turning the wrong switch with inflammation fuels cancer and...

[Lani]

there are already drugs available and/or in Phase III if this turns out to be clinically useful:

19 February 2007



Antibody signal may redirect inflammation to fuel cancer

SAN FRANCISCO -- As evidence mounts that the body's normally protective inflammation response can drive some precancerous tissues to become fully malignant, UCSF scientists report discovering an apparent trigger to this potentially deadly process.

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.

UCSF is a leading university that advances health worldwide by conducting advanced biomedical research, educating graduate students in the life sciences and health professions, and providing complex patient care.

###

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. ###

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[Hopeful]

Lani, question for you: Is an allergic response similar to an inflammatory response? I ask because I developed a severe allergic response (hives, hives and more hives) to a medication during the 18 months prior to my dx. I stopped the meds, but the itching continued for a year until finally knocked out by a steriod cream. This episode has lingered in the back of my mind for association with the bc. I would be interested in your thoughts.

Hopeful

[Lani]

to a different set of cells (eosinophils) and different mechanism, but now allergy is included in a bigger field recognizing that many of the same pathways and immune cells may be involved.

Stanford has recently combined fields which involve similar research and treatment in one big institute to try to accelerate improvements in treatment --the institute is called immunity, transplantation and infection.

I have heard anecdotal evidence of herceptin "curing " a lifelong allergy--one that involved sneezing when exposed to a certain flower and a severe rash when touching the leaves of the same plant. This is the opposite of what you are asking but...

Am interested if others have had similar experience.

The immune system is still poorly understood. If I hear/read more which helps explain your symptoms, I will try to remember and post

Hope this helped more than confused!

[R.B.]

Thanks Lani for the very interesting post.

There have been several posts on possible links between BC and inflammation.

There are a number of posts on the relationship of omega six to the inflammatory pathways and the possible moderating impact of omega threes.

Clicking on search above and entering say omega six and inflammation or similar should produce some of the previous posts.


RB

[Hopeful]

Lani,

Thank you. I find all information useful, and I learn so much from the articles you post and the information everyone here shares. I know that Herceptin is supposed to enhance the immune system response, so your anectdotal evidence of it curing allergies makes perfect sense.

I know that some cases of skin eruptions are linked to auto-immune diseases, which seem to occur at a higher rate in bc patients. I guess someday all the interactions of these pathways will be mapped, but for now it is more a labrynth than anything else.

Hopeful

[Lani]

there are papers showing treatment to decrease T regulatory cells enhances the efficacy of antiher2 vaccines (or vaccines against other breast cancer antigens)-- see papers by K.Knutson of Mayo Clinic

Actually decreasing T regulatory cells is said to be a good thing in breast cancer patients, as it helps the body recognize the breast cancer as something to be attacked. However, decreasing T regulatory cells can also
cause a patient to attack their own self-antigens CAUSING an autoimmune-like disease.

I have read that herceptin decreases T regulatory cells, but don't know by how much ie, what the risk of autoimmune like disease might be. But there are many people on this board who have been on herceptin for years and noone has listed that yet as a sideeffect, real or perceived, from herceptin (I started such a thread perhaps a year ago and it pops up intermittently)

We are only in the infancy of understanding of the immune system it seems

[heblaj01]

The findings described in the previous posts about the role of inflammation in cancer, brings up in my mind one of the possible related roles of vitamin D3 in regulating the immune system from over or under stimulation.

For instance preclinical studies have shown that vitamin D3 fights autoimmune diseases & one clinical trial has been verifying its effects on rhumatoid arthritis (which incidentally has been found associated with greater incidence of cancer):
http://clinicaltrials.gov/ct/gui/sho...25714?order=42
Vitamin D Deficiency Causes Immune Dysfunction and Enables or Perpetuates the Development of Rheumatoid Arthritis

http://www.blackwell-synergy.com/lin....01204.x/full/
Identification and immune regulation of 25-hydroxyvitamin D-1-α-hydroxylase
in murine macrophages

This indirect role of vitamin D on inflammation would be one of its other modes of action
which are claimed to provide protection against cancer as evidenced by the statitics published last year.