New BC Cancer Agency study

The body is a battlefield, with daily wars being waged by the immune system against invading microorganisms and pre-cancerous cells. New research at the BC Cancer Agency, an agency of the Provincial Health Services Authority, is helping scientists to understand what turns an immune cell called a 'killer' macrophage into a 'healer' macrophage, and how this process helps cancerous tumours grow and escapes immune detection.

This research, published today in the prestigious journal Immunity, builds on the earlier BC Cancer Agency discovery of a protein which regulates how the body responds to microbial infections and inflammation-inducing agents. This protein – called SHIP (for Src homology 2-containing inositol 5'-phosphatase) – ensures that the body's immune cells do not overreact to inflammation-inducing conditions.

When there is a cut on the body, 'killer' macrophages, a type of front-line immune cell just under the skin, mount an immediate response to engulf and repel invading organisms. Once their job is done, it's the responsibility of 'healer' macrophages to take over, by stimulating the growth of new skin cells and scar tissue. What Dr. Gerald Krystal's team has discovered is a molecule switch that regulates the balance between these 'killer'and 'healer' macrophages.

"It's a Jekyll versus Hyde phenomenon," says lead author Michael Rauh, BC Cancer Agency researcher and MD/PhD student. "Macrophages have dueling personalities, and successful cancers exploit this conflict to their advantage."

"Sometimes half the mass of a successfully growing tumour is composed of healer macrophages," explains Dr. Krystal. "Tumour cells convert incoming killer cells to become healer cells, which then stimulate the growth of the tumour. One of SHIP's functions is to prevent killers from becoming healers."

Dr. Krystal's team found that killer macrophages turn into healer macrophages through a process involving the "PI3 kinase pathway." One of SHIP's normal functions is to inhibit the conversion of a killer cell to a healer by repressing the pathway.

As a result of this research, Dr. Krystal, together with Drs. Alice Mui, Ray Andersen, and Chris Ong, has formed a company called AquaGenyx Pharmaceuticals, to identify small molecule activators and inhibitors of SHIP. These small molecules could prove to be very useful for treating not only cancer, but a variety of inflammatory disorders such as asthma, arthritis, and lupus.

"We have strong evidence that SHIP's activity can be regulated," explains Dr. Krystal. "In the case of cancer, we want to increase SHIP's activity within macrophages to make sure that killer macrophages are not converted into healer cells."

Rauh, who has recently returned to the clinic to complete the MD portion of the MD/PhD training program, hopes that his future career will see the translation and application of these novel anti-cancer strategies. "The war on cancer will be waged on many fronts, including efforts to boost our body's natural immune defences."

This study was supported by the National Cancer Institute of Canada (Canadian Cancer Society), with funds from the Terry Fox Foundation, and core support from both the BC Cancer Foundation and the BC Cancer Agency. Rauh holds a Canadian Institutes of Health Research MD/PhD Studentship and a Michael Smith Foundation for Health Research Trainee Incentive Award. Co-author Laura Sly holds a Leukemia Research Fund of Canada Fellowship. 

The BC Cancer Agency, an agency of the Provincial Health Services Authority, is committed to reducing the incidence of cancer, reducing the mortality from cancer, and improving the quality of life of those living with cancer. It provides a comprehensive cancer control program for the people of British Columbia by working with community partners to deliver a range of oncology services, including prevention, early detection, diagnosis and treatment, research, education, supportive care, rehabilitation and palliative care. The BC Cancer Research Centre conducts research into the causes and cures for cancer.

For more information, please contact:
Nicole Adams
Communications Specialist
BC Cancer Agency
604.877.6272
nadams@bccancer.bc.ca