SUMMARY REPORTS OF EXCHANGE SCIENTISTS

(1) Michinari Hamaguchi
Institute for Diseases, Mechanisms and Control
Nagoya University School of Medicine

SPONSOR AND HOST INSTITUTION:
Host: Dr. Hidesaburo Hanafusa, The Rockefeller University
Date of Visits: August 10 - September 3, 1992

SUMMARY OF ACTIVITIES:
The mechanisms of invasion and metastasis of cancer cells is one of the most important and urgent subjects to be elucidated. We have been studying the tyrosine-phosphorylated proteins in Rous sarcoma virus (RSV)-transformed cells to clarify the signaling pathway of transformation by use of anti-phosphotyrosine antibody. To search for the substrates critical for the oncogenic changes of cellular function correlated with invasion and metastasis in RSV-transformed cells, we focused on cadherin, a family of glycoprotein that regulates homophilic adnesion of cells. We found that cadherin and its regulatory proteins, catenins were tyrosine phosphorylated and that cadherin-dependent cell adhesion was strongly suppressed in RSV-transformed cells.
Based on these findings, we studied the extent of tyrosine phosphorylation of cadherin-catenin complex in cells infected with various types of src mutants to examine the structural and functional requirements of v-src gene for phosphorylation. We found that cadherin-catenin complex was tyrosine phosphorylated only in cells infected with transforming src viruses, suggesting its strong correlation with cell transformation. While cadherin-catenin complex was not phosphorylated in cells infected with c-src and nonmyristylated mutants of v-src, which are active in kinase but defective in transformation, these proteins were strongly phosphorylated in cells inflected with a transforming c-src mutant NYCHB, Fujinami sarcoma virus and avian sarcoma virus Y73. These results strongly suggest that tyrosine phosphorylation of cadherin-catenin complex correlates with transformation.
In addition to these experiments, we studied gelatinase secreted from RSV-transformed cells. Studies with various mutants of src showed elevation of gelatinase in RSV-transformed cells strongly correlates with the transforming activity of src gene.
A part of these results will be reported in 9th Meeting on Oncogenes, and manuscripts are currently in preparation.



(2) Hiroyasu Esumi
National Cancer Center Research Institute

SPONSORS AND HOST INSTITUTIONS:
Host: Dr. Richard H. Adamson, National Cancer Institute
Dr. Kenneth Olden, National Institute for Environmental Health Sciences
Dr. Zeev A. Ronai, American Health Foundation
Date of Visits: January 16 - January 24, 1993

SUMMARY OF ACTIVITIES:
At the laboratory of Dr. Richard H. Adamson, National Cancer Institute, Bethesda, an arrangement was made for the collaborative study to establish a sensitive method to detect early genetic changes of colon tumor in monkey colon administered with heterocyclic amines by using enriched PCR. Future study is expected by exchanging information and samples between the two laboratories.
At the National Institute of Environmental Health Science, I discussed the possibility of collaborative research on the casual relationship of phytoestrogen and colon cancer, breast cancer and prostatic cancer with Drs. John McLachlan and Terry Damstra. Detailed structure of possible collaborative research was also discussed.
At the American Health Foundation, I gave a seminar entitled "Nitric Oxide and Cancer" and also discussed the protocol for our collaborative work on enriched PCR with Dr. Zeev A. Ronai and work on cancer prevention with Dr. John H. Weisburger. Collaborative research on the development of method for enriched PCR and it's application for the analysis of risk of human colon to develop cancer are ongoing.



(3) Kazuo Tajima
Division of Epidemiology
Aichi Cancer Center Research Institute

SPONSORS AND HOST INSTITUTIONS:
Host: Dr. Robert W. Miller, Clinical Epidemiology Branch
National Cancer Institute
Dr. Dimitrios Trichopoulos, Department of Epidemiology
Harvard School of Public Health
Dr. Ronald K. Ross, Department of Preventive Medicine
University of Southern California
Date of Visits: January 5 - January 17, 1993

SUMMARY OF ACTIVITIES:
In order to clarify both host-specific and environmental risk factors which affect cancer progression, we have been conducting a hospital-based epidemiological study on a large scale at the Aichi Cancer Hospital during the last 6 years. Through such a study epidemiologists can play an important role in the development of both a basic study on cancer risks and an applied study on cancer prevention in cooperation with physicians and basic scientists. In the process of an advancing hospital based epidemiological study, important information will be built-up for the comprehensive measurement of cancer prevention. In the US, the concept of clinical epidemiology has been well established and many institutions have developed hospital-based epidemiological studies on cancers. It is well known that some risk factors for cancers in Japan might be similar and/or different from those in the US. On this occasion, to exchange our mutual idea on cancer epidemiology, with special reference to the hospital-based epidemiological studies on risk factors for cancer, I visited the three leading institutions: National Cancer Institute (NCI), Harvard School of Public Health, (HSPH) and University of Southern California (USC), where I gained fruitful information through discussion with many professional staff in those institutions.
In NCI, Dr. Miller introduced the importance of comparative epidemiological studies on cancer risks among different ethnic groups. The pattern of cancer incidence in the US is quite different from that of Japan, which might be affected by ethnicity-specific and/or environmental factors. In the NCI Family Studies Section, Dr. Tucker and her associates are focusing on malignant melanoma and Hodgkin's disease to investigate cancer-prone families and other high-risk groups to delineate mechanism of genetic susceptibility and host-environmental interaction. Dr. Blot and his associates are advancing international cooperative studies to prevent gastric cancer in China. They are investigating the relation of helicobacter infection and nitrosamine exposure to the development of chronic gastritis and gastric cancer and also developing an intervention trial by using vitamin E, beta-carotene and epigallocatechin.
In HSPH, Dr. Trichopoulos, chairman of the Department of Epidemiology, encouraged me to promote our on-going hospital-based epidemiological study on cancers. Dr. Willet and his associates are conducting three cohort studies to clarify the relation of dietary habits and cancers. Generally, it is not very easy to keep the high compliance (90%) of participants during the whole cohort-study period. I was very much impressed that they encouraged cohort members by a local newspaper to keep in mind the importance of their cooperation. Dr. Paffenbarger and his associates are continuing their cohort studies to clarify the cancer-risk reduction by exercise. I think such a study will become more important than before in the field of cancer prevention in the future. Dr. Muller and her associates are promoting etiology-based studies on tumor virus-associated cancers. They are conducting the Japan-US cooperative study on HTLV-I associated diseases in Miyazaki. It will be very important to compare the results obtained from their studies with those of our studies on HTLV-I related diseases in Japan.
At the USC, Dr. Mack and his associates have been conducting an attractive twin study during the last 7 years to clarify genetic risk factors and gene-environmental interactions. Generally homozygous twins have common genetic factors; they collected 16,000 twin pairs (50% of homozygous), where at least one twin has or had cancer. Recently they started analysis to search risk factors for breast cancer and Hodgkn's disease. We expect their interesting reports will come out soon. Dr. Ross and his associates recently started the molecular epidemiology focusing on bladder cancer and p53 cooperating with biochemists. We are also interested in the host-specific factors affecting cancer progression, and are now planning to promote such a study in our institute.