Enzyme eliminated by cancer cells holds promise for cancer treatment
20.07.2007
An enzyme that cancer cells eliminate, apparently so they can keep
proliferating, may hold clues to more targeted, effective cancer
treatment, scientists say.
In a high-stakes tit for tat, protein kinase G enables healthy cells
to stay on task to proliferate, differentiate then provide a useful
function. Cancer somehow reduces or eliminates PKG and cells get
stuck proliferating.
"The bottom line is, in normal tissue, you can see PKG being
expressed; but tumors or cell lines that correlate with those tissues
don't have nearly as much," says Dr. Darren Browning, cancer
researcher at the Medical College of Georgia.
Cell lines used for all types of research appear to support his
hypothesis. Many are actually cancer cells because of their
proclivity to keep producing; Dr. Browning and others have shown PKG
is lost in these cells. "You split them once or twice and they kind
of lose their character," he says.
The same appears true for tumors in people, says Dr. Browning, whose
lab has found dramatic differences in PKG levels in tumors compared
to even nearby, healthy tissue removed in surgery to ensure a cancer-
free margin.
The findings made him wonder if the change in PKG level was just an
artifact or was critical to cancer survival. "A lot of proteins are
lost by cancer cells, so we asked, 'What happens if we put PKG back
into the cancer cells?'"
He took metastatic colon cancer cells, created a system for
reintroducing PKG, then put the cells into mice without an immune
system. He admits he was disappointed that the PKG-enhanced cells
grew but became very interested in how they grew.
Cancer cells without PKG created hard, solid tumors that spread. PKG-
enhanced cells created a soft, non-invasive tumor that literally fell
apart on contact and seemed to grow in little islands. After
consultation with pathologists and others, he realized the PKG-
enhanced cells were congregating around the few blood vessels. "We
know that cancer cells, particularly colon cancer cells, are very
aggressive at bringing blood vessels into the tumor," he says. Cells
poor at recruiting blood vessels don't grow well, which seems to be
the case for PKG-enhanced colon cancer cells.
Now he wants to know how PKG nullifies aggressive metastatic cancer
cells. "We think PKG inhibits cancer by getting rid of a cancer-
promoting gene called beta-catenin, which slows growth and blocks the
tumor's ability to recruit blood vessels that are needed to grow
bigger," says Dr. Browning, who recently received a $720,000 American
Cancer Society grant to pursue his hypothesis. His proposal was
ranked number one by the ACS Cell Structure and Metastasis Study
Section.
He's already shown that PKG can reduce vascular endothelial growth
factor, or VEGF; anti-VEGF drugs are the focus of numerous anti-
cancer trials underway in the country because of VEGF's critical role
in development of new blood vessels. "Maybe by activating PKG or
increasing PKG expression in tumors, we are going to reduce the
amount of VEGF they produce," he says. "We don't know whether PKG has
a role in going from normal tissue to the initiation of a tumor, but
we think it's important to the tumor both in terms of angiogenesis
and blocking metastasis." He points to one of his studies in which
colon cancer's spread to the lungs – a common path for metastatic
colon cancer – was completely blocked by PKG expression.
A big part of the magic of PKG may be its impact on a gene called
beta-catenin, which enables many stem cells, including those in the
skin, bone marrow and colon, to proliferate throughout life. Little
pits called crypts in the wall of the colon contain Wnt hormone which
stimulate nearby stem cells, causing an increase in beta-catenin. The
net effect is the colon makes new cells to replace cells lost to the
ongoing grind of absorbing water and minerals from food and forming
and eliminating waste.
As cells start moving out of the crypt, away from the Wnt hormone,
beta-catenin levels go down so cells should stop dividing and start
maturing. Essentially all colon cancers have an aberration in this
beta-catenin system that prevents normal degradation and allows cell
to keep proliferating.
"In the normal cells that line the colon, you don't see very much
beta-catenin. We think PKG in these cells keeps it that way to keep
the cells from continuing to proliferate and spread," says Dr.
Browning, who has already shown that in the test tube at least,
adding PKG lowers beta-catenin levels. Interestingly, beta-catenin
also is known to regulate VEGF expression in colon cancer.
"In a nutshell, the first and most important genetic lesions leading
to colon cancer cause increased beta-catenin levels," says Dr.
Browning. "We found PKG can knock down beta-catenin levels by up to
80 percent in some colon cancer cells and we think that is part of
the mechanism by which PKG is able to block tumor angiogenesis and
metastasis."
He's excited by the implications and is involved in extensive
collaborations to understand how PKG regulates beta-catenin and how
it might be used in cancer therapies.
Evidence of PKG's effectiveness in fighting colon cancer in humans
may already be available. Colon and rectal cancer is the third most
common cancer in men and women in the United States but it's rare in
developing countries where residents eat less processed food and
ingest more bacteria. Some of these bacteria make a protein, STa,
which appears to prevent and even kill colon cancer cells. Dr.
Browning believes that PKG is responsible for STa's anti-cancer
effects.
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StemCells subscribers may also be interested in these sites:
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Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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