Protease enzyme found to cause cancer
Cell surface enzyme can trigger the formation of tumor cells
NIH release
August 15, 2005
Scientists Find Cell Surface Enzyme Matriptase Causes Cancer
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 dont 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 bulls
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, or movement.
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 overexpressed and deregulated,
or uncontrolled within the cell, 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, thats 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. Its 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.
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