Blood cells that normally protect the body from bacterial infection sometimes can produce enough germ-killing toxic substances over a long enough time to cause normal tissue to become malignant, researchers at Massachusetts General Hospital and Harvard Medical School in Boston report in the March 8 SCIENCE. They believe some cancers can be caused not only by toxic substances in the environment but also by toxic substances released by cells called phagocytes to fend off environmental carcinogens. The researchers showed that human neutrophils — phagocytic white blood cells that ingest bacteria and foreign substances–release toxic free radicals (oxygen metabolites) that can cause normal mouse connective tissue to become malignant.
They injected 43 mice with cells treated with human neutrophils activated to produce toxic oxygen metabolites and injected a control group of 53 mice with untreated cells. Five of the mice given treated cells developed malignant tumors and six developed benign tumors. None of the control mice developed tumors. Humans need phagocytes to protect against bacteria in the environment. The body has several elaborate chemical mechanisms to detoxify phagocytes’ oxygen products, “but it’s a relative resistance,” says Sigmund Weitzman, who directed the research. “If there are too many of these metabolites, they can damage normal tissue.” The most common human model in which phagocytes accumulate and ultimately cause cancer is ulcerative colitis, a chronic bowel inflammation.
After about 20 years of constant bathing with toxic phagocytic products, colorectal cancer may result. The researchers believe the mechanism of phagocytic accumulation and production of toxic metabolites might also help explain the origins of lung and breast cancer. People who smoke gather particles of soot and nicotine in their lungs. Phagocytes then accumulate and release their toxic products, which may interact with the chemical carcinogens in cigarettes to cause lung cancer, says Thomas P.
Stossel, an author of the paper. The mechanism’s role in breast cancer is more tenuous, Stossel says. Female as cells of breast ducts are replaced by new ones.
Phagocytes are called in to get rid of the degenerating cells, releasing their “nasty chemicals” in the process. Repeated exposure to toxic phagocytic products over time could contribute to the development of breast cancer, Stossel says. The researchers do not know the specific molecules ultimately responsible for causing normal tissue to become malignant. Phagocytes produce superoxide, hydrogen peroxide and hydroxyl radicals, as well as other toxic substances.
These substances can interact with membrane components of phagocytes or their target cells to generate other toxic products, such as peroxides and aldehydes. Although earlier work suggests an important role for hydroxyl radicals in the overall process, according to the SCIENCE paper “the ultimate carcinogen remains to be defined.”