SUMMARY REPORTS OF EXCHANGE SCIENTISTS
(1) Masae Tatematsu
Laboratory of Ultrastructure Research
Aichi Cancer Center Research Institute
Sponsors and Host Institutions:
Dr. Theresa P. Pretlow Institute of Pathology, Case Western Reserve University
Dr. Lawrence J. Werther Division of Gastroenterology, Department of Medicine The Mount Sinai Medical Center
Dr. Michael Samloff Department of Veterans Affairs Medical Center
Dates of Visit: October 24 - November 6, 1991
Summary of Activities:
1. Dr. Pretlow has reported aberrant colonic crypts with decreased hexosaminidase activity as preneoplastic changes in carcinogen treated rats. The idea underlying these aberrant crypts is basically the same as that of pepsinogen altered pyloric glands (PAPG) in the rat stomach. To clarify the scientific bases of these lesions as preneoplastic changes and their applicability as endpoints for early detection of carcinogenic chemicals for the digestive tract in vivo, three dimensional reconstruction analysis of colonic aberrant crypts prepared by Dr. Pretlow and PAPG will be performed using an image analyzer in Aichi Cancer Center as a U.S.-Japan collaborative investigation.
2. Dr. Lawrence J. Werther is a main host scientist of this U.S.-Japan Cooperative Cancer Research Program. I gave a lecture entitied “cellular differentiation of gastric cancer cells” for the members of the Gastroenterology and Pathology Divisions of the Mount Sinai Medical Center covering the following: recent developments in the histochemisty of mucins [such as paradoxical concanavalin A staining, galactose oxidase-Schiff (GOS) and sialidase-CS] and the immunohistochemistry of pepsinogen (Pg) have made it possible to determine the phenotypic expression of gastric and intestinal epithelium and gastric cancer cells. Thus, gastric cancer cells can be clearly classified into a gastric type, including pyloric gland cell and surface mucous cell subtypes, and an intestinal type, including goblet cell and intestinal absorptive cell subtypes. Sialilated mucin antigen (sialogyl-Tn) expression by human colorectal cancers is associated with a worse survival and a greater chance of tumor recurrence. As a U.S.-Japan collaborative investigation, the relation between sialosyl-Tn expression and cellular differentiation of gastric cancer cells was studied and sialogyl-Tn found to be strongly expressed in goblet cell type gastric cancer cells. To determine whether cellular differentiation of gastric cancer cells with special attention to sialogyl-Tn expression may have prognostic value in gastric cancers, well-defined populations of U.S. and Japanese patients who have undergone surgical resection for gastric cancer and for whom there is follow-up data concerning disease recurrence and mortality will be studied as a future collaborative work.
The purpose of the visit to the laboratory of Dr. Samloff was to discuss the pepsinogen (Pg) expression in cancer cells of the digestive tract. Since Pg expression is found not only in gastric cancers but also in pancreatic cancers and gall bladder cancers at high incidence, its relevance to cancer in the digestive tract is complicated. For better understanding of cellular differentiation, broad-based collaborative approaches will be tried with multi markers to establish characteristics of cellular differentiation in the various epithelial cells of the digestive tract.
Additional Comments:
The exchange program was of great help in establishing international collaborative work, especially in forging close relationships with other researchers.
(2) Hiroyasu Esumi
National Cancer Center Research Institute, Tokyo
Sponsors and Host Institutions:
Dr. Richard Adamson Division of Etiology National Cancer institute
Dr. Ken Olden National Institute of Environmental Health Sciences
Dr. Tim Bowden University of Arizona
Dr. Sarawachi Sukumar Salk Institute
Dr. Lawrence Loeb University of Washington
Dates of Visit: March 12 - 22, 1992
Summary of Activities:
Objectives
Carcinogenicity of a series of food mutagens, heterocyclic amines, has been proven both in mice and rats. All the heterocyclic amines so far tested are all carcinogenic to mice and rats. One of these heterocyclic amines, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), was proven to be carcinogenic to a non-human primate, Macaca fascicularis. Interestingly, 5 out of 7 heterocyclic amines so far tested for their carcinogenicity in rats induced colon cancer, but none of 10 heterocyclic amines proven to be carcinogenic in mice induce colon carcinomas. Therefore, from the standpoint of human carcinogenesis, it is quite interesting to determine whether heterocyclic amines are carcinogenic to the monkey. We are also examining the molecular mechanism(s) of carcinogenesis by heterocyclic amines in experimental animals. Recently, several very sensitive methods for detecting mutations of oncogenes have been developed. It is important to know how early and how frequently ras gene mutation occur during the course of carcinogenesis by heterocyclic amines.
