14. Carcinogenesis Division

The carcinogenesis studies being undertaken in this division use animal model systems. These have a number of advantages over studying humans directly. Another major area of study is the role of serine/threonine protein phosphatase in carcinogenesis.

Heterocyclic Amine (HCA) Carcinogenesis

The food mutagen, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) forms DNA adducts in various organs. Although this adduct formation is the first step in the development of mutations, the mutation rate of the lacI gene was found not to correlate directly with DNA adduct levels, but rather, with the product of the DNA adduct level and the cell proliferation rate.⁽¹⁴²⁾ Another HCA, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induces colon tumors in male rats, but not in female rats. Our studies showed that there were no differences in the adduct levels of males and females after the administration of PhIP in the diet, but the cell proliferation rate and formation of aberrant crypt foci (ACF) were elevated in males.⁽¹⁴³⁾ Furthermore, a proximate form of PhIP, N-hydroxy-PhIP enhanced intestinal polyp development in Apc^{del 716} knockout male mice but not in female mice.⁽¹⁴⁴⁾ ACF which is considered to be a useful preneoplastic biomarker of colon carcinogenesis, was demonstrated to be induced within as little as 6 weeks with 2 week-feeding of a PhIP diet.⁽¹⁴⁵⁾ In rat colon tumors induced by PhIP, a characteristic mutation, a guanine deletion from a GGGA sequence was detected in all Apc mutation positive tumors.^(146,147) Microsatellite mutations were also detected in PhIP-induced colon tumors, but not in 2-amino-3-methylimidazo[4,5-f]quinoline(IQ)-induced colon tumors.^(146,147) Microsatellite mutations were detected at a high rate in PhIP induced mammary tumors but at a low rate in 7,12-dimethylbenz[a]anthracene induced mammary tumors.⁽¹⁴⁸⁾ LOH, specifically at rat chromosome 10, which corresponds to the human chromosome 17q, was observed.⁽¹⁴⁸⁾ In another study, the role of Ha-ras mutations in 2-amino-6-methyldipyrido[1,2-a: 3',2'-d]imidazole (Glu-P-1)-induced hemangioendothelial tumors was investigated using the human-Ha-ras transgenic mouse.⁽¹⁴⁹⁾ It was thought that high levels of Ha-ras expression might play a role in Glu-P-1 induced hemangioendothelial tumorigenesis. However, food mutagens themselves may not be sufficient to induce tumors in humans. The role they play in human carcinogenesis was discussed, based on evidence obtained from HCA adduct levels in human tissues and the mutational spectrum.^(147,150)

Rat Genome Study

Animal model systems may provide the most appropriate method of analyzing susceptibility to cancer development. For this purpose, we started a rat genome study. We established a linkage map with a panel composed of 105 ACI x BUF F2 intercross rats, using polymorphic markers isolated by representational difference analysis (RDA), and genetically directed RDA (GD-RDA).^(151,152) Arbitrarily primed polymerase chain reactions were also demonstrated to be useful in the identification of genetic markers.⁽¹⁵³⁾ Using the linkage map described above, p53 was mapped to chromosome 10.⁽¹⁵⁴⁾

Serine/threonine Protein Phosphatases (PPs) in Carcinogenesis

Okadaic acid (OA), a strong inhibitor of PP2A, PP4 and PP5, was found to induce genomic instability, although there is no evidence that OA itself interacts with DNA. Diphtheria toxin resistant mutations, sister chromatid exchanges, exclusion of amplified transgenes and minisatellite recombinations were induced by OA in cultured cells.⁽¹⁵⁵⁾ The mycotoxin, fumonisin B1 which has recently been found to be a tumor promoter, was demonstrated to inhibit PP5.⁽¹⁵⁶⁾ This result suggests that the food contaminant, fumonisin B1 has a genotoxic effect although it exhibits no interactive activity with DNA. A PP1gamma1 isotype was found to be expressed in the salivary gland.⁽¹⁵⁷⁾ OA was found to suppress the expression of the neurofilament-L gene in the P19 embryonal carcinoma cell.⁽¹⁵⁸⁾

LEC, the Wilson Disease Model Rat

The LEC rat accumulates copper in the liver, resulting in the development of acute hepatitis and later, hepatic cancer. Administration of trientine completely suppressed hepatitis development and cholangiofibrosis and reduced the incidence of hepatic tumors.⁽¹⁵⁹⁾ A one-tenth dose of the food-carcinogen, 2-amino-3,8-dimethyl-imidazo[4,5-f]quinoxaline (MeIQx) was found to induce hepatic cancer in LEC rats, thus demonstrating the cancer promoting effects of inflammation.⁽¹⁶⁰⁾ In the acute phase of hepatitis, epsilon-dA and epsilon-dC adduct levels were elevated to 5-25 times those of the control rats.⁽¹⁶¹⁾

Human Prostate Cancer

Microsatellite mutations but not Apc mutations were detected in Japanese prostate cancer patients.^(162,163)

List of papers from this division

Table of Contents