UCSD Medical Researchers Are First To Demonstrate
Molecular Link Between Inflammation And Cancer
of Pro-Inflammatory Gene
Dramatically Reduces Tumor Development
By Sue Pondrom
of the molecular link between inflammation and cancer has been
shown by researchers at the University of California, San Diego
(UCSD) School of Medicine. Featured as the cover article in
the August 6, 2004 issue of the journal Cell, the study
also demonstrated that inactivation of a gene involved in the
inflammatory process can dramatically reduce tumor development
in mice with a gastrointestinal form of cancer.
The investigators found
that a gene called I-kappa-B kinase (IKK beta), a pro-inflammatory
gene, acts differently in two cell types to cause cancer. When
IKK beta was deleted, the cancer incidence and tumor growth
in mice was decreased by nearly 80 percent.
IKK beta is required
for activation of a protein called nuclear factor kappa B (NF-kB),
that acts as a master switch to turn on inflammation in response
to bacterial or viral infections. In epithelial cells, NF-kB
promotes the development of cancer not through inflammation,
but through inhibition of a cell-killing process called apoptosis.
In myeloid cells, NF-kB causes the expression of pro-inflammatory
molecules that stimulate the division of genetically altered
epithelial cells and thereby increase tumor size.
Because recurrent inflammation
and chronic infections contribute to a large number of different
cancers, the researchers chose one of these cancers –
colitis associated cancer (CAC) – as their model for study.
CAC occurs in people suffering from chronic colitis, which puts
them at very high risk for cancer.
shown how tumors arise from chronic inflammation that acts together
with chemical carcinogens,” said the study’s senior
author, Michael Karin, Ph.D., UCSD professor of pharmacology,
American Cancer Society Research Professor, and a member of
the Rebecca and John Moores UCSD Cancer Center.
to chronic infection, the interplay between immune cells and
the epithelial cells of the intestinal tract, which become genetically
transformed to give rise to malignant cells by the carcinogen,
results in increased tumor growth and suppression of apoptosis,
whose role is to reduce cancer incidence,” Karin added.
“Our studies show how NF-kB acts very early in the carcinogenesis
process, in two different ways.”
The relationship between
cancer and inflammation due to chronic infection has been suspected,
but not proven, for many years. In a 1986 study, for example,
one researcher compared the inflammatory response to a wound
healing response, saying tumors were wounds that do not heal.
Even without proof of the inflammation-cancer link, cancer therapies
have been developed that utilize non-steroidal anti-inflammatory
drugs (NSAIDs) to inhibit NF-kB and other mediators of inflammation,
and to act as chemo-preventive agents that reduce the risk of
gastrointestinal cancers. Some of these therapies, however,
have been only partially effective because the precise molecular
pathway targeted by the treatment has not been known.
In their study of NF-kB,
the researchers began by administering two compounds to mice.
The first was a pro-carcinogen called azoxymethane (AOM), which
is commonly used to induce colorectal cancer in experimental
animals. The second compound was a pro-inflammatory irritant
called dextran sulfate sodium salt (DSS), that eroded the intestinal-tract
epithelial cells, allowing the entrance of enteric bacteria,
with resulting inflammation generated by the body to fight the
In normal mice, these
two compounds trigger both inflammation and, a few months later,
tumors called adenocarcinomas. In this study, DSS and AOM were
given to two additional groups of mice – one group bred
without IKK beta in the epithelial cells of the intestine; the
second group without IKK beta in myeloid cells, which play an
important role in the immune system by generating white blood
cells called macrophages to induce inflammation and fight infection.
Focusing on the epithelial
cells deficient in IKK beta, the researchers found that DSS
induced inflammation in the mice, even without NF-kB activation.
And yet, the incidence of tumor development decreased by 80
percent as compared to normal mice. Using biochemical analysis
of the tissue without IKK beta, the scientists determined that
stimulation of a process called apoptosis had decreased cancer
A form of cell suicide,
apoptosis prevents the growth of unwanted cells. It is a normal
process the body uses to kill mutated or chemically transformed
cells, as well as useful cells that have outlived their purpose.
Evading apoptosis is one of the hallmarks of cancer.
In their study, the
UCSD team found that apoptosis was increased in mice bred without
IKK beta. Specifically, without NF-kB activation, there was
an increase of pro-apoptotic proteins Bak and Bax, and a decrease
in a protein called Bcl-xL, known to inhibit apoptosis.
Turning their focus
to myeloid cells, the team found that inactivation of IKK beta
reduced the expression of many genes that contribute to the
inflammatory process. When NF-kB was not activated, there was
a 50 percent reduction in tumors caused by DSS/AOM. The tumors
that grew were significantly smaller in size than those in the
normal mice that had received the two compounds.
To understand how IKK
beta in myeloid cells affects tumor development, the researchers
first examined the affect of IKK beta deletion on apoptosis
and found none. What they discovered, instead, was that IKK
beta deletion in myeloid cells decreased the expression of pro-inflammatory
molecules such as cyclooxygenase, also known as COX-2, and interleukins
1 and 6, which are expressed at sites of inflammation.
establish for the first time the role of myeloid cells in inflammation-associated
tumor promotion in addition to their role in tumor progression
and invasiveness,” the authors stated in the Cell
The authors added that
“in addition to identifying a key molecular mechanism
connecting inflammation and cancer, our results suggest that
specific pharmacological inhibition of IKK beta may be very
effective in prevention of colitis associated cancer.”
In addition to Karin,
the study’s authors were first author Florian R. Greten,
M.D., UCSD Department of Pharmacology; and Lars Eckmann, M.D.,
UCSD Department of Medicine; Jin Mo Park, Ph.D., UCSD Department
of Pharmacology; Zhi-Wei Li, Ph.D., UCSD Department of Pharmacology
and the Moffit Cancer Center and Research Institute, Tampa,
Florida; Laurence J. Egan, M.D., UCSD Department of Medicine
and the Gastroenterology Research Unit, Mayo Clinic, Rochester,
Minnesota; and Martin F. Kagnoff, M.D., UCSD Department of Medicine.
The study was supported
by grants from the National Institutes of Health, the Superfund
Research Program, the Crohn’s and Colitis Foundation of
America, and the Deutsche Forschungsgemeinschaft Cancer Research
and Prevention Foundation.
Media Contact: Sue Pondrom (619) 543-6163