Enzyme with a critical role in cancer blood supply leads a double life
After being studied for decades for their essential role in making proteins within cells, several amino acids known as tRNA synthetases were recently found to have an unexpected and critical additional role in cancer metastasis. Threonyl-tRNA synthetase (TARS) leads a double life, functioning as a critical factor regulating a pathway used by invasive cancers to induce angiogenesis and as a new food supply to sustain their growth.
Cancerous tumors quickly outgrow their local blood supply. When they do, the cancer cells send out signals, TARS is secreted, and the angiogenesis process is initiated.
“In our study, we showed that TARS, once thought to only function in the housekeeping role of protein synthesis within cells, moonlights as a secreted signaling agent in the endothelial cells that line vessels, in response to factors commonly produced by cancer cells,” said first author Tamara Williams, PhD, of University of Vermont.
The study's in vivo model of angiogenesis was performed using a chick chorioallantoic membrane assay. This experiment uses the vascular membrane that surrounds a 10-day-old chicken embryo, which is removed from its shell. Williams and her research team placed small pieces of surgical sponges on the surface of the membrane and added compounds, including TARS, to the sponges. The researchers took images of the sponges and surrounding tissues every 24 hours for 3 days and then analyzed the images to assess the impact of the compounds on local blood vessel development around the sponge. Their test determined whether the compound was angiogenic (creates new blood vessels), had no effect, or was angiostatic (inhibits blood vessel development).
Using this assay, the group was able to demonstrate that TARS prompts angiogenesis by increasing the directional movement, or migration, of vessel cells towards the cancer cell signals. The group's research also showed that a potent inhibitor of TARS activity, known as inhibitor BC194, blocked its induction of angiogenesis.
“The implications of these novel and surprising findings are substantial for the cancer research community and include potential opportunities to develop new, early, and sensitive diagnostics,” Williams said.
Williams added that the antiangiogenic activity of the potent inhibitor of TARS paves the way for new therapeutics to block tumor growth and metastasis by stopping TARS-induced angiogenesis.
“These types of therapeutics could be used in combination with other treatments that target and kill cancer cells as part of a personalized cancer medicine approach to treat patients with greater success,” she said. This research was published in Nature Scientific Reports (2013; doi:10.1038/srep01317).