Breast cancer cells induce stromal fibroblasts to express MMP-9 via secretion of TNF-α and TGF-β

Abstract

We used 2D-cocultures employing fibroblasts of different genetic backgrounds and MCF10A-derived human breast epithelial cells of increasingly malignant potential to investigate tumor-stroma interactions in breast cancer and to identify possible signaling pathways involved. Tumor cells induced expression of matrix-metalloproteinase 9 (MMP-9) in fibroblasts in a pattern dependent on the degree of their malignancy. In-situ zymography localized the main gelatinolytic activity around stromal cells in cocultures and xenografted tumors. Use of Smad3 knockout fibroblasts, small molecule inhibitors, and neutralizing antibodies showed that MMP-9 expression was induced by tumor cell-derived TNF-α and TGF-β, dependent on Smad-, Ras-, and PI3-kinase-signaling, and likewise modulated by subsequent HGF- and EGF-signaling. Together, our results indicate that MMP-9 levels in tumor fibroblasts are regulated by a complex tumor-stroma cross-talk, involving multiple ligands and cellular signaling pathways.

Association Between EGF, TGF-β1 and TNF-α Gene Polymorphisms and Hepatocellular Carcinoma

“…This also appears to protect cancer cells from the toxic actions of chemotherapy and radiotherapy, rendering these treatment modalities less effective. Many epithelial tumor entities including gastric and cervical cancer as well as cancers of head, neck, breast and lung express high levels of EGF, TGF-β1 and TNF-α, which are associated with advanced disease and poor clinical prognosis (Stuelten et al, 2005;Jakowlew et al, 2006;Van et al, 2006;Bussink et al, 2008;Wu et al, 2009). Higher level expression of EGF, TGF-β1 and TNF-α have been inversely correlated to survival in these patients and high expression levels have been found in advanced tumor stages (Friess et al, 1999;Ghaneh et al, 2002).…”

Inhibition of tumor cell growth in the liver by RNA interference-mediated suppression of HIF-1α expression in tumor cells and hepatocytes

“…There are some published papers reporting that MMP-9 expression is directly or indirectly regulated by HIF-1. [24][25][26] Therefore, we hypothesized that increased HIF-1 transcription activity in normal cells in the liver contributes to MMP-9 production induced by tumor cell inoculation. Intravenous administration of pshHIF-1a was effective in reducing the expression of MMP-9 after tumor inoculation, which indicates that HIF-1 expression in tumor cells and normal cells in the liver might play an important role in MMP-9 production.…”

Extracellular influences on tumour angiogenesis in the aged host

“…The relationship between a well-formed matrix and MMP expression is expected as extracellular matrix proteins regulate, in part, the production of the enzymes responsible for their turnover and degradation (Phillips and Bonassar, 2005). Once tumour cells express MMPs, they can induce MMP secretion from their associated stromal cells thereby further amplifying their potency (Stuelten et al, 2005). MMP activity also has been shown to be a key component of VEGF-induced angiogenesis in tumours (Bergers et al, 2000), reflecting another pathway by which MMPs interact with components of the ECM to facilitate vessel formation and tumour growth.…”