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."
According to Szabo, that's when things took an unexpected turn. He and his colleagues biopsied the lesions and, to their surprise, found that they were tumors that had already advanced in most cases to a type of cancer called squamous cell carcinoma, a strong indication that the excess matriptase was driving the process.
The scientists next wondered whether excess matriptase and sustained exposure to a chemical carcinogen might be a dangerous combination, a scenario with obvious real world implications. They applied various doses of the chemical DMBA, a well-characterized carcinogen present in tobacco products, to a small area of skin on each of 40 newborn matriptase overproducers. Within seven weeks, 95 percent of these mice developed tumors compared to roughly 2 percent of normal, healthy mice. The group also found that the higher the exposure to DMBA in the matriptase overproducers, the greater the chances were that the tumors would turn cancerous.
"What we found is deregulated matriptase sends a strong and versatile pro-growth signal that can travel along more than one route to the cell nucleus," said Dr. Karin List, the other lead author and an NIDCR scientist. "But the key point is, like a classic oncogene, matriptase initiates the erroneous growth signal. As further confirmation of this, when we turned off matriptase, not only the tumors but the precancerous lesions never appeared in the mice."
"What this work really shows is the current list of about 100 known oncogenes remains very much a work in progress," said Bugge. "It's also clear that matriptase and the approximately 200 other distinct cell-surface proteases will have a lot more to tell us about human health and disease in the coming years."
The article is titled "Deregulated matriptase causes ras-independent multistage carcinogenesis and promotes ras-mediated malignant transformation." It is published in the August 15, 2005 issue of the journal Genes and Development. The authors are: Karin List, Roman Szabo, Alfredo Molinolo, Virote Sriuranpong, Vivien Redeye, T. Murdock, B. Burke, B. S. Nielsen, Silvio J. Gutkind, and Thomas H. Bugge.
The National Institute of Dental and Craniofacial Research is the nation's leading funder of research on oral, dental, and craniofacial health.