Communication between epithelial and stromal cells

Epithelial-stromal interactions are critical for the development of organs, such as the mammary gland. The mammary mesenchyme is required for the initiation of mammary ductal branching morphogenesis in females and the destruction of the mammary epithelial bud in males. For both functions the mammary mesenchymal cells must be activated by PTHrP (parathyroid hormone-related protein). By binding to the PTH1 (parathyroid hormone 1) receptor PTHrP triggers the expression of the androgen receptor and activates LEF1 and β-catenin, components of the Wnt signaling pathway (Dunbar et al., 1999; Dunbar et al., 1998; Foley et al., 2001). Such paracrine ligand/receptor interactions are a classical way by which the epithelial and stromal compartments communicate. Other factors that mediate crosstalk are Ihh (Indian hedgehog), IGF-I (insulin growth factor-I) and GH (growth hormone). Ihh is produced by mammary epithelial cells and interacts with Ptc-1 (patched-1) in stromal cells. Mice haploinsufficient for Ptc-1 exhibit hyperplasia and dysplasia of mammary ducts (Lewis et al., 1999). Epithelial GH activates the GH receptor in stromal cells which, in response, produce IGF-I which acts back on epithelial cells by activating their IGF-I receptor (Wiseman and Werb, 2002). Both factors, GH and IGF-I, are required for normal mammary gland development. Another paracrinely acting ligand is TGFβ (transforming growth factor β). Produced by the mammary epithelium TGFβ interacts with the TGFβ receptor in adjacent fibroblasts which, in turn, cause a decelerated ductal growth into the mammary fat path (Crowley et al., 2005). In addition to fibroblasts, macrophages are involved in mammary gland development. Macrophages attracted by CSF-1 (colony stimulating factor-1) to the mammary gland promote ductal invasion during puberty (Gouon-Evans et al., 2000).

Dysregulated signaling in the stromal compartment can lead to epithelial tumorigenesis (Bierie and Moses, 2006). E.g., fibroblasts with non-functional TGFβ signaling pathway show increased expression of paracrine HGF (hepatocyte growth factor), TGFα (transforming growth factor α) and MST1 (macrophage stimulating 1). By activating their receptors (MET, EGFR or RON) in adjacent epithelial cells these factors can induce epithelial proliferation and invasion (Bhowmick et al., 2004; Cheng et al., 2005). Certain populations of fibroblasts, such as carcinoma associated fibroblasts (CAFs), are even able to permanently transform epithelial cells by inducing chromosomal changes (Olumi et al., 1999). CAFs are different from normal fibroblasts in that they are showing higher proliferative activity and in that they may carry mutations (Moinfar et al., 2000; Tlsty and Coussens, 2006). CAFs are found in a number of tumors, such as breast and prostate carcinoma, and involved in the development of desmoplasia that contributes to the recruitment of inflammatory cells to the tumor and to the induction of tumor-associated neo-angiogenesis. CAFs may also facilitate migration and invasion of carcinoma cells. By secreting uPA (urokinase plasminogen activator) and/or MMPs (matrix metalloproteases) CAFs are able to induce the degradion of the extracellular matrix thereby helping carcinoma cells to migrate into the surrounding tissue (Mueller and Fusenig, 2004). In the so-called collective invasion, a fibroblast cell may be the leading cell which paves the way for the following carcinoma cells (Gaggioli et al., 2007). Macrophages are also a major player in epithelial tumorigenesis. Though they may exert an anti-tumorigenic effect by activating cytotoxic T-cells, the pro-tumorigenic effect is believed to prevail (Leek and Harris, 2002). Recruited to the tumor by CSF-1, macrophages secret EGF (epidermal growth factor) that can stimulate proliferation of breast cancer cells. At a certain tumor size (usually 2–4mm³) tumor cells may experience a shortage of oxygen and nutrients. Hypoxia is a classical stimulator of the expression of VEGF-A (vascular endothelial growth factor-A). Carcinoma cell-derived VEGF-A activates endothelial cells by interacting with the endothelial receptor VEGFR (usually VEGFR-2) and, as a consequence, induces neo-angiogenesis (Kerbel, 2008). Another stromal cell, the mesenchymal stem cell (MSCs), has recently attracted much attention for its ability to interfere with tumor metastasis. Bone-derived MSCs have been shown to be recruited to epithelial tumors, such as breast cancer, where they secret the chemokine CCL5 (Karnoub et al., 2007). CCL5 is recognized by CCR5, a receptor expressed by breast cancer cells, leading to metastatic dissemination of these cells. A number of other tumors have been shown to benefit from the presence of MSCs, although also anti-tumorigenic effects of MSCs have been described (Yen and Yen, 2008).

It has become clear that cross-talks between the epithelial and stromal compartment of tissues

are essential for the development and maintainance of organs and that they are also heavily involved in tumorigenesis and tumor progression.

References:

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