Tumour suppressor gene function in carcinoma-associated fibroblasts: from tumour cells via EMT and back again?

Abstract

Recent reports indicate that inactivation of the RB, TP53 or PTEN tumour suppressor genes is detected in tumour stroma of oropharyngeal, breast and other human cancers. Mouse models have validated the tumour-promoting effects of deleting Rb, Pten or p53 in fibroblasts that converts them from normal fibroblasts to carcinoma associated fibroblasts (CAFs). The tumour-promoting activity of CAFs in these contexts was associated with increased paracrine signaling to tumour cells through production of specific growth factors, chemokines and MMPs by CAFs. The conversion of NOFs into CAFs through acquisition of specific mutations, such as loss of tumour suppressors, or deregulated expression of microRNAs or key epigenetic events, can clearly occur independently of genetic and epigenetic changes in tumour cells but an alternative source of CAFs that is being reconsidered is that CAFs derive from the tumour cells by EMT. Recent mouse models employing lineage-tracing techniques have suggested that this can take place in vivo and the extent to which this is relevant more broadly is discussed.

Keywords: EMT; Pten; RB; TGFβ; carcinoma-associated fibroblasts; lineage tracing; micro-RNAs; p53; trophic support.

Figure 1

Loss of key tumour suppressor genes in CAFs promotes tumour cell progression to malignancy. Loss of RB in normal and carcinoma-associated fibroblasts promotes proliferation, inhibits differentiation and increases invasion through collagen of co-cultured keratinocytes and tumour epithelia [32,36]. The effect of RB loss in fibroblasts was dependent on production of keratinocyte growth factor (KGF) that acted on co-cultured epithelial cells to promote growth through the KGF receptor (FGFR2b) and signalling through AKT to Ets-2 and its target genes, such as MMPs. Similarly, loss of PTEN in CAFs promoted production of MMPs and chemokines through deregulation of Ets-2, achieved in part through phosphorylation of Ets-2 by Akt and also via loss of PTEN-induced repression of miR-320 that targets Ets-2.

Figure 2

Dual mechanisms explaining the origin of CAFs and their tumour-promoting activity. Tumour cells recruit normal fibroblasts (NOFs) and promote their conversion to carcinoma-associated fibroblasts (CAFs) in part through deregulation of miRNAs, although how deregulation of these miRNAs is achieved is not known. CAFs also likely arise in some tumour types through EMT from tumour epithelia and thus harbour some of the same mutations, such as inactivation of p53, PTEN and RB, as the tumour cells from which they are derived. The extent to which CAFs are derived from NOFs as opposed to tumour epithelia via EMT is also unknown, and clearly may vary in real time as a function of selective pressures and prevalence of unique tumour clones and other cell types in the tumour microenvironment. CAFs promote tumour cell progression to invasiveness through secretion of key chemokines and MMPs, but may be susceptible to targeted therapies that promote their ‘reversion’ to NOFs, perhaps by sponging miRNAs that drive conversion, or by specific inhibitors of EMT.