(1) Tomoyuki Shirai First Department of Pathology
Nagoya City University Medical School
SPONSOR AND HOST INSTITUTION :
Dr. Maartin C. Bosland
Nelson Institute of Environmental Medicine
New York University Medical Center
Dates of Visit: March 1-8, 1998
SUMMARY OF ACTIVITIES:
Animal Models of Prostate Cancer and Their Utilization for Chemoprevention
I visited three researchers working on prostate animal models in order to discuss their systems and their utilization for chemoprevention studies of prostate carcinogenesis. My first aim is to ascertain pathological characteristics of the induced tumors in the male accessory sex organs of rats and mice and to compare them with those of our model in which F344 rats are given a prostate carcinogen 3,2’-dimethyl-4-aminobiphenyl (DMAB), with or without testosterone propionate (TP).
With Dr. Maartin Bosland, Department of Environmental Medicine, New York University Medical Center, I discussed his rat prostate protocol which is composed of a N-methylnitrosourea injection and a subsequent treatment with testosterone. Carcinomas are produced in the dorso-lateral and anterior prostate and seminal vesicles. They are all invasive type. There is apparently a merit in using testosterone instead of TP in a Silastic tubes because it is long lasting and the application of 2 tubes can maintain the serum level of testosterone at 4-5 ng/ml for up to 12 weeks. His prostate tumors are androgen independent as are ours. Dr. Bosland and I focused on the histogenesis and pathogenesis of prostate carcinomas in the Bosland model. He showed me early carcinomas localized in the lateral lobe of the rat prostate and advanced ones. Medium-sized carcinomas were rarely found and I had the impression that the precise histogenesis of the tumors should be clarified in future experimentation. I was told that he is now doing DHEA-chemoprevention study with the MNU-testosterone model and so far exciting data have been obtained. Furthermore, combined treatment of testosterone and estrogen in Noble rats resulted in the development of lateral prostate carcinomas which are definitely invasive and clearly originated from the ducts. Tumors were located periurethral area and therefore, origin of tumors induced by combined effects of androgen and estrogen may differ from that of tumors induced by a carcinogen and testosterone. Tumor development was also found in our model when animals were treated with DMAB then TP and ethinylestradiol. Thus, sex-hormone related tumor development in male accessory sex organs of rats seems to be a common phenomenon in terms of origin and hormone dependency, regardless of chemical carcinogen administration. He is now carrying out an experiment to examine whether or not maternal exposure could sensitize the offspring’s prostate to internal and/or external androgens. This will be very important for understanding risk factors for prostate cancer in man.
Then I visited Dr. Jeffrey Green, Senior Investigator, at Laboratory of Cell Regulation and Carcinogenesis, NIH Bethesda. He has developed transgenic mice (heterozygous C3(1) SV40 Large T antigen transgenic mice based on FVB/N mice) which develop prostate and mammary carcinomas. Slid reviewing of tumors in his transgenic mice indicated that all prostate carcinomas developed in the ventral prostate and early lesions are atypical hyperplasias which very similar to those induced by DMAB in the same lobe. Furthermore, many intra-acinar proliferating foci composed of cells with cellular and nuclear atypia were evident, which also resemble rat ventral carcinomas in situ. The difference between the Tg mice and rats is the presence of invasive growth in the transgenic case. These findings suggest that rat ventral early carcinoma has a potential to progress to invasive carcinoma, a quite encouraging finding for myself and will stimulate work on my DMAB-induced ventral prostate lesions The possibility that ventral non-invasive carcinomas of rats may progress to invasive ones under a certain circumstance clearly warrants further attention. We have agreed to carry out collaborative experiments with his transgenic mice.
At the last, I visited Dr. Jerrold Word, Chief of Veterinary Tumor Pathology, NCI, NIH Frederic who has much experience in rat and mice prostate carcinogenesis. We discussed several experimental animal models as tools for chemoprevention research and showed me histological slides from CYP1A2 knockout mice which treated with a prostate carcinogen, PhIP. Interestingly, several proliferative lesions in the accessory sex organs were induced.
I am very grateful to the US-JAPAN Program for giving me the opportunity to visit the U.S.A. This experience will be very beneficial for me to our future research on prostate carcinogenesis.
