Growth of common skin cancer blocked in gene-switch mice

December 28, 2004

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.
-end-


Cold Spring Harbor Laboratory

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.