Newcastle University Research Fellowship Candidate Seminar
Speaker: Dr Adam Pickard, Centre for Cancer Research and Cell Biology, Queen's University Belfast
Venue: Lecture Theatre E, Dental School
Date and Time: 15th December 2014 11.00-12.00
Dr Pickard will present: '' Stromal control of epithelial differentiation and cancer invasion – a role for the retinoblastoma protein, pRb''
The retinoblastoma proteins (Rb) is a key regulator of cell division and also epithelium differentiation. Animal studies have demonstrated that Rb can regulate the growth and differentiation of neighbouring cells, and this has been explored further using a three-dimensional organotypic culture system. Depletion or inactivation of Rb in primary human fibroblasts, disrupts the differentiation of the neighbouring epithelium, through altered secretion of the keratinocyte growth factor (KGF). Phosphorylation (inactivation) of Rb, has been identified in the stromal compartment of human tumours (Head and Neck cancers), specifically within the FSP1-positive population of fibroblasts. Rb inactivation promotes invasion of a cancerous epithelium with KGF driving expression of MMP1. Myofibroblasts, a sub-population of fibroblasts often associated with poor –disease outcome, also promote epithelium invasion, therefore the role of Rb in myofibroblast differentiation was examined. Rb is degraded by the proteasome during TGFβ mediated differentiation, and Rb-depleted fibroblasts behave as myofibroblasts in collagen contraction assays. Both cell types produce higher levels of EGF which alone promotes epithelial invasion through inducing an epithelial to mesenchymal-transition. Low doses of the EGFR targeted therapies efficiently inhibit the invasion process mediated by myofibroblasts, myofibroblasts are postulated as a marker of prognosis or therapeutic response.
Differentiation, Invasion, Fibroblasts, Myofibroblasts, Keratinocytes, Human Papillomavirus (HPV), Retinoblastoma
Chair: Professor John Isaacs