Study finds key link responsible for colon cancer initiation and metastasis

November 11, 2013, Arizona State University

Chronic inflammation has long been known as a key risk factor for cancer—-particularly colon cancer—-but the exact mechanisms of how inflammation heightens the immune response, and ultimately influences the initiation and progression of cancer have remained elusive. It is well established that anti-inflammatory drugs, like aspirin, reduce the risk of colorectal cancer.

Now, an ASU research team led by Biodesign Institute executive director Dr. Ray DuBois, M.D., PhD, has shown that a key genetic culprit, called CXCR2, is implicated in the , growth and progression in a mouse model of .

"We have been trying for the past several years to understand the precise molecular links between and , said DuBois. "We have demonstrated that CXCR2 mediates a critical step in the setup of the blood circulatory machinery that feeds tumor tissue. This provides an important new clue for the development of therapeutic targets to neutralize the effect of CXCR2 on colon cancer."

The DuBois' Laboratory for Inflammation and Cancer, which includes lead author Hiroshi Katoh, and colleagues Dingzhi Wang, Takiko Daikoku, Haiyan Sun, and Sudhansu K. Dey, published the results in the November 11 issue of Cancer Cell.

The results provide critical new clues toward the prevention of , the second leading cause of cancer deaths in the U.S. Despite the availability of colonoscopy screening, the 5-year survival rate remains low, due to a large number patients presenting with advanced stages of the disease. Currently, there are no clinically available blood tests for the early detection of sporadic colon cancer.

Inflammation has long been associated with increasing one's risk for colon cancer. For instance, more than 20 percent of patients with a form of inflammatory bowel disease (IBD) develop colorectal cancer within 30 years of diagnosis. This colitis-associated cancer has a slow progression, but a very poor response to treatment and a high mortality rate.

Researchers have known that the broad mechanisms of cancer involve an interplay with the immune system response that includes: recruiting immune cells that influence the tumor microenvironment, escaping from host immunosurveillance and suppression, shifting of the host immune response, and tumor-associated angiogenesis to establish the blood supply.

For the study, the research team first "knocked-out" or removed the CXCR2 gene in mice, and found that the signs typically associated with inflammation were prevented. Furthermore, they demonstrated that CXCR2 dramatically suppressed colonic inflammation and the colitis associated tumor formation, growth and progression in mice.

CXCR2 decorates the outer part of called myeloid-derived suppressor cells, or MDSCs, that work to block the immune response of killer CD8+ T cells. In the knockout mice, without CXCR2 present, the MDSC cells could no longer migrate from the circulatory system to the colon, dodge the killer CD8+ T cell immune response, and feed the blood supply of the tumor environment. Furthermore, when they transplanted normal MDSC cells (with normal CXCR2) into the knockout mice, tumor formation was restored.

"These results provide the first genetic evidence that CXCR2 is required for recruitment of MDSCs into inflamed colonic mucosa and colitis-associated tumors," said DuBois.

For DuBois, who has devoted his career to unraveling the inflammatory circuitry responsible for colon cancer, the results help connect the dots between the immune system, inflammation and tumor formation and metastasis.

DuBois' team was the first to show that colorectal tumors contained high levels of the enzyme cyclo-oxygenase-2 (COX-2), a key step in the production of pro-inflammatory mediators such as prostaglandin E2 (PGE2). PGE2 triggers production of a CXCR2 molecule that fits into CXCR2 like a baseball into a glove's pocket and activates it. CXCR2, like the pied piper, recruits MDSCs from the bloodstream to sites of inflammation, causing the colon cancer tumors to evade the immune killer CD8+ T .

"Our findings reveal not only how MDSCs are recruited to local inflamed tissues and and how local MDSCs contribute to colorectal cancer progression, but now also provide a rationale for developing new therapeutic approaches to subvert - and tumor-induced immunosuppression by using CXCR2 antagonists and neutralizing antibodies," said DuBois.

Explore further: Microbes in the gut help determine risk of tumors

Related Stories

Microbes in the gut help determine risk of tumors

November 5, 2013
Transferring the gut microbes from a mouse with colon tumors to germ-free mice makes those mice prone to getting tumors as well, according to the results of a study published in mBio, the online open-access journal of the ...

Research findings reveal that tumors promote myeloid-derived suppressor cell accumulation through IRF-8 loss

September 17, 2013
(Medical Xpress)—Researchers at Roswell Park Cancer Institute (RPCI) have uncovered a new pathway by which cancer cells, such as in breast cancer, stimulate the expansion of myeloid-derived suppressor cells (MDSCs), a blood ...

Researchers discover how cancer 'invisibility cloak' works

October 28, 2013
Researchers at National Jewish Health have discovered how a lipid secreted by cancer tumors prevents the immune system from mounting an immune response against it. When lysophosphatidic acid (LPA) binds to killer T cells, ...

Inflammatory mediator promotes colorectal cancer by stifling protective genes

January 22, 2012
Chronic inflammation combines with DNA methylation, a process that shuts down cancer-fighting genes, to promote development of colorectal cancer, scientists at The University of Texas MD Anderson Cancer Center report today ...

Researchers probe the enigma of healing element that is also the enemy

April 3, 2013
The same factor in our immune system that is instrumental in enabling us to fight off severe and dangerous inflammatory ailments is also a player in doing the opposite at a later stage, causing the suppression of our immune ...

Blocking tumor-induced inflammation impacts cancer development

October 3, 2012
Researchers at the University of California, San Diego School of Medicine report the discovery of microbial–dependent mechanisms through which some cancers mount an inflammatory response that fuels their development and ...

Recommended for you

More evidence of link between severe gum disease and cancer risk

January 16, 2018
Data collected during a long-term health study provides additional evidence for a link between increased risk of cancer in individuals with advanced gum disease, according to a new collaborative study led by epidemiologists ...

Researchers develop a remote-controlled cancer immunotherapy system

January 15, 2018
A team of researchers has developed an ultrasound-based system that can non-invasively and remotely control genetic processes in live immune T cells so that they recognize and kill cancer cells.

Pancreatic tumors may require a one-two-three punch

January 15, 2018
One of the many difficult things about pancreatic cancer is that tumors are resistant to most treatments because of their unique density and cell composition. However, in a new Wilmot Cancer Institute study, scientists discovered ...

New immunotherapy approach boosts body's ability to destroy cancer cells

January 12, 2018
Few cancer treatments are generating more excitement these days than immunotherapy—drugs based on the principle that the immune system can be harnessed to detect and kill cancer cells, much in the same way that it goes ...

Cancer's gene-determined 'immune landscape' dictates progression of prostate tumors

January 12, 2018
The field of immunotherapy - the harnessing of patients' own immune systems to fend off cancer - is revolutionizing cancer treatment today. However, clinical trials often show marked improvements in only small subsets of ...

FDA approves first drug for tumors tied to breast cancer genes

January 12, 2018
(HealthDay)—The U.S. Food and Drug Administration on Friday approved the first drug aimed at treating metastatic breast cancers linked to the BRCA gene mutation.

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

Neal Asher
1 / 5 (10) Nov 12, 2013
The paragraph beginning 'For the study, the research team first "knocked-out"' is contradictory and makes no sense at all.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.