**4.2.2 HA/stromal fibroblast/epithelial cell interaction and tumour progression**

To begin to define the role played by TAFs in tumour progression, Micke *et al.* (2007) conducted cDNA microarray analyses comparing the transcriptome of TAFs from basal cell carcinoma with normal dermal fibroblasts (Micke *et al*., 2007). This study showed that TAFs overexpress multiple growth factors such as PDGF, EGF, and VEGF, chemokines such as SDF1 and CXCL12 and matrix proteins such as MMP11, LAMA2 and COL5A2. In fact, these TAFs are known to secrete IGF-2, FGF-7, TGF-β, leptin, and NGF, which bind to their cognate receptors on BCA cells to stimulate HA production (Szabo *et al*., 2011). This then promotes expression of cytokines such as TGF-β that attract and stimulate TAFs to proliferate. This paracrine effect is a positive feedback mechanism, because proliferating TAFs secrete additional growth factors, cytokines, chemokines, and MMPs that sustain BCA transformation and promote BCA progression. Additionally, VEGF, produced by TAFs, and HA oligosaccharides induce angiogenesis. HA itself also impairs immune surveillance, and/or activates TAMs and neutrophils that have tumour enhancing potential. Overexpression of HAS in a non-transformed rat fibroblast, 3Y1, increases high MW HA production and the resultant pericellular HA coat provides cells with a proliferation advantage that is accompanied by loss of contact inhibition of growth. This is achieved through HA-mediated activation of PI3 kinase. Lower MW HA also increases proliferation in these cells but has no effect on the HA matrix (Itano *et al*., 2002). TAFs affect not only BCA cells but also normal cells in which the tumour is embedded. For example, TAFs induce stem cell-like behaviour and aberrant differentiation in normal fibroblasts, which can affect BCA progression. TAFs promote the expression of stem-cell markers such as Oct4 and Sox2 in 3T3 cells (Szabo *et al*., 2011) and stimulate trans-differentiation of normal fibroblasts into myofibroblasts when they are confronted with primary BCA cells.
