using FSP1-Cre (Tgfbr2FSPKO), we have shown that loss of TGF-ss signaling enhances the initiation and progression of carcinomas in adjacent epithelia. Because of the short life span of the homozygous Tgfbr2FSPKO animals, we have employed recombination of Tgfbr2FSPKO and control mammary fibroblasts with mouse mammary carcinoma cells that are transplanted beneath the renal capsule of nude mice. The results of these studies show that Tgfbr2FSPKO fibroblasts enhance carcinoma growth, invasion and metastasis. Mechanisms identified so far include increased secretion of HGF, MSP and TGF-? by Tgfbr2FSPKO fibroblasts relative to control fibroblasts with increased activating phosphorylation of cognate receptors on adjacent carcinoma cells. Inhibition of c-Met attenuates the effects of the Tgfbr2FSPKO fibroblasts. Further, the Tgfbr2FSPKO fibroblasts secrete increased levels of several chemokines with associated increased infiltration of BMDCs that are known to promote carcinoma progression. Based on these observations and other data, we hypothesize that TGF-ss signaling in a subset of mammary gland fibroblasts is tumor suppressive for adjacent epithelia by regulating expression of growth factors, cytokines and chemokines. As a corollary, altered TGF-ss signaling in these stromal cells enhances mammary carcinoma initiation and progression by regulating secretion of both selected growth factors (i.e., HGF, MSP, TGF-?) that act in a paracrine manner on the epithelial cells and chemokines that recruit BMDCs to the tumor site. The BMDCs in turn express high levels of TGF-ss and MMPs that further promote tumor progression. These hypotheses can only be tested in animal models, and we will examine them through the following specific aims.
Specific aim 1. Determine the effect of TGF-ss signaling in different subsets of mammary fibroblasts on mammary gland development and oncogene-induced mammary carcinomas.
Specific aim 2. Determine mechanisms and effects of recruitment of BMDC caused by Tgfbr2 knockout in different subsets of fibroblasts on mammary carcinoma initiation and progression.
Specific aim 3. Determine whether altered mammary fibroblast TGF-ss signaling contributes to progression of human breast cancer.
Increasing evidence, a significant amount derived from work supported by this grant, indicates that TGF-beta signaling in stromal fibroblasts can play a significant role in the initiation and progression of carcinomas. This resubmission application proposes to investigate the role of TGF-beta signaling in regulating chemokine expression, recruitment of immature bone marrow-derived cells to the tumor microenvironment, and the effect of these cells on tumor initiation and progression. This work will identify new targets for cancer therapy.
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