Researchers Discover Signaling Process Linked to Obesity and Cancer

From left, Jian-Chang Liu, Douglas Feldman, Chia-Lin Chen and Keigo Machida Researchers Discover Signaling Process Linked to Obesity and Cancer

The findings, which surfaced while the researchers were trying to determine what distinguishes cancer stem cells from normal tumor cells, appear in the January issue of the Proceedings of the National Academy of Sciences. They hold potential for the creation of therapies that can block the proliferation of tumor-initiating stem cells, which generate the spread or relapse of cancer. Conventional therapies often have failed to stop these stem cells.

Keigo Machida, assistant professor of molecular microbiology and immunology at the Keck School, served as principal investigator of the study. Douglas Feldman, a postdoctoral fellow in Machida’s research laboratory, was co-correspondence author for the study. Machida also received assistance from Vasu Punj, associate professor of research medicine of the bioinformatics core at the USC Epigenome Center. Also contributing were pathology professor Hidekazu Tsukamoto and lab technician Chia-Lin Chen.

In the study, the researchers described how the signaling process between leptin, a hormone produced by fat tissue that controls appetite, and OB-R, a hormone receptor produced by the brain’s hypothalamus, is a characteristic feature of a variety of tumor-initiating stem cells. They also explained that leptin plays a key role as an intermediary between excess accumulation of adipose tissue, the connective tissue that stores fat cells, and activation of tumor-generating genes related to obesity.

“Stem cells usually have the ability to repair damaged tissue,” Machida said. “They proliferate and then stop proliferating after they do the repair. But tumor-initiating stem cells continuously and unrestrictedly proliferate. Many therapies target normal tumor cells, but the tumor-initiating stem cells survive this therapy. They’re the leaders that can’t be destroyed.”

Machida pointed to the strong correlation between obesity and cancer, but noted that the mechanics of how obesity contributes to cancer development were not well understood until now.

“In characterizing the tumor-initiating stem cells, we discovered that leptin is the master regulator of stem cells, signaling them to self-renew themselves,” he said. “If there is a mutation or dysfunction in the hormone, some of the mice in the study would be constantly hungry, overeat and become obese, which raised their risk of cancer.”

The study is related to Machida’s previous research, which showed that obesity enhanced tumor development in the liver. Now he is seeking a more detailed characterization of the mechanics of tumor-initiating stem cells in humans.

“If we’re able to develop therapy to shut down the tumor-initiating stem cell’s lifeline through targeted drug therapy, we may be able to develop something that gets rid of these stem cells altogether,” Machida said.

The study was supported by funding from the National Cancer Institute, the National Institute on Alcohol Abuse and Alcoholism and the National Institute of Allergy and Infectious Diseases, as well as a trainng grant from the National Institutes of Health.

The University of Southern California