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U-M scientists find genes that control growth of common skin cancer

--added 1/8/05

Ann Arbor, MI. -- Scientists at the University of Michigan's Comprehensive Cancer Center and the National Cancer Institute have identified genes that promote the growth and recurrence of skin cancer.

Basal cell carcinoma before and after
Basal cell carcinoma before (top) and three weeks after (bottom) U-M scientists switched off the Gli2 gene in their experimental mice. Photo credit: Andrzej Dlugosz, U-M Medical School

Andrzej Dlugosz, M.D., a professor of dermatology in the U-M Medical School, and colleagues at the University of Michigan and the National Cancer Institute examined the functions of the Hedgehog (Hh) signaling pathway in basal cell carcinoma – the most common form of cancer – and uncovered a subset of tumor cells that were resistant to inhibition of the Hedgehog pathway. The new finding has important implications for the treatment of this widespread disease.

Their report will be published in the Jan. 15, 2005 issue of Genes & Development, but is available now on the journal's Web site.

Basal cell carcinoma (BCC) affects over 1,000,000 Americans each year and frequently develops 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 spread or 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 Hedgehog 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. 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 an 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 Dlugosz and colleagues turned Gli2 off, the BCC tumor cells stopped growing and were eliminated by 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 Dlugosz.

In some of the regressed tumors Gli2 reactivation leads to resumption of BCC tumor growth, suggesting that the residual cell populations may represent BCC tumor stem cells, but Dlugosz cautions that there is as yet no definitive evidence that tumor stem cells exist in BCC.

In additional studies, the researchers found that regressing BCC cells could be reprogrammed to differentiate into various epithelial cell types, ultimately capable of assembling fully-formed hair follicles. These results suggest that BCCs contain cells capable of multi-lineage differentiation, similar to normal hair follicle stem cells from which they may arise.

If the results of this study are applicable to human BCC, the discovery of residual tumor cells and tumor recurrence may be particularly important given the current efforts to develop Hh pathway inhibitors as a means of combating human BCCs, as well as other cancers. In contrast to other cancer models where inhibition of Hh signaling leads to durable tumor regression, Dlugosz's new work raises the possibility that Hh pathway inhibition in BCCs, while effectively diminishing tumor size, may not be curative due to the survival of this residual tumor cell population.

“Our work demonstrates that BCC growth in this model remains strictly dependent on the Hh pathway,” says Mark Hutchin, M.D., a U-M resident in dermatology and lead author on the paper. This is different from many other genetic mouse models of cancer, in which tumor regression following inhibition of an oncogene is frequently followed by the emergence of malignancies that have activated alternative cancer-causing pathways.

According to Hutchin, the fact that this does not happen in regressed mouse BCCs suggests that any residual human BCC cells, if present, should also remain in check as long as the Hh pathway is effectively inhibited.

Funding for this research was provided by grants from the National Cancer Institute and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Press release courtesy of Genes & Development, a publication of Cold Spring Harbor Laboratory Press.

For information on previous research in the Dlugosz lab:
www.med.umich.edu/opm/newspage/2003/hair.htm .

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