Manuela Baccarini, Professor for Cell Signalling at the Centre of Molecular Biology of the University of Vienna (Max F. Perutz Laboratories) and colleagues reveal the function of a protein in the Ras signalling pathway. Their findings provide the basis for research on novel therapeutic strategies in Ras-induced skin cancers, e.g. melanoma. The results of her work are published in the scientific journal Cancer Cell.
Ras is a protein which is a master regulator of several signalling cascades in cells, and has been demonstrated to be a proto-oncogene. If the protein is mutated or misregulated by outside influences, it contributes to the development of skin cancers such as melanoma.
Skin cancer develops from a progenitor skin cell population that expands unrestrictedly (proliferation) and does not migrate from the deeper skin layers (stratum basale) to the surface (stratum corneum) to differentiate into specialized skin cells or keratinocytes. In addition, compared to normal cells, tumour cells have also lost the ability to react to "cell suicide signals" (apoptosis).
Cell differentiation decisive for melanoma development
Up until now it was believed that the crucial process for skin cancer development is the unrestricted cell proliferation of the progenitor cells. Baccarini and colleagues now show in a mouse model that the Ras signalling pathway is coupled to the Raf-1 protein. Unexpectedly, the Raf-1 protein plays a key role in the differentiation process of the progenitor skin cells and not in the proliferation as previously assumed. Raf-1 ablation induced total regression of the epidermal tumours in mice. Mice without epidermal Raf-1 did not develop skin cancer, even though the Ras pathway was active.
Enzyme complex allows novel therapeutic strategies
The disruption of the normal pathway from progenitor cell to keratinocyte allows for the possibility of skin cancer development, as cancers (eg. melanoma) frequently arise from these progenitor cells. "We showed that Raf-1 builds an enzymatic complex with the protein Rok. This complex inhibits the differentiation to a skin cell and the way is clear for skin cancer development", Manuela Baccarini explains. She also identifies novel therapeutic avenues: "In the treatment of leukaemia substances are administered which stimulate cells to differentiate, combined with chemotherapy."
This combined therapy could be used for skin cancer treatment as well, if a substance is discovered that destroys the Raf-Rok complex and therefore enables differentiation. "The search for such substances up to the clinical application is a long road", Baccarini cautions. But with the discovery of this basic mechanism of skin cancer development Manuela Baccarini and colleagues provide the basis for research on novel therapeutic strategies.
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