Dr. Katsusaburo Yamagiwa, a Japanese pathologist at Imperial Tokyo University, and his research assistant, Dr. Koichi Ichikawa, carried out an experiment in which they repeatedly painted the inner side of 101 rabbit ears with coal-tar for 150 days. This led to some interesting discoveries. On day 35, some rabbits began to show the initial signs of cancer, 12 days later some rabbits developed full-blown cancer, and by day 150, cancer was evident in all the rabbits. The cancer turned out to be squamous cell carcinoma, the same type that tends to appear in sun-exposed areas of the body.
Was the cancer that developed on the ears of the rabbits induced by 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 latch 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 also occurs in tobacco smoke and grilled meats, explaining their carcinogenicity. Since the first identification of coal-tar 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 inducing cancer? German physician Dr. Rudolf Virchow was the first to link chronic inflammation to cancer, based on observations that immune cells were found to co-exist with cancer cells. This conjecture was proven to be true by Dr. Yamagiwa’s ground-breaking experiment. Today it is widely acknowledged that chronic inflammatory conditions can cause DNA damage and induce cancer over time.
According to the CDC, ~65% of liver cancer is linked to chronic hepatitis C or hepatitis B. The National Cancer Institute describes long-lasting HPV infection as related to cancer of the cervix and oropharynx. Dr. David Tuveson, MD, PhD and President-Elect of the American Association of Cancer Research (AACR), describes pancreatitis (inflammation of the pancreas) as the #1 devastating hallmark of pancreatic cancer. But cancer isn’t built in a day. A common pattern of inflammation-induced cancers is the time factor, that is, chronic and persistent bombardment of inflammatory conditions over the span of years. But exactly how does inflammation contribute to transforming healthy cells into cancer cells at the molecular and cellular levels?
It turns out that in addition to supplying a host of favorable factors that, ironically, collectively boost cancer cell proliferation and metastasis, inflammatory cells also release reactive oxygen species (ROS) and reactive nitrogen species (RNS) both of which are unstable free radicals that can damage DNA, induce mutation and cancer over time.
Clearly, a common denominator of chemical carcinogenesis and cancer being induced by chronic inflammatory conditions is the cumulative and irreversible damage to DNA. Chronic inflammation in the presence of carcinogens exacerbates cancer incidence by significant magnitudes, compared with the action of a carcinogen or of inflammation alone. This also explains why the rabbits developed full-blown cancer in just a few months of time in Dr. Yamagiwa’s famous experiment. Inflammation and carcinogen, a definite devastating duo.
Take-home message:
- Chimney sweepers are more susceptible to cancer, but it was only in 1915 in a lab in Japan, that it was shown due to exposure from coal-tar
- The hypothesis of chronic irritation-induced cancer was first experimented and tested to be true in rabbits in 1915 in Japan
Dr. Nancy Liu-Sullivan holds a Ph.D. in Molecular and Cellular Pharmacology and served as a senior research scientist at Memorial Sloan Kettering Cancer Center. She currently teaches biology at the College of Staten Island, City University of New York.
