Medical Pike
Family of Natural Cancer Fighter Proteins Identified
June 24, 2000 - A UCSF-led team has identified
five proteins in mice that trigger the immune system to attack cancer.
The research greatly increases
the number of known targets for drugs or vaccines to boost the immune
systems natural cancer-fighting ability, say the scientists.
The proteins present in
cancer cells, but not normal healthy tissues, mark these cells
for swift attack by the immune system's natural killer (NK) cells.
Although the proteins were discovered in mice, the scientists have
evidence of their counterparts in humans. Two related proteins were
identified in humans last year.
The research on the five
new proteins and the genes that code for them is being reported by
scientists at UCSF and the DNAX Research Institute in Palo Alto.
In mice as well as humans,
NK cells aggressively attack cancer cells once they are tagged by
these proteins. This can be demonstrated using tumor cell cultures,
where a single NK cell will destroy a marked cancer cell within a
few minutes; then move on to eliminate the next enemy cell, the researchers
point out. Studies are under way to determine if NK cells are equally
aggressive in mice bearing tumors tagged with the newly discovered
proteins.
"The immune system's natural
killer cells are swift to attack once cancer cells are tagged as foreign,"
says Lewis Lanier, PhD, senior author on the paper reporting the research.
"But cancer cells are part of one's 'self,' and the immune system
usually has difficulty recognizing them as invaders."
Lanier is professor of
microbiology and immunology at the UCSF Comprehensive Cancer Center,
part of the UCSF Medical Center. The new study is published in the
current issue of the journal Immunity. First author is Adelheid Cerwenka,
PhD, a post-doctoral researcher in Lanier's lab at UCSF, who recently
moved with him from their prior laboratory at the DNAX Research Institute.
With five more proteins
identified that alert NK cells to attack, researchers have a number
of new targets for drugs to strengthen the immune system's ability
to fight cancer, Lanier suggests.
These proteins on cancer
cells naturally bind to receptors on the surface of the NK cells.
The chemical linkage between the receptor on the NK cell and the protein
on the tumor unleashes a sequence of chemical events that destroy
the cancer cells.
The NK receptors, known
as NKG2D, are in plentiful supply, expressed on all NK cells and in
other immune soldiers such as CD8+ T cells. Altogether, NKG2D receptors
are found on about half of all immune cells, Lanier says.
"One of the major goals
in cancer research is finding how to enhance the immune system's ability
to fight the disease, just as we have contained smallpox and polio
with vaccines," Lanier says. "The ultimate goal of this research is
to deliberately establish auto-immunity against cancer."
If the NK receptors launch
attacks against cancer whenever they detect the key proteins, some
of the more deadly cancers have probably evolved a way to silence
the genes coding for these proteins, Lanier suggests.
"If so, then finding drugs
to turn these genes back on may provide a useful therapy against cancer,"
he says.
The NKG2D receptor is found
in NK cells of both mice and humans. The two human proteins identified
so far which link up with the receptors to launch attacks are known
as MICA and MICB. Neither has been found in mice. Researchers had
been wondering why the mouse had the NKG2D receptor, but no MICA or
MICB. With the five new proteins identified, they are now surprised
how many proteins bind to the NKG2D receptor, Lanier says.
"It is common for receptors
to have more than one protein that binds to it, he says. "But finding
five -- or seven, if we count the two human proteins identified last
year -- is very unusual. We now have more targets for potential drugs
either to directly boost the protein's expression or turn their genes
back on if the cancer silences them," Lanier says.
When they searched the
gene database for the five genes, Lanier and his colleagues were surprised
to find that the genes had already been identified as ones that are
active in the normal mouse fetus, but silent in normal, healthy adults.
However, Cerwenka and her co-workers have now shown that these genes
are turned back on in cancer cells in adult mice. This is very similar
to prior reports of other "oncofetal" antigens -- genes that are active
in embryonic life and tumor cells, but not present in normal healthy
adult tissues. This striking phenomenon is a puzzle to cancer biologists.
With the five mouse genes
now identified, the researchers are developing a mouse model, first
to confirm the role of the proteins in flagging invading cancers,
and then to test ways to immunize mice against cancer -- a giant step
toward developing anti-cancer vaccines for humans.
Links
Immunity (Journal)
UCSF
Comprehensive Cancer Center
Lewis
Lanier's UCSF Homepage
E-mail [email protected]
