Proto-oncogene Responsible for Ovarian Cancer Metastasis Identified

Anil K. Sood, MD

Activation of a signaling pathway involving the proto-oncogene Src is responsible for disease progression and metastasis in cancer, especially in ovarian cancer, and beta blocker drugs could be used to reduce mortality in these patients, according to findings published in the journal Nature Communications.

A proto-oncogene like Src is a normal gene that is capable of becoming an oncogene when its expression is increased. Researchers at The University of Texas MD Anderson Cancer Center, led by Anil K. Sood, MD, professor in the departments of Gynecologic Oncology and Cancer Biology, discovered a chain reaction that causes Src to become an oncogene and subsequently allow for tumor progression.

The pathway associated with metastasis begins with noradrenaline (NA), the stress hormone found in most abundance in the ovary. Previous research had shown that NA modulates multiple cellular functions responsible for cancer progression, but exactly how it was involved was not clear. Activation of stress hormones, in general, is associated with cancer progression, as well.

Knowing that both NA and Src were somehow linked in their involvement in the progression of cancer, Sood and his colleagues exposed ovarian cancer cells to NA and identified a number of proteins altered by stress hormones. They then performed a bioinformatics analysis that narrowed the proteins down to those that were potential mediators to Src activation.

The researchers determined that NA was able to affect tumor growth and spread through beta-adrenergic (ADRB) receptors expressed on tumor cells that help promote angiogenesis, or the formation of blood vessels. The ADRB signaling is then able to mediate Src activation through a mechanism involving protein kinase A (PKA). Researchers identified PKA as the “switch” that is able to “turn on” Src. The signaling pathway occurs on the cell S17.

“When Src is triggered by stress, it works like a dam letting out water that causes a flood downstream,” Sood said. “Src, like the dam, is a master regulator switch that causes a chain reaction in the cells.”

Using this knowledge, Sood and his team further tested the connection between this pathway and outcomes by looking into which patients with various cancers used beta blockers, a class of drugs prescribed to treat conditions such as heart disease, high blood pressure, and migraines. These drugs are also known as beta-adrenergic blocking agents, and they act on ADRB receptors. Beta blockers are believed to disrupt angiogenesis.

By looking at data from the FDA’s Adverse Event Reporting System, the researchers determined that mortality in patients with all major cancer types was reduced by 17% when the patients received beta blockers. Patients with ovarian and cervical cancer who were treated with beta blockers experienced a 14.64% decrease in mortality. The authors wrote that these findings suggest that beta blockers can significantly reduce cancer-related mortality.

“Prior to our work, the concept of stress hormones driving cancer growth was very new, and only very limited information about the effect of beta blockers on cancer outcomes in humans has been available,” said Guillermo Armaiz-Pena, PhD, instructor of Gynecologic Oncology and Reproductive Medicine and first author of the study. “This study provides incentive to further explore beta blockers as a possible supplement to traditional cancer therapies.”

Through continued research, Sood hopes to identify which cancer patients will benefit the most from treatment with beta blockers. He is also looking at how stress may impact other diseases, such as gastrointestinal disorders.

“This is a major step forward in understanding the biology and impact of stress on cancer progression, and it opens the door to the study of drugs that could inhibit this unique signaling pathway,” Sood said

Armaiz-Pena GN, Allen JK, Cruz A, et al. Src activation by β-adrenoreceptors is a key switch for tumour metastasis [published online ahead of print January 29, 2013]. Nat Commun. doi:10.1038/ncomms2413.