Stopping Process Could Make Cancer a Chronic Disease

Cancer biologist Danny R. Welch, PhD, who heads the National Foundation for Cancer Research Center for Metastasis Research at UAB, has focused his laboratory’s efforts on metastasis suppressors — a class of proteins that block metastasis without inhibiting primary tumor formation. “When cancer cells migrate to a secondary location, a few proliferate and colonize and some lie dormant. A subset of suppressors keep disseminated cells inactive,” he says.

Investigators have identified more than 20 metastasis suppressors, but little is known about how they work. “Metastasis suppressors exhibit diverse mechanisms of action and act on different steps of the metastatic cascade,” Welch says. Breast cancer metastasis suppressor 1 (BRMS1), for example, suppresses breast, melanoma, bladder, and ovarian cancer cells. It inhibits transcription of osteopontin, a tumor-metastasis activator, by abrogating NF-kB, a nuclear transcription factor that regulates multiple tumorigenic and metastatic processes.

The KISS1 gene suppresses melanoma, ovarian, and breast cancer by altering tumor cells’ interaction with the microenvironment at the secondary site. “The exact mechanisms remain a mystery although recent studies provide clues,” Welch says.

Genes, such as KISS1, that stop colonization — the final step in the metastatic cascade — have the most translational potential (J Natl Cancer Inst. 2007;99:309-321). “Therapeutic intervention at any point except the endpoint is virtually fruitless. Even with early diagnosis of a primary tumor, cancer cells may be sitting in a distant site as occult micrometastases,” Welch says.

“Modulation of KISS1 protein function may enable us to hold disseminated cells in a dormant state for extended periods, making cancer a chronic disease.” Investigators have restored suppressor gene expression in metastatic cells and found that the cells did not colonize. Some epidemiological studies suggest the genes may predict a patient’s tendency for metastasis and survival.

Welch’s laboratory also strives to explain how tumor cells invade bones, the most common metastatic site for breast and prostate cancers. He and his colleagues have demonstrated that breast carcinoma cells enter the bone and manipulate normal homeostasis by killing osteoblasts. The process may explain why patients receiving bisphosphonates fail to build bone despite inhibiting osteoclast-mediated bone resorption. Welch aims to repair the defects caused by osteoblast loss by genetically engineering preosteoblastic mesenchymal stem cells that home in on regions of bone damage and replace lost osteoblasts.

Welch notes the hope behind metastasis research is that clinicians will one day exploit molecular targets scientists are now uncovering to effectively treat metastatic disease. “Although translation to the clinic is years ahead, emerging knowledge of metastatic suppressor gene function will provide new targets for novel drugs and therapies that halt metastasis.”

For more information:
Dr. Danny Welch
1.800.UAB.MIST
mist@uabmc.edu