Urokinase-type-plasminogen-activator(UPA) production by human breast (myo)fibroblastsin vitro: Influence of transforming growth factor-β1 (TGFβ1) compared with factor(s) released by human epithelial-carcinoma cells

Abstract

The urokinase‐type plasminogen activator (uPA) may be considered as a key enzyme in the processes of cancer cell invasion and metastasis. Evidence has been presented that, in breast stroma, uPA is expressed predominantly by myofibroblasts located at the invasive areas of the tumor. To examine whether transforming growth factor type‐1 (TGFβ1) produced by breast‐carcinoma cells is a candidate responsible for the induction of uPA‐producing myofibroblasts, we studied in vitro the capacity of normal and tumor‐derived human breast fibroblasts to express uPA and the myofibroblast marker α‐smooth‐muscle actin in response to TGFβ1. Next, we compared these influences with those elicited by factor(s) released by epithelial‐cancer cells. In all 8 fibroblast strains tested, TGFβ1 induced a similar concentration‐dependent increase in the fraction of α‐smooth‐muscle‐actin‐positive fibroblasts. While uPA expression was decreased by TGFβ1 in most of the fibroblast strains, 2 strains were relatively insensitive to TGFβ1 in this respect. Although factors present in media conditioned by non‐uPA‐producing epithelial‐tumor cells could trigger fibroblasts to become potent producers of uPA, the TGFβ1 content of the conditioned media were linked to the differential effects of externally added TGFβ1 with respect to uPA expression. The data demonstrate that, although fibroblasts may utilize TGFβ1 secreted by tumor cells to differentiate into myofibroblasts, tumor cells secrete factor(s) other than TGFβ1 ultimately responsible for the generation of powerful uPA‐producing fibroblasts. Int. J. Cancer 76:829–835, 1998.© 1998 Wiley‐Liss, Inc.

Tumour-derived TGF-β1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells

“…Interactions between epithelial cells and fibroblasts have a major role in many biological processes and it follows that the interactions between tumour cells and neighbouring myofibroblasts may be biologically significant, probably mediated by soluble factors such as growth factors and cytokines. This has been demonstrated previously in breast cancer where TGF-b1 produced by breast cancer cells activates normal breast stromal fibroblasts and promotes them to produce proteases (Ronnov-Jessen and Petersen, 1993;Sieuwerts et al, 1998). Similar interactions have been shown in prostatic carcinomas (Olumi et al, 1999;Webber et al, 1999), and in the fibrosis observed in organs such as the kidney (Lewis and Norman, 1998) and liver (Kinnman and Housset, 2002).…”

“…They upregulate the expression of serine and matrix metalloproteinases, which degrade and remodel extracellular matrix, possibly potentiating cell invasion and migration (Sieuwerts et al, 1998). In addition, Ramos et al (1997) showed that peritumour FCM upregulated the expression of the integrin avb6 in SCC cells, and we have previously demonstrated that de novo expression of this integrin promotes invasion of oral carcinoma (Thomas et al, 2001a, b).…”

“…However, another mechanism by which TGF-b1 could promote tumour development is by inducing the transdifferentiation of stromal fibroblasts, producing an activated, myofibroblast-rich stromal microenvironment. For example, it has been shown that TGF-b1 produced by breast cancer cells activates normal breast stromal fibroblasts and promotes them to produce urokinase-type plasminogen activator, a serine protease important in cancer cell invasion and metastasis (Sieuwerts et al, 1998). Such changes have a potential role in tumorigenesis since, if tumour stroma becomes activated and immobilised in the vicinity of tumour cells, paracrine interactions may be established between the separate cellular compartments, some of which could encourage tumour development.…”

Pericellular proteolysis in cancer

“…The proinflammatory cytokines tumor necrosis factor-a (TNF-a) and transforming growth factor-b (TGF-b) play central roles in this process. Breast cancer cells induce uPA and MMP9 expression in stromal fibroblasts via secretion of TGF-b and/or TNF-a (Sieuwerts et al 1998;Stuelten et al 2005). Recent reports propose a shift from TGF-b signaling in primarily epithelial cells in normal and adenoma tissue to stromal cells (i.e., fibroblasts, T cells, macrophages, and endothelial cells), which promoted tumor invasion and metastasis (Calon et al 2012;Hawinkels et al 2014).…”

Peripheral lymph node stromal cells can promote growth and tumorigenicity of breast carcinoma cells through the release of IGF‐I and EGF

“…[25][26][27][28]30 Tumor cells can also regulate ECM degradation and tumor cell motility and invasion, either directly, by releasing proteolytic enzymes, or indirectly, by activating their expression in stromal cells. [31][32][33][34] The strong evidence that stromal cells can regulate breast carcinoma growth and invasion at the primary site prompted us to ask whether similar cell-cell interactions may also determine tumor take and progression within invaded regional lymph nodes. Studies based on leukemia and lymphoma models have demonstrated that lymph node stromal cells can provide growth-modulating and antiapoptotic signals to leukemic cells through cell-cell contact and the elaboration of soluble factors.…”