In vivo chemical carcinogenesis is the main theme, with emphasis on elucidation of mechanisms underlying tumor development and metastasis and research into modifiers (inhibitors and promoters) of carcinogenesis.
1. Experimental approaches to mechanisms of prostate carcinogenesis and suppression of prostate cancer development:
(a) We have established two rat models of prostate cancer development using two distinct carcinogens, 3, 2-dimethyl-4-aminobiphenyl (DMAB) and 2-amino-1-methyl-6 phenylimidazo[4,5-b]pyridine (PhIP), the latter being well-known as a food-derived carcinogenic heterocyclic amine. With these models, two types of prostate cancer, non-invasive and invasive adenocarcinomas, can be differentially induced and we have been able to extensively study interactions of testosterone and estrogen with their genesis. Furthermore, three cell lines have been established from invasive adenocarcinomas.
(b) We have also successfully generated a probasin-SV40T gene transgenic rat which features specific expression of SV40 T antigen in prostate tissue by using the probasin gene as a promoter. 100% of the transgenic rats develop prostate carcinomas at as early as 10 weeks of age.
2. Prostate cancers in man:
Using human normal prostate and prostate cancer tissues taken at autopsy and total prostatectomy, the significance of latent carcinomas, relationships between prostatic intraepithelial neoplasia (PIN) and cancer and mechanisms of androgen dependency and independence are being targeted by histopathological and molecular approaches.
3. Analysis of mammary carcinogenesis and suppression of tumor growth:
Using human H-ras transgenic rats and cell lines, mechanisms of mammary carcinogenesis are under analyzed. It is also a priority to establish experimental model(s) to detect mammary carcinogen(s) and chemopreventor(s).
4. Relationship between intercellular communication and cytotoxicity and/or carcinogenesis:
Lowering or loss of intercellular communication have been reported to be features of cancer cells. We have established a transgenic rat with impaired intercellular communication of hepatocytes in their livers and this model is now being used to explore the roles of intercellular communication in susceptibility or resistance to cytotoxicity and carcinogenic stimuli of chemicals in the liver.
Toxicogenomic approaches are attracting a great deal of attention for elucidation of mechanisms of toxicity, including malignant transformation. In our Department, toxicogenomics has been applied for detection of carcinogens using both in vivo and in vitro systems. From our most recent data, there is strong evidence that toxicogenomic approaches are very useful methods for prediction of carcinogenic hazard.
6. Electromagnetic field (EMF) influence on carcinogenesis:
We have already performed two long-term (2-year period) experiments to elucidate effects of 1.5 and 1.95 GHz EMF chronic exposure to the heads of rats on brain tumor development, with no evidence of any promotion of lesion development. Effects of EMF on the fetus and newborn rats are now under study in order to clarify possible contribution to developmental and behavior abnormalities.
7. Chemoprevention of cancer development:
Using the medium-term liver and medium-term multi organ bioassay models, a survey of chemicals, particularly food-derived substances that have potential for cancer prevention are being carried out.
8. Biohazard identification and evaluation:
The examination of agents for hazard in terms of carcinogenic potentials also a major theme in our group.
Recent demand to clarification of feasibility of toxicogenomics facilitates our group to perform ﾒToxicogenomics projectﾓ. Toxicogenomics will be a promising new technology to identify toxic substances with mechanistic mode of action. We have just started a 5-year project for carcinogenic substances.