Dr. Andrzej Dlugosz and colleagues at the University of Michigan and the National Cancer Institute have examined the functions of the Hedgehog (Hh) signaling pathway in basal cell carcinoma, the most common form of cancer, and have uncovered a subset of tumor cells that are resistant to inhibition of the Hh pathway. This new finding has important implications for the treatment of this widespread disease.
Their report is being released online tomorrow, in advance of its January 15th publication date by the journal Genes & Development (http://www.genesdev.org/cgi/doi/10.1101/gad.1258705).
Basal cell carcinoma (BCC) affects over 1,000,000 Americans each year and frequently arises on sun-exposed sites such as the face. Surgical removal of BCCs is an effective approach to treating these cancers, which generally have a slow growth rate and seldom metastasize. However, untreated BCCs can cause extensive local tissue damage, and surgical procedures can produce significant scarring in cosmetically sensitive locations such as the face.
The Hh signaling pathway plays a key role in normal development, and its dysfunction has been implicated in a number of different human diseases and neoplasms, including BCCs in skin and cancers arising in brain, lung, prostate, pancreas and other gastrointestinal organs. Dr. Dlugosz and colleagues focused on the function of uncontrolled Hh pathway signaling in the growth of BCC.
The investigators used genetically engineered mice in which they could manipulate expression of a Hh pathway component, called Gli2, effectively turning it on or off at will in the skin. As expected, expression of Gli2 resulted in BCC formation. In addition, the researchers found that sustained expression of Gli2 is necessary for the continued growth of these tumors. When Dr. Dlugosz and colleagues turned Gli2 off, the BCC tumor cells stopped growing and were eliminated via execution of a programmed cell death process. These results are consistent with previous work from other labs studying different Hh-associated tumors, "but we were very surprised to see that some tumor cells persisted after shutting down Gli2 expression," said Dr. Dlugosz.