Dr. Katsusaburo Yamagiwa, a Japanese pathologist at Tokyo Imperial University, and his research assistant, Dr. Koichi Ichikawa, conducted an experiment in which they repeatedly painted the insides of 101 rabbit ears with tar. coal for 150 days. This led to some interesting discoveries. By day 35 some rabbits began to show the first signs of cancer, 12 days later some rabbits developed full-blown cancer, and by day 150 cancer was evident in all rabbits. The cancer turned out to be squamous cell carcinoma, the same type that tends to appear in areas of the body exposed to the sun.
Was the cancer that developed on the rabbits’ ears caused by the coal tar or by persistent inflammatory irritation? The answer is both.
Coal tar is a complex chemical mixture that contains benzo[a]pyrene, a metabolite of which can lock onto DNA to form extensions called DNA adducts. If these are not repaired, they can induce mutations and initiate cancer. Besides coal tar, benzo[a]pyrene is also present in tobacco smoke and grilled meats, explaining their carcinogenicity. Since coal tar was first identified as a cancer trigger, many other substances such as asbestos, cadmium and benzene have joined the infamous list of “carcinogens”.
What role did chronic inflammatory irritation play in cancer induction? German physician Dr Rudolf Virchow was the first to link chronic inflammation to cancer, based on observations that immune cells coexist with cancer cells. This conjecture was proven to be true thanks to Dr. Yamagiwa’s groundbreaking experiment. Today, it is widely recognized that chronic inflammatory conditions can damage DNA and induce cancer over time.
According to the CDC, approximately 65% of liver cancers are related to hepatitis C or chronic hepatitis B. The National Cancer Institute describes long-lasting HPV infection as being linked to cancer of the cervix and oropharynx. Dr. David Tuveson, MD, PhD and president-elect of the American Association for Cancer Research (AACR), describes pancreatitis (inflammation of the pancreas) as the main devastating feature of pancreatic cancer. But cancer is not built in a day. A common pattern of inflammation-induced cancers is time factor, that is, the chronic and persistent bombardment of inflammatory states over several years. But how exactly does inflammation help turn healthy cells into cancer cells at the molecular and cellular levels?
It turns out that in addition to providing a host of favorable factors that, ironically, collectively stimulate cancer cell proliferation and metastasis, inflammatory cells also release reactive oxygen species (ROS) and reactive oxygen species. nitrogen (RNS), both of which are unstable free radicals that can damage DNA, induce mutations and cancer over time.
Clearly, a common denominator of chemical carcinogenesis and cancer induced by chronic inflammatory conditions is cumulative and irreversible DNA damage. Chronic inflammation in the presence of carcinogens significantly exacerbates cancer incidence, compared to the action of a carcinogen or inflammation alone. This also explains why rabbits developed full-blown cancer in just a few months in Dr. Yamagiwa’s famous experiment. Inflammation and carcinogenic, a definitely devastating duo.
Take home message:
– Chimney sweeps are more susceptible to cancer, but it wasn’t until 1915 in a laboratory in Japan, that it was shown due to exposure to coal tar
– The irritation-induced chronic cancer hypothesis was first experimented and tested in rabbits in 1915 in Japan
Dr. Nancy Liu-Sullivan holds a Ph.D. in Molecular and Cellular Pharmacology and was a Principal Investigator at Memorial Sloan Kettering Cancer Center. She currently teaches biology at the College of Staten Island, City University of New York.