No abstract

Scirrhous gastric carcinoma is characterized by cancer cells that infiltrate rapidly in the stroma with extensive growth of fibroblasts. In the present study, we examined the effect of gastric fibroblasts on the invasiveness of a Scirrhous gastric cancer cell line, OCUM‐2D, using an invasion assay. Gastric fibroblast‐derived conditioned medium (CM) significantly stimulated the invasiveness of OCUM‐2D cells, as did transforming growth factor‐β (TGF‐β) and hepatocyte growth factor (HGF). The stimulating activity of gastric fibroblast‐derived CM was inhibited significantly by anti‐TGF‐β neutralizing antibody or anti‐HGF neutralizing antibody. TGF‐β and HGF were detected in the gastric fibroblast‐derived CM, and TGF‐β receptor and C‐met (HGF receptor) were expressed on OCUM‐2D cells. Thus, TGF‐β and HGF produced by gastric fibroblasts appear to affect the invasiveness of scirrhous gastric cancer cells. TGF‐β was also detected in the conditioned medium derived from OCUM‐2D cells, though HGF was not. TGF‐β appears to affect the invasiveness of OCUM‐2D cells in both paracrine and autocrine fashions.

S‐Methylcysteine (SMC) occurs in a variety of plants, including Allium sativum, Phaseolus vulgaris, and Cruciferae. In this study, we synthesized five organosulfur compounds (OSCs), SMC and four analogs, and examined their modifying effects on diethylnitrosamine‐induced neoplasia of the liver in male F344 rats, using the medium‐term bioassay system of Ito (Ito test) based on the two‐step model of hepatocarcinogenesis. In addition, we investigated the modifying effects of SMC and cysteine on the initiation stage of rat hepatocarcinogenesis. Carcinogenic potential was scored by comparing the numbers and areas of induced glutathione 5‐transferase placental form (GST‐P)‐positive hepatocellular foci. All OSCs examined had a tendency to decrease the number of GST‐P‐positive foci when given in the promotion stage of the Ito test, and in particular SMC and cysteine exerted significant inhibitory effects. When given during the initiation stage, these two OSCs also significantly inhibited focus formation. Regarding the mechanism underlying the inhibitory effects of SMC and cysteine, measurement of ornithine decarboxylase in SMC‐ and cysteine‐treated liver tissues after partial hepatectomy (PH) revealed a significantly reduced activity, and the proportion of hepatocytes positive for proliferating cell nuclear antigen was significantly decreased by SMC or cysteine administration. Moreover, examination of the expression of the early response proto‐oncogenes, c‐fos, c‐jun, and c‐myc, after PH demonstrated down‐regulated induction of c‐jun mRNA transcripts by SMC, sustained for an eight‐hour period. Our results support the view that SMC and cysteine are chemopreven‐tive agents for rat hepatocarcinogenesis and that their intake may he of importance for cancer prevention.

Arsenicals are epidemiologicaUy significant chemicals in relation to induction of liver cancer in man. In the present study, we investigated the dose‐dependent promotion potential of dimethylarsinic acid (DMAA), a major metabolite of inorganic arsenicals in mammals, in a rat liver carcinogenesis model. In experiment 1, glutathione‐S‐transferase placental form (GST‐P)‐positive foci, putative preneoplas‐tic lesions, were employed as endpoints of a liver medium‐term bioassay for carcinogens (Ito test). Starting 2 weeks after initiation with diethylnitrosamine, male F344 rats were treated with 0, 25, 50 or 100 ppm of DMAA in the drinking water for 6 weeks. All animals underwent two‐thirds partial hepatectomy at week 3 after initiation. Examination of liver sections after termination at 8 weeks revealed dose‐dependent increases in the numbers and areas of GST‐P‐positive foci in DMAA‐treated rats as compared with controls. In experiment 2, ornithine decarboxylase activity, which is a biomarker of cell proliferation, was found to be significantly increased in the livers of rats treated with DMAA. In experiment 3, formation of 8‐hydroxydeoxyguanosine, which is a marker of oxygen radical‐mediated DNA damage, was significantly increased after administration of DMAA. These results indicate that DMAA has the potential to promote rat liver carcinogenesis, possibly via a mechanism involving stimulation of cell proliferation and DNA damage caused by oxygen radicals

Chemopreventive effects of bovine lactoferrin (bLF), which is found at high concentrations in colostrum, on rat bladder carcinogenesis were investigated using a rat bladder medium-term bioassay. In experiment 1, a total of 80 F344 male rats, 6 weeks old, were divided into 5 groups. Groups 1 and 2 were treated with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in the drinking water for 8 weeks and after a 1-week interval, received dietary supplementation with 2% and 0.2% bLF, respectively. Group 3 received 0.05% BBN for 8 weeks and then no treatment. Group 4 was administered 2% bLF alone from week 9, without prior carcinogen exposure. Group 5 was maintained without any treatment throughout the experiment. All rats were killed at the end of week 36. Group 1 demonstrated a significantly decreased multiplicity of the bladder tumors (carcinomas and papillomas) as compared with group 3. Maximum cut surface areas of bladder tumors were also significantly decreased in groups 1 and 2 compared with group 3. No bladder tumors were observed in groups 4 or 5. In experiment 2, a total of 60 rats were divided into two groups (30 rats each); both were treated with 0.05% BBN for 4 weeks and after a 1-week interval, one received 2% bLF (group 1) and the other, basal diet (group 2) for 4 weeks. Group 1 demonstrated a tendency for decrease of the 5-bromo-2′ ′ ′ ′-deoxyuridine (BrdU) labeling index. bLF was detected in the urine of rats fed bLF by ELISA as well as western blot analysis. The findings indicate that 2% bLF can inhibit BBN-induced rat bladder carcinogenesis, and that this may be due to bLF in the urine.