(2) Motoharu Seiki
Institute of Medical Science
University of Tokyo
SPONSOR AND HOST INSTITUTION:
Dr. Henning Birkedal-Hansen
Dental Research Institute
National Institutes of Health
Dates of Visit: July 10-20, 1997
SUMMARY OF ACTIVITIES:
Objectives:
I am interested in elucidating the physiological roles of membrane-type matrix metalloproteinases in tissue remodeling associated with cancer invasion and metastasis, its molecular mechanisms and regulation. In 1994, I reported the first case of membrane-type enzyme (MT-MMP) in the MMP family and three other related enzymes were reported successively since then. Now many MMP researchers interested in MT-MMPS in relation to their experimental systems. The objectives of my trip supported by the grant was to meet scientists in the related research area, exchange most recent information and establish relationship for future collaboration.
Achievements:
Dr. Birkedal-Hansen and Dr. Stetler-Stevenson organized a workshop to overview recent progress on MMP research at NIH and I was invited to the meeting as a speaker. In the meeting, I present recent data that MT1-MMP is expressed on the cell surface. Activated form of MT1-MMP can induce autocatalytic activation of progelatinase A. However the reaction is thought to be inefficient so far as the enzyme is fixed on the cell surface. TIMP-2 can specifically inhibits the activated MT1-MMP. Once the activated enzyme is inhibited by TIMP-2, the TIMP-2 in the complex served as a progelatinase A binding site. This is thought to be a device to concentrate the substrate to the enzyme site. Thus I proposed the dual roles of MT1-MMP on the cell surface, one is as a receptor for progelatinase A and the other is as its activator. I also presented the same data in the Gordon Conference entitled “Matrix Metalloproteinase”.
In the both meetings I met many scientists in the field including collaborators in USA and Europe. I think this will facilitate future collaboration with them.
(3) Hiroyuki Tsuda
Chemotherapy Division
National Cancer Center Research Institute
SPONSOR AND HOST INSTITUTION:
Dr. Henry C. Pitot
Department of Hematology/Oncology
McArdle Laboratory for Cancer Research
University of Wisconsin
Dr. Jerrold M. Ward
Office of Laboratory Animal Sciences
NCI Vaterinary Pathology, NCI-FCRDC
Dr. Snorri Thorgeirsson
Laboratory of Experimental Carcinogenesis
National Cancer Institute
Dr. Glenn T. Merlino
Molecular Genetics Section
National Cancer Institute
Dates of Visit: January 21 - February 1, 1998
SUMMARY OF ACTIVITIES:
1) I visited Dr. Henry C. Pitot at McArdle Laboratory for Cancer Research, University of Wisconsin who has been studying SV40 T antigen transgene-induced hepatocellular damage and hepatocellular carcinoma development and more recently human TGF!!
!transgenic rats which exhibit a high incidence of hepatocellular carcinoma and pancreatic islet cell tumors. I presented our data on the human c-Ha-ras transgenic rats recently generated in our laboratory and discussed future collaboration regarding creation of double transgenic rats carrying human c-Ha-ras protooncogene and SV40 T antigen or human TGF!!!genes. 2) To obtain an update susceptibility of Helicobacter hepaticus (HP)-infected mice to chemopreventive agents, I visited Dr. Jerrold M. Ward at Office of Laboratory Animal Sciences, NCI Veterinary Pathology at NCI-Frederick. He has shown that HP-infected mice exhibit a chronic active hepatitis which is eventually associated with development of hepatocellular carcinomas. Furthermore, when athymic mice are infected with HP, they develop enteritis associated with a strong mucosal proliferative reaction. In our collaboration work, Dr. Ward is studying the anti HP potential of lactoferrin, known to possess antibacterial influence, and has found it has a static effect in vitro. The possible application of lactroferrin for in vivo eradication effects in both normal andathymic-HP in infected mice was discussed.
3) I visited Dr. Snorri Thorgeirsson and his colleagues at NCI-Bethesda, who are currently studying various functional parameters in TGF!!
!and c-myc double transgenic mice. Discussions regarding their susceptibility to liver carcinogenesis facilitated our future plan to generate transgenic rats highly susceptible to liver carcinogenesis. 4) To discuss the possibility of curing HP-infected high cancer risk animals by introduction of a lactoferrin transgene, I carried out discussions with Dr. Glenn T. Merlino, Molecular Genetics Section at NCI-Bethesda, who was responsible for the generation of TGF!!
!transgenic mice showing high susceptibility to liver and gastric carcinogens. The applicability of TGF!!!transgenic mice for short/medium term carcinogen/chemopreventive tests is presently under investigation in this laboratory as a collaborative project.