The role of normal neighbouring keratinocytes and fibroblasts on clonal expansion of oral cancer (stem) cells

Recent studies, including ours, have shown that the invasive behaviour of cancer cells is not solely due to mechanisms intrinsic to the individual tumour cell. Genetic changes of individual cells in a specific tissue are not sufficient for invasive cancer to develop. Rather, there is a vivid crosstalk between the transformed cells and normal surrounding cells that affects cancer cell growth and invasion. The project tests the hypothesis that in addition to genetic changes harboured by transformed oral ke ratinocytes, pro-invasive signals from activated stromal fibroblasts and abnormal communication between cancer cells and normal neighbouring keratinocytes critically influence progression of oral neoplasia, due to their effects on survival and expansion o f oral cancer stem cells. The role that normal oral keratinocytes and fibroblasts have on clonal expansion and survival of cancer cells will be investigated on in vitro and in vivo human tissue-based experimental models that allow such cell-to-cell inter actions. In vitro three-dimensional models of normal and neoplastic human oral mucosa are well established in our laboratory. Advanced three-dimensional confrontation models in which clones of green fluorescent protein / alkaline phosphatase marked cancer cells develop surrounded by normal oral cells are currently engineered in our laboratory. A small subset of cells with stem properties has been isolated from oral squamous cell carcinomas (OSCC) derived cell lines by prof. Ian Mackenzie's research grou p at the Centre for Molecular Science, University of London. In collaboration with this research group and the local Stem Cell Research Group at the University of Bergen, we are currently isolating and characterising putative stem cell populations from fr esh tissues (normal human oral mucosa and OSCC), as well as from OSCC- and normal oral mucosa-derived cell lines. Our plan is to further use these putative stem cell populations in confrontation models.