Achievements
(1) The colons of monkey that received 20 mg/day of IQ were examined for the presence of aberrant crypts of the colon after brief staining with 0.2% methylene blue. Five colons were carefully examined, but only lymphoproliferative lesions, not aberrant crypt were observed. When IQ was administered to rats at 400 ppm in the diet for 2 weeks, considerable number of aberrant crypts were induced. At least as far as aberrant crypts are concerned, IQ seems not to be carcinogenic to the monkey.
(2) I visited NIEHS and discussed with several persons the subject of risk evaluation of environmental carcinogens, including food mutagens.
(3) Professor Tim Bowden's laboratory developed a PCR system for detecting ras gene mutation with extremely high sensitivity. I visited his laboratory and discussed future collaboration for detecting specific ras mutation induced by heterocyclic amines.
(4) Dr. S. Sukumar’s laboratory recentiy developed a very sensitive PCR method. The sensitivity for detecting specific mutations is about I out of 107. The method is based on the specific amplification of mutated ras gene by digesting with type gene. Therefore, the major difficulty with applying this method to the study of mechanism carcinogenicity is its inability to quantify the mutation frequency. I discussed this point with Dr. Sukumar and also a possible way of quantification.
(5) Dr. Loeb’s laboratory established a method for detecting in vitro mutations using a x phage system. The method basically depends on the in vitro modification of x DNA and its in vitro replication. We discussed possible collaborative work on the induction and sequence specificity of mutation by heterocyclic amines using this system. In summary, the visit to several laboratories this time was quite informative.
(3) Tadatsugu Taniguchi
Institute for Molecular and Cellular Biology Osaka University
Sponsors and Host Institutions:
Prof. Roger M. Perlmutter
University of Washington, Department of Immunology
Dates of visit: January 16 - 30, 1992
Summary of Activities:
The main objective of my visit to USA was to visit with Dr. Roger Perlmutter of Washington University, and to exchange of information with other US scientists working in the field of cancer research, visiting with them at conference sites. My group has collaborated with Dr. Perlmutter on the functional and physical interaction of the interleukin-2 (IL-2) receptor chain (IL-2R) and a lymphocyte specific protein tyrosine kinase, p56lck which belongs to the src family of kinases. This time Dr. Perlmutter and I discussed extensively our collaboration, and we reached the following agreements. (1) We have decided to collaborate further on the potential coupling of IL-2R with other s7lc family kinases, including p58fyn in a lymphocyic line BAF-B03 in which II-2R transmits growth signal but p56lck expression is not detectable. This study will be important to extend further the participation of other src family kinases in IL-2 signalling. (2) We further examined the role of p56lck further in lymphocyte proliferation, by overexpressing a kinase-inactive mutant of p56lck in order to suppress the endogenous p56lck (or other src-kinase) activity.
I also discussed cell growth regulation with Dr. E. Fisher, Dr. R. Eisenman in Seattle. In San Francisco, I visited Dr. D. Rittman and colleagues at UCSF to discussed p56lck in T lymphocyie activation. These visits were particularly useful and important to develop further our research projects on the growth control mechanisms of lymphocytes.
I also attended two Keystone Symposia, and met with Drs. R. Weinberg, C. Sherr, T. Hunter, L. Cantley and others. These Symposia thus provided another opportunity to exchange information and ideas about the role of tyrosine kinases, PI-3 kinases, cyclins, Rb proteins in cell cycle and cell transformation. In fact, I have also set up collaborations with Drs. Sherr and Cantley on functional similarity of the IL-2R and CSF-1R, and on the PI3-kinase involvement in IL-2 signalling, respectively.
In summary, my visit to US was extremely useful and fruitful, both scientifically and personally (i.e. making stronger friendships with the above people for future cooperation).