Antibody Signal May Redirect Inflammation To Fuel Cancer

Typically, the "innate" immune system's Pac-Man-like white blood cells, or leukocytes, engulf and destroy invading microbes when receptors on their surface receive a signal from serum in the blood -- often an antibody produced by a B cell in the separately evolved "acquired" immune system.

Now UCSF researchers have found that in the presence of precancerous tissue, leukocyte antibody receptors can also be activated to turn on a dangerously different program: inducing leukocytes to boost cell growth, increase the number of blood vessels and "remodel" tissue in the area -- all of which help cancer develop.

The finding adds a critical and surprising detail to the emerging view that inflammation, usually a helpful response to invading pathogens, can become misdirected and fuel cancer.

The new research was presented today (February 19) by UCSF scientist Lisa M. Coussens, PhD, at the annual meeting of the American Association for the Advancement of Science (AAAS) in a session titled "healthy aging: inflammation and chronic diseases."

"Immunologists have known for decades that B cells of the so-called adaptive or acquired immune system are activated following a bacterial infection and in response, produce antibodies that signal leukocytes to attack," said Coussens, associate professor of pathology in the UCSF Cancer Research Institute. "But in precancerous tissue in mice, we have found that leukocytes apparently receive signals to switch programs, stimulating cell growth and increasing blood supply -- processes that would normally help healing from an infection, but can instead fuel cancer cell development."

The researchers have not yet identified what specific signal or signals are involved, but preliminary evidence indicates that antibodies may signal specific receptors on leukocytes to enhance the cancer-promoting pathway. Part of the receptor for the antibody known as immunoglobulin appears to be involved, Coussens said.

The good news, she adds, is that potential drugs to block this pathway are already being tested in clinical trials to treat B cell lymphoma and auto-immune diseases made worse by inflammation, such as rheumatoid arthritis.

"We already know that inflammation accelerates skin, cervical and colon cancer, and most likely also lung and breast cancer," she said. "If we confirm that what we've discovered in the mice studies also occurs in human cancers, we may soon be in a good position to slow this cancer process using drugs already under study for severe immune disorders."

Coussens envisions a therapeutic strategy similar to treating people with HIV. The goal would not be to necessarily eliminate every last cancer cell, but to control the inflammation process needed for the cancer to progress to a more threatening stage.

The new UCSF finding comes from studies with mice genetically engineered to carry some of the genes of the human papilloma virus (HPV), a pathogen that is known to cause human cervical cancer. By comparing cancer progression in these mice compared with gene "knock-out mice" that lacked the antibody receptors normally active on the leukocyte surfaces, Coussens and her colleagues discovered that the receptors were involved for the cancer to progress rapidly.

The new discovery follows one by Coussens and colleagues two years ago, published in "Cancer Cell" (1) that determined that antibody-producing B cells are essential for the harmful redirection of the leukocyte response. The finding startled many in the field because the B cells do not act at the site of inflammation where the leukocytes are located, so they apparently send the crucial signals remotely through the blood's serum. The surprising nature of the discovery and its implications were explored in a June 2005 commentary in "Nature" (2).

A review this month by Coussens and Ting-Ting Tan, PhD, a postdoctoral fellow in Coussens' laboratory, brings together many related threads of research in this fast-evolving area of inquiry. It was published February 1 in "Current Opinion in Immunology" (3).

Coussens stresses that because of the unique antibody makeup of each person, there is no evidence and no likelihood that periodic booster shots of the immunoglobulin antibody, or even blood transfusions from someone with precancerous tissue could trigger cancer progression in a recipient.

Coussens is a member of UCSF's Comprehensive Cancer Center, a designation given by the National Cancer Institute in recognition of the program's excellence in basic science, clinical research, epidemiology, cancer control and patient care, and its successful translation of research into improved treatments.

References

(1) deVesser KE, Korets LV, Coussens LM: De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. "Cancer Cell" 2005, 7:411-423.

(2) Mantovani, Alberto: Inflammation by remote control. "Nature" 2005, 435:752-753.

(3) Tan, Ting-Ting and Coussens, Lisa: Humoral immunity, inflammation and cancer. "Current Opinion in Immunology" 2007: 19:1-8.