Scientists at the National Institute of Dental and Craniofacial Research (NIDCR) and colleagues report in animal studies that a single, scissor-like enzyme called matriptase, when left to its own devices, can cause cancer.
This finding, published in the current issue of the journal Genes and Development, marks the first report of a protein-cleaving enzyme, or protease, on the cell surface that can efficiently trigger the formation of tumor cells. The authors also note that matriptase is the first known cell-surface protease that can act as an oncogene, an umbrella term for mutated genes and their proteins that prompt cells to divide too rapidly, a hallmark of tumor cells.
"What makes matriptase potentially such a good molecular target to treat cancer is its accessibility," said NIDCR scientist Dr. Thomas Bugge, the senior author on the paper. "We don't have to trick the tumor cell to internalize a drug, then hope it reaches its destination in an appropriate concentration and duration. In this case, the bull's eye is right on the cell surface."
Bugge said the exact function of matriptase in healthy human cells remains a bit of a mystery. Previous studies show that cells comprising the outer lining, or epithelium, of nearly all human organs express the protease. They also suggest that matriptase might play a role in activating other membrane-bound proteins on the cell surface that are involved in signaling basic cellular activities, such as growth and motility.
Since its discovery nearly 13 years ago, scientists also have suspected that matriptase might have a dark side. It is overly abundant in a variety of epithelial-derived tumors, including breast, prostate, ovarian, colon, and oral carcinomas. Then, in 2002, scientists reported women with breast and ovarian cancer have poor prognoses if their tumors contain high levels of matriptase. In fact, just two months ago, researchers reported for the first time that increased expression of matriptase is associated with more serious forms of cervical cancer.
Still unanswered, however, was the larger question of whether the protease, when deregulated and overexpressed, might actually cause cancer. To find the answer, Bugge and colleagues produced mice that expressed the human version of the matriptase gene in a stable, readily measurable manner. "After our initial round of experiments, we found that the skin of the mice was quite sensitive to fluctuations in the levels of matriptase," said Dr. Roman Szabo, a co-lead author on the study and an NIDCR scientist. "So much so, that all 10 of the mice that produced too much matriptase developed distinctive, splotchy skin lesions within a year."