ETIOLOGY PROGRAM AREA

SUMMARY OF ACTIVITIES

The year April 1, 1981 to March 31, 1982 is the third year of the second Five-Year Program of the U.S.-Japan Cooperative Cancer Research Program. The aim of the Etiology Area of the Program is to clarify the cause of human cancers and to determine the mechanism of carcinogenesis. It has been envisaged that cancer prevention could be materialized eventually by the progress in science of etiology of cancer.
The Etiology Area covers epidemiology, chemical carcinogenesis, viral carcinogenesis, and molecular biology. During the previous two years of this second Five-Year program, emphasis was placed on identification of causative agents, initiators and promoters. However, except cancer derived from some occupational exposure and iatrogenic exposure to chemical and physical agents, causes for most cancers found in human beings have not been pinpointed yet. More multifactorial events than expected previously could be involved.
Even a nonspecific substance such as sodium chloride may produce chronic inflammation in gastric mucosa by damaging mucosal cells. Repeated damage and regeneration result in the formation of intestinal metaplasia of the stomach. High incidence of intestinal metaplasia is related to high incidence of stomach cancer, especially well-differentiated adenocarcinoma. Therefore, sodium chloride may not be the sole cause of intestinal metaplasia. Meanwhile, there are varied consequences from intestinal metaplasia. Acidity in the stomach fluid decreases by replacing stomach epithelium with intestinal epithelium; thus, intestinal metaplasia renders bacterial growth possible. Bacteria can reduce nitrate to nitrite, which can produce nitrosamines with secondary amines. The carcinogenic process in the human organ may be more complicated than that produced by single chemical administration to rodents.
The Etiology Area held a seminar to discuss the epidemiology, biochemistry, histopathology and clinical aspects of "Intestinal Metaplasia, which could be a high risk for development of stomach cancer. Prevention of intestinal metaplasia may result in prevention of stomach cancer, but it is not sure yet whether removal of initiators and tumor promoters in a strict sense may be efficient for this purpose. Instead, improvement of diet and nutrition may be a more effective means of prevention. This example would indicate that the Etiology Area would need to pay more attention to environmental factors other than typical initiators and tumor promoters.
In November 1981 in Hawaii, the Etiology Program Area held a seminar entitled "Carcinogenesis and Gene Expression in Liver Cell Culture," which dealt with patterns of expression on various genes during carcinogenesis, especially hepatocarcinogenesis. Changes in expression of various genes were reflected by the production of enzyme and proteins which were not found in the original liver. The change is so pleiotropic that the mechanisms of some of these changes would be intrinsically relevant to the carcinogenic process.
The Etiology Program Area had seven exchange scientists representing the disciplines of viral and chemical carcinogenesis and molecular biology. The Exchange Scientist Program was very useful in fostering the exchange of new, often unpublished information between the U.S. and Japanese scientists. The exchange scientist program frequently motivated new collaborative investigations in the U.S. and Japanese laboratories.
The successful operation of the Program has been due largely to the efforts of Drs. Thomas L. Benjamin and Hidesaburo Hanafusa, Principal Advisors for the United States and Dr. Hiroto Shimojo, Principal Advisor for Japan. A consensus was reached that because of the difference in the scientific and social background between the U.S. and Japan in the area of tumor virology, an exchange of scientists was more preferable than larger meetings or seminars.
During 1981 Drs. Kei Fujinaga, Kanji Hirai and Akinori Ishimoto visited the U.S. and Drs. Walter Troll and Nobuyoshi Shimizu visited Japan. Dr. Fujinaga visited the laboratory of Dr. Maurice Green, St. Louis, Mo., and succeeded in isolating adenovirus type 7 mutants, which are useful for both Drs. Fujinaga and Green. Dr. Hirai visited the laboratory of Dr. Meihan Nonoyama, Tampa, Florida, and determined the virulent strain-specific fragments of Marek's disease virus DNA, a finding which is useful for both Drs. Hirai and Nonoyama. Dr. Ishimoto visited the laboratory of Dr. James W. Gautch, Scripps Clinic and Research Foundation, La Jolla, California, and examined the origin of a B-tropic xenotropic murine leukemia virus. The results of this study are useful for both Drs. Ishimoto and Gautch. Dr. Walter Troll visited the laboratory of Dr. Takashi Sugimura, National Cancer Center, Tokyo, and discussed approaches to studying the role of free oxygen radicals in tumor promotion, cocarcinogenesis and comutagenesis. It is thought that free oxygen radicals may be the agents responsible for the damage caused by promoting agents. Dr. Nobuyoshi Shimizu visited Dr. Takashi Sugimura, National Cancer Center, Tokyo, and performed experiments on new tumor promoters including telocidin and the effect of telocidin on EGF binding to cell surface receptors. Future collaborative experiments were identified in this and other areas.