Scientists Find Cell Surface Enzyme Matriptase Causes Cancer

This finding, published in the current issue of the journal Genes andDevelopment, marks the first report of a protein-cleaving enzyme, orprotease, on the cell surface that can efficiently trigger theformation of tumor cells. The authors also note that matriptase is thefirst known cell-surface protease that can act as an oncogene, anumbrella term for mutated genes and their proteins that prompt cells todivide too rapidly, a hallmark of tumor cells.

"What makes matriptase potentially such a good molecular target totreat cancer is its accessibility," said NIDCR scientist Dr. ThomasBugge, the senior author on the paper. "We don't have to trick thetumor cell to internalize a drug, then hope it reaches its destinationin an appropriate concentration and duration. In this case, the bull'seye is right on the cell surface."

Bugge said the exact function of matriptase in healthy human cellsremains a bit of a mystery. Previous studies show that cells comprisingthe outer lining, or epithelium, of nearly all human organs express theprotease. They also suggest that matriptase might play a role inactivating other membrane-bound proteins on the cell surface that areinvolved in signaling basic cellular activities, such as growth andmotility.

Since its discovery nearly 13 years ago, scientists also have suspectedthat matriptase might have a dark side. It is overly abundant in avariety of epithelial-derived tumors, including breast, prostate,ovarian, colon, and oral carcinomas. Then, in 2002, scientists reportedwomen with breast and ovarian cancer have poor prognoses if theirtumors contain high levels of matriptase. In fact, just two months ago,researchers reported for the first time that increased expression ofmatriptase is associated with more serious forms of cervical cancer.

Still unanswered, however, was the larger question of whetherthe protease, when deregulated and overexpressed, might actually causecancer. To find the answer, Bugge and colleagues produced mice thatexpressed the human version of the matriptase gene in a stable, readilymeasurable manner. "After our initial round of experiments, we foundthat the skin of the mice was quite sensitive to fluctuations in thelevels of matriptase," said Dr. Roman Szabo, a co-lead author on thestudy and an NIDCR scientist. "So much so, that all 10 of the mice thatproduced too much matriptase developed distinctive, splotchy skinlesions within a year."

According to Szabo, that's when things took an unexpected turn. He andhis colleagues biopsied the lesions and, to their surprise, found thatthey were tumors that had already advanced in most cases to a type ofcancer called squamous cell carcinoma, a strong indication that theexcess matriptase was driving the process.

The scientists next wondered whether excess matriptase and sustainedexposure to a chemical carcinogen might be a dangerous combination, ascenario with obvious real world implications. They applied variousdoses of the chemical DMBA, a well-characterized carcinogen present intobacco products, to a small area of skin on each of 40 newbornmatriptase overproducers. Within seven weeks, 95 percent of these micedeveloped tumors compared to roughly 2 percent of normal, healthy mice.The group also found that the higher the exposure to DMBA in thematriptase overproducers, the greater the chances were that the tumorswould turn cancerous.

"What we found is deregulated matriptase sends a strong and versatilepro-growth signal that can travel along more than one route to the cellnucleus," said Dr. Karin List, the other lead author and an NIDCRscientist. "But the key point is, like a classic oncogene, matriptaseinitiates the erroneous growth signal. As further confirmation of this,when we turned off matriptase, not only the tumors but the precancerouslesions never appeared in the mice."

"What this work really shows is the current list of about 100 knownoncogenes remains very much a work in progress," said Bugge. "It's alsoclear that matriptase and the approximately 200 other distinctcell-surface proteases will have a lot more to tell us about humanhealth and disease in the coming years."

The article is titled "Deregulated matriptase causes ras-independentmultistage carcinogenesis and promotes ras-mediated malignanttransformation." It is published in the August 15, 2005 issue of thejournal Genes and Development. The authors are: Karin List, RomanSzabo, 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 isthe nation's leading funder of research on oral, dental, andcraniofacial health.