Controlling pancreatic cancer may depend on a molecular 'fulcrum'
The key to stop the growth and spread of pancreatic cancer could be found in a microRNA called MiR-198, said researchers at Baylor College of Medicine in a report that appears online in the journal Clinical Cancer Research.
Their findings reveal a treatment target that, when modulated in the lab setting, reduces tumors and makes them more susceptible to chemotherapy.
Network of interacting factors
"In cancer, there are always different things that go wrong at different times. When one mechanism stops functioning properly, it affects other molecules. In the case of pancreatic cancer, a network of tumorigenic molecules is triggered when miR-198 expression is reduced," said Dr. Christian Marin-Muller, former postdoctoral associate with the molecular surgeon research center in the Michael E. DeBakey Department of Surgery at BCM and first author on the study.
In the laboratory, the researchers identified a network of interacting factors that make up a tumor signature that governs the virulence of pancreatic cancer. This network is interconnected through this microRNA (miR-198). When miR-198 expression is reduced, the tumorigenic network is formed, which results in a dismal prognosis for patients. When levels of the miR-198 are normal or higher, the tumor signature network is disrupted and prognosis improves.
Finding targets to use against pancreatic cancer is critical. Pancreatic cancer is a particularly deadly disease, with an estimated 6 percent of those diagnosed surviving at five years. It is the 10th most common cancer diagnosis among men and the 9th most common among women in the United States. In 2013, an estimated 45,220 new cases of pancreatic cancer will be diagnosed nationwide with 38,460 estimated deaths, indicating effective treatment is urgently needed.
In a past study, Dr. Cathy Yao, professor of surgical research in the Michael E. DeBakey Department of Surgery at BCM, and her colleagues had shown the overexpression of a protein known as mesothelin (MSLN) enhanced proliferation, invasion and migration of pancreatic cancer. In the current study, they looked at pancreatic cancer cells from 37 patients and compared them to cells from normal adjacent tissue. They found that MSLN and miR-198 are involved in an intricate reciprocal regulatory loop, where MSLN represses miR-198. This in turn leads to overexpression or suppression of a number of other molecules that lead to increasing the aggressiveness of pancreatic cancer.
New treatment strategies
"Most of these factors that make up this network have not been revealed to be connected with pancreatic cancer before such as FSTL1, OCT-2, PBX-1, and VCP. We have dissected the mechanisms and found that they are all directly or indirectly modulated by the expression of miR-198," said Yao, also a professor in the Departments of Molecular Virology and Microbiology, Pathology and Immunology at BCM and also corresponding author to the study.
Most significantly, they found that when increasing expression of miR-198 in the mouse models, tumor cells begin dying with reduced tumor size and metastasis, presenting a promising effective pancreatic cancer treatment strategy.
Yao adds that since all the molecules are novel, more studies are needed to understand detailed molecular mechanism of action in pancreatic cancer and if a combination therapy with multiple targets will further improve the treatment efficacy. They plan to explore if miR-198 regulated tumorigenic network also play a role in other cancers, therefore, the treatment strategy can be applied to many other MSLN high-expressing cancers.
Others who took part in the study include: Dr. Dali Li, postdoctoral associate in surgical research; Uddalak Bharadwaj, instructor of medicine – infections disease; Dr. Changyi Johnny Chen, professor of surgical research; Sally Hodges, research coordinator department of surgery; Dr. William Fisher, professor of surgery; Dr. Qianxing Mo, assistant professor of medicine in the NCI-desginated Dan L. Duncan Cancer Center, all of BCM; and Dr. Min Li, associate profession of Neurosurgery at University of Texas M.D. Anderson Cancer Center in Houston; Mien-Chie Hung, with China Medical University in Taiwan, and the University of Texas M.D. Anderson Cancer Center.
Funding came from the National Institutes of Health Research Grants CA140828, and Dan L. Duncan Cancer Center pilot grant, and the Cancer Prevention Research Institute of Texas – CPRIT RP101499.