Loss of TGF-β type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-α-, MSP- and HGF-mediated signaling networks

Abstract

Stromal fibroblasts regulate epithelial cell behavior through direct and indirect cell-cell interactions. To clarify the role of TGF-beta signaling in stromal fibroblasts during mammary development and tumorigenesis, we conditionally knocked out the TGF-beta type II receptor gene in mouse mammary fibroblasts (Tgfbr2(fspKO)). Tgfbr2(fspKO) mice exhibit defective mammary ductal development, characterized in part by increased ductal epithelial cell turnover associated with an increase in stromal fibroblast abundance. Tgfbr2(fspKO) mammary fibroblasts transplanted with mammary carcinoma cells promote growth and invasion, which is associated with increased activating phosphorylation of the receptors: erbB1, erbB2, RON, and c-Met. Furthermore, the increased receptor phosphorylation correlates with increased secretion of the cognate ligands by Tgfbr2(fspKO) fibroblasts. Treatment of tumor cells with fibroblast-conditioned medium leads to increased tumor cell proliferation and motility, which are blocked by addition of pharmacologic inhibitors of TGF-alpha signaling or neutralizing antibodies to macrophage-stimulating protein (MSP), HGF, or c-Met. These studies characterize a significant role for stromal TGF-beta signaling in mammary tissue homeostasis and mammary tumor progression via regulation of TGF-alpha, MSP, and HGF signaling pathways.

The LIM-only factor LMO4 regulates expression of the BMP7 gene through an HDAC2-dependent mechanism, and controls cell proliferation and apoptosis of mammary epithelial cells

“…Finally, it is likely that LMO4 effects are context-dependent; LMO4-mediated signaling to stroma and/or other neighboring cells may be important for the pro-proliferative and pro-tumorigenic effects of LMO4 upregulation in vivo. In this regard, the identification of BMP7 as a target gene of LMO4 is relevant because BMP7 has striking effects on stromal cells (Dean et al, 2004), and it is known that growth signaling from stromal fibroblasts during mammary gland development is regulated by TGFb ligands (Cheng et al, 2005). Like LMO4, BMP7 is highly expressed in the ductular end buds of the developing mammary gland (Sum et al, 2005a, b), the site of active proliferation and stromal invasion of the mammary epithelium.…”

The ecology of brain tumors: lessons learned from neurofibromatosis-1

“…One of the key signaling molecules produced by cancer-associated fibroblasts is transforming growth factor-b (TGF-b): TGF-b activates fibroblasts to increase ECM formation (Keski-Oja et al, 1988) and promotes epithelial cell and fibroblast proliferation, depending upon the complement of growth factors present in the local microenvironment (Roberts et al, 1985). Collectively, these studies support a model of tumorigenesis in which TGF-b signaling creates a permissive stromal state for epithelial cancer initiation and progression (Bhowmick et al, 2004;Cheng et al, 2005).…”

From sentinel cells to inflammatory culprits: cancer‐associated fibroblasts in tumour‐related inflammation

“…Ablation of TGF-β responsiveness in fibroblasts exacerbates neoplastic progression in several tissues, including prostate, stomach, and breast, [18,28,29]. Others have reported that stromal ablation of the tumour suppressor Pten during mammary carcinogenesis results in accelerated tumourigenesis, via Ets2 inactivation, suggesting multiple pathways by which fibroblasts can inhibit neoplastic growth [30,31].…”