Inactivation of Rb in stromal fibroblasts promotes epithelial cell invasion.
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.
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast City Hospital, UK.
Adam
A
Pickard
Ann-Christin
AC
Cichon
Anna
A
Barry
Declan
D
Kieran
Daksha
D
Patel
Peter
P
Hamilton
Manuel
M
Salto-Tellez
Jacqueline
J
James
Dennis J
DJ
McCance
D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D051523:Fibroblast Growth Factor 7 / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D050787:Proto-Oncogene Protein c-ets-2 / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*
C494069:ETS2 protein, human; C496453:FGF7 protein, human; D050787:Proto-Oncogene Protein c-ets-2; D016160:Retinoblastoma Protein; D051523:Fibroblast Growth Factor 7; D051057:Proto-Oncogene Proteins c-akt; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1