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.
In some of the regressed tumors Gli2 reactivation leads to resumption of BCC tumor growth, suggesting that the residual cell population may represent BCC tumor stem cells, but Dr. 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, Dr. 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.
Nevertheless, "our work demonstrates that BCC growth in this model remains strictly dependent on the Hh pathway," says Dr. Mark Hutchin, 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. 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.
Hutchin ME, Kariapper MS, Grachtchouk M, Wang A, Wei L, Cummings D, Liu J, Michael LE, Glick A, Dlugosz AA.
Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: conditional skin tumorigenesis recapitulates the hair growth cycle.
Genes Dev. 2004 Dec 29
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