Inactivation of Rb in stromal fibroblasts promotes epithelial cell invasion

Abstract

Stromal-derived growth factors are required for normal epithelial growth but are also implicated in tumour progression. We have observed inactivation of the retinoblastoma protein (Rb), through phosphorylation, in cancer-associated fibroblasts in oro-pharyngeal cancer specimens. Rb is well known for its cell-autonomous effects on cancer initiation and progression; however, cell non-autonomous functions of Rb are not well described. We have identified a cell non-autonomous role of Rb, using three-dimensional cultures, where depletion of Rb in stromal fibroblasts enhances invasive potential of transformed epithelia. In part, this is mediated by upregulation of keratinocyte growth factor (KGF), which is produced by the depleted fibroblasts. KGF drives invasion of epithelial cells through induction of MMP1 expression in an AKT-and Ets2-dependent manner. Our data identify that stromal fibroblasts can alter the invasive behaviour of the epithelium, and we show that altered expression of KGF can mediate these functions.

p63 drives invasion in keratinocytes expressing HPV16 E6/E7 genes through regulation of Src-FAK signalling

“…We have previously reported elevated levels of MMP1 and MMP14 in tissue sections from oro-pharyngeal cancer patients and also identified MMP14 as a direct p63 regulated gene in normal HFK [9, 22]. The microarray analysis of oro-pharyngeal cancers indicated increased levels of MMP1, but not MMP2, 9 and 14 in these tumours compared to normal tissue (Supplementary Fig.…”

“…To investigate the role of p63 in oro-pharyngeal squamous cell cancers (OPSCC) we utilised transformed HFKs expressing high risk HPV16 E6 and E7 genes, which we have previously shown to invade into the collagen-I plugs when cultured with retinoblastoma-depleted fibroblasts [20, 22]. Importantly, comparison of control (pBabe) HFK with early and late passage E6/E7-HFK indicates that invasion only occurs in late passage cells (> 12 passages) (Fig.…”

CAF-like state in primary skin fibroblasts with constitutional BRCA1 epimutation sheds new light on tumor suppressor deficiency-related changes in healthy tissue

“…In particular depletion of tumor suppressor genes was reported to convert normal fibroblasts to CAFs. 15,25,26 As a result the question arises, if constitutional disruption of tumor suppressors may also provoke a CAF-like state in vivo in healthy tissue of persons epigenetically predisposed to hereditary cancers.…”

The Interaction Between Human Papillomaviruses and the Stromal Microenvironment

“…Paracrine factors produced by stromal cells may impact the growth and invasiveness of HPV-containing epithelia 27 . Much effort has been focused on how stromal interactions contribute to cancer development, but how stromal interactions impact the normal, benign life cycle of HPVs or progression of benign lesions to cancer is less understood.…”

“…In a fascinating series of studies of the role of the stroma in HPV biology, keratinocytes expressing E6/E7 were grown in organotypic culture with fibroblasts depleted of the tumor suppressor Rb. The resulting epithelia showed a striking increase in MMP expression and invasion into the stroma, which depended on increased KGF expression by Rb deficient fibroblasts 27,166 . Although organotypic cultures containing Rb depleted fibroblasts had normal gross morphology, differentiation markers were reduced and proliferation markers were increased 166 , showing that the proliferation-differentiation balance so central to the HPV life cycle can be directly regulated by stromal factors.…”