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Senior Citizen Health & Medicine
Proteins from Inflammation are 'Smoking Gun' in
Spread of Prostate Cancer
‘Prostate biopsies, may, ironically, hasten
progression of metastasis”
 March
19, 2007 - Many would assume that “mounting an immune response” or
“having your body fight the cancer” is a good thing. Now, research at
the University of California, San Diego (UCSD) School of Medicine
strongly suggests that inflammation associated with the progression of
tumors actually plays a key role in the metastasis of prostate cancer.
The research, appearing online today in advance of
publication in the journal Nature, identifies a mechanism which triggers
metastasis, which is the spread of cancer in late stages of prostate
cancer development.
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The findings by Michael Karin, Ph.D., professor of
pharmacology in UCSD’s Laboratory of Gene Regulation and Signal
Transduction, and colleagues may help solve the puzzle of why it takes
so long for cancer to metastasize, as well as what causes it to do so.
Furthermore, this new work may lead to development of anti-metastatic
therapies.
A major hypothesis in cancer research has been that
whether the cancer metastisizes or not is determined by genetic changes
within the cancer cell itself. But this hypothesis didn’t explain why
metastases appear many years after the initial tumor.
“Our findings suggest that promoting inflammation
of the cancerous tissue, for instance, by performing prostate biopsies,
may, ironically, hasten progression of metastasis,” said Karin. “We have
shown that proteins produced by inflammatory cells are the ‘smoking gun’
behind prostate cancer metastasis. The next step is to completely indict
one of them.”
One in six men will be diagnosed with prostate
cancer, and one in 33 will die of metastatic disease. Early tumors
confined to the prostate can be treated, but no effective treatments are
available for metastatic disease, according to Steven L. Gonias, M.D.,
Ph.D., professor and chair of the UCSD Department of Pathology, a study
investigator.
“This study helps explain the paradox that, in
certain types of malignancy, inflammation within a cancer may be
counterproductive,” said Gonias.
In research using mouse models and confirmed in
human tissue, the scientists observed that a protein kinase called IĸB
kinase α (IKKα) turns down the expression of a single gene called
Maspin, which has well-established anti-metastatic activity in breast
and prostate cancers. They found that the production of Maspin is
repressed by a series of events triggered by tumor inflammatory cells,
with the result that prostate cancer cells spread.
“An excellent inverse correlation between IKKα
activation and Maspin production was detected, such that advanced
prostate cancer cells contain high amounts of activated IKKα in their
nuclei and express little or no Maspin,” said Karin. He noted that a
perfect correlation between nuclear accumulation of activated IKKα and
reduced maspin expression was also seen in human prostate cancer, and
both correlated with the clinical stage of the disease.
Karin and his colleagues discovered a signaling
pathway that increased metastases in a mouse model of prostate cancer.
The pathway is activated by a ligand that binds to a Receptor that
Activates Nuclear factor Kappa-B (RANK). RANK ligand has been shown in
previous studies to be an important inflammatory protein (cytokine) that
can lead to bone loss through activation of bone resorbing cells.
RANK ligand, produced by inflammatory cells that
invade advanced prostate tumors, triggers a chain reaction in which IKKα
is activated, allowing it to enter the nucleus of the cancer cell,
repressing Maspin.
IKKα is a key linchpin in the pathway that turns
off the Maspin gene and activates the metastatic program. The new
results also support the view that RANK ligand is a general promoter of
prostate, and possibly breast, cancer metastasis.
“Maspin is a very potent inhibitor of metastasis;
in a patient with metastasis, cells have found a way to turn off Maspin,
which may depend on invasion of the tumor with RANK ligand-producing
cells that activate IKKα,” said Karin.
Malignancies progress through stages. In early,
non-metastatic tumors, a high level of Maspin is present, but it is
turned off in late stages. Early tumors contain low amounts of active
nuclear IKKα, whereas late-stage tumors contain the highest levels of
active nuclear IKKα.
The researchers also found a striking elevation in
expression of RANK ligand in late tumors, but it was not expressed by
the cancer cells. Instead, it is expressed by invading inflammatory
cells. Interference with RANK ligand production or activation, as well
as interference with IKKα activation, may offer new therapeutic
strategies for prevention of metastatic disease.
Editor’s Notes:
The study was funded by the National Institutes
of Health, the U.S. Army Medical Research and Material Command, the
Prostate Cancer Foundation, the Aventis-UICC Translational Cancer
Research Fellowship, the Lopiccola Fellowship of the UCSD Moores Cancer
Center, and the Life Science Research Fellowship.
Additional contributors include first author
Jun-Li Luo,Wei Tan and Olexandr Korchynskyi, UCSD Laboratory of Gene
Regulation and Signal Transduction, Department of Pharmacology and
Moores Cancer Center; David A. Cheresh and Jill M. Ricono, UCSD
Department of Pathology and the Moores Cancer Center; and Ming Zhang,
Baylor College of Medicine, Department of Molecular and Cellular
Biology.
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