Researchers discover key to early-stage melanoma

The protein Stat3 appears to be a "master regulator" responsible for the activation of genes involved in epithelial cancer development. It is essential for the initiation, promotion and progression stages of cancer development. Stat3 represents a target for intervention to check and perhaps even roll back development of the early stages of cancer.

"The first part of our study was a genetic one where we deleted the gene for Stat3 in skin keratinocytes and showed that we could dramatically inhibit skin tumor formation" in knock out mice, John DiGiovanni, Ph.D., tells Dermatology Times.

The animals deficient in Stat3 did not develop tumors when exposed to standard challenges of the carcinogen DMBA and the tumor promoter TPA. Stat3 deficient keratinocytes were more sensitive to DMBA-induced apoptosis and were significantly less proliferative when exposed to TPA.

The research was conducted at the M.D. Anderson Cancer Center's Science Park - Research Division near Smithville, Texas - where Dr. DiGiovanni is director - and was published in the September 2004 issue of the Journal of Clinical Investigation.

A number of previous studies have shown that the family of Stat (signal transducers and activators of transcription) molecules are activated in many types of epithelial cancers. They turn on genes such as cyclin D1, c-myc and bcl-XL, all of which are important for tumor cell growth and survival.

Dr. DiGiovanni calls Stat3 "a master regulator of a number of genes. If you knock down the master regulator, you can shut down a lot of those other genes that are being turned on. And it should have a fairly global effect on the growth of the tumors.

"Earlier studies have all looked at cancer cells from established tumors. By then you might have many different genetic alterations," he says. Altering only one genetic pathway at that point might not be sufficient to have a clinical impact on tumor development.

"The big difference in our study is that we show if you target Stat3 early in the process, when there aren't so many genetic changes, you might be able to prevent tumor development altogether," he says.

At the cellular level, UV or chemical factors can activate Stat3. The protein is phosphorylated and forms homodimers with another Stat3 molecule. These translocate to the nucleus where they home in on and bind to the target genes. The upregulated genes produce cascades of signaling molecules that can contribute to cancerous growth.

Another part of the study used an oligonucleotide decoy that is taken up by cells and binds to the Stat3 homodimers. This prevents Stat3 homodimers from binding to the target genes. The decoy was injected into established premalignant skin tumors in mice and more than half of the tumors shrank by more than 60 percent.

Dr. DiGiovanni is most excited by the prevention potential of inhibiting early Stat3 activation before the pattern of gene upregulation becomes self-reinforcing. He says, "Perhaps some kind of topical treatment could be used to minimize the impact of Stat3 activation in sunburns. It's something that we are going to try and do in mice."

Using this approach to inhibit Stat3 is likely to be more problematic in treating malignant tumors. It raises issues of delivering sufficient quantities of the oligo inside the tumor mass, a problem shared with many other existing therapies. But limiting Stat3 activation may come to have a role in combination with other interventions in treating tumors, particularly if small molecule inhibitors can be developed to effectively target this transcription factor.