Role of polyamines in arginine-dependent colon carcinogenesis in Apc(Min) (/+) mice

We evaluated the role of polyamines in arginine-dependent intestinal tumorigenesis in Apc(Min) (/+) mice. Arginine is a substrate for ornithine synthesis and thus can influence polyamine production. Supplementing the diet with arginine increased intestinal and colonic polyamine levels and colonic carcinogenesis. Inhibiting polyamine synthesis with D,L-alpha-diflouromethylornithine (DFMO) decreased small intestinal and colonic polyamine pools. In mice provided basal diet, but not when supplemented with arginine, DFMO decreased small intestinal tumor number and burden, and increased intestinal apoptosis. In mice provided supplemental arginine in the diet, DFMO induced late apoptosis and decreased tumorigenesis in the colon. DFMO slightly reduced tumor incidence, number, and size while significantly decreasing tumor burden and grade. These changes in colon tumorigenesis did not occur in mice not provided supplemental arginine. Our study indicates that polyamines play unique roles in intestinal and colonic carcinogenesis in Apc(Min) (/+) mice. Inhibition of polyamine synthesis suppresses the arginine-dependent risk of colon tumorigenesis, resulting in apoptosis induction and decreased tumorigenesis, in this murine model.     

The plant lignans matairesinol and secoisolariciresinol administered to Min mice do not protect against intestinal tumor formation

The lignans matairesinol (MAT) and secoisolariciresinol (SECO) were fed to Min mice at 0.02% (w/w) in diet to study their effects on intestinal tumor development. The mean number (67 vs. 51, P=0.052) and size (1.4 vs. 1.2 mm, P=0.011) of tumors in the MAT group was elevated when compared with the control group. Tumor formation of the SECO group did not differ from the control group. Intake of MAT increased the level of both MAT and enterolactone in the plasma while SECO feeding increased SECO, enterodiol, and enterolactone (P=0.001). These results showed that MAT or SECO do not prevent intestinal carcinogenesis in Min mice and that MAT may have adverse effects.     

Tumor-initiating potency of a novel heterocyclic amine, aminophenylnorharman in mouse colonic carcinogenesis model

A novel heterocyclic amine, 9-(4'-aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman, APNH), which is formed from nonmutagenic 9H-pyrido[3,4-b]indole (norharman) and aniline, is mutagenic to bacteria and mammalian cells and potently carcinogenic in rats. APNH is detected in human urine samples, suggesting that humans are continuously exposed to APNH. In the present study, (32)P-postlabelin analysis revealed that the levels of APNH-DNA adduct 24 hr after the treatment with APNH (1, 5 and 20 mg/kg body weight) in male ICR mice were increased in a dose-dependent manner in the colon and liver. Based on these findings, we determined the tumor-initiating potency of APNH in an inflammation-related and two-stage mouse colon carcinogenesis model. Male Crj: CD-1 (ICR) mice were given a single intragastric administration (1, 2, 5 or 10 mg/kg body weight) of APNH and subsequent 1-week oral exposure to dextran sodium sulfate (DSS, 2% in drinking water). Treatment with APNH and DSS resulted in numerous colon tumor development: the incidence and multiplicity of the tumors were the highest in the mice received 10 mg/kg body weight of APNH and followed by DSS. Development of colon tumors was dose-dependent of APNH. Seven of 9 (77.8%) colonic adenocarcinomas developed in mice treated with APNH (10 mg/kg body weight) and DSS had beta-catenin gene mutations at codons 32 and 37, being predominantly transversion. These findings indicate that APNH has an initiating activity in inflamed mouse colon and the APNH-DNA adduct formation correlates with its tumorigenic potential.     

Promotion of intestinal tumor formation by inulin is associated with an accumulation of cytosolic beta-catenin in Min mice

Inulin, polydisperse beta (2-1) fructan, has been suggested to protect against colon carcinogenesis and is currently used in a number of food applications. However, the data regarding the role of inulin in intestinal carcinogenesis remains controversial since the results of our previous study suggested that inulin promotes intestinal tumor formation in Min mice, an animal model for intestinal cancer with a mutation in the Apc tumor suppressor gene (Carcinogenesis 2000;21:1167-73). In our present study, we further examined the effects of inulin on intestinal tumor formation in Min mice by carefully analyzing beta-catenin expression and cellular localization at 3 different time points during the tumorigenic process. Min mice were fed a high-fat inulin-enriched (10% w/w) diet or the high-fat diet without any added fiber from the age of 6 weeks to the ages of 9, 12 or 15 weeks. The results showed that inulin significantly increased the number (by 20%) and especially the size (by 44%) of adenomas in the small intestine. At week 15, the promotion of tumor development was accompanied by an accumulation of cytosolic beta-catenin in the adenoma tissue. In the normal appearing mucosa, levels of membrane beta-catenin and PCNA were reduced in the inulin-fed mice, possibly indicating impaired enterocyte migration. These data do not support the earlier suggestions on the cancer preventive effects of inulin and emphasize the need for further research and evaluation where health claims for inulin are concerned.     

The possible mechanism of enhanced carcinogenesis induced by genotoxic carcinogens in rasH2 mice

Microarray and RT-PCR analyses were performed for the transgene and Ras-related genes in forestomach squamous cell carcinomas (SCCs) induced by 7,12-dimethylbenz[a]anthracene (DMBA) in rasH2 mice; these results were compared with our previous molecular data of N-ethyl-N-nitrosourea-induced forestomach SCCs and urethane-induced lung adenomas in rasH2 mice. Overexpression of the transgene was detected in the DMBA-induced SCCs, suggesting that the transgene plays an important role in enhanced carcinogenesis in rasH2 mice. In addition, the mouse endogenous ras genes were up-regulated in the DMBA-induced SCCs, and are probably involved in the tumorigenesis of forestomach SCCs. Genes such as osteopontin, Cks1b, Tpm1, Reck, gelsolin, and amphiregulin that were commonly altered in these three different carcinogen-induced tumors may contribute to the development of tumors in rasH2 mice.     

双气囊小肠镜诊断小肠恶性肿瘤的作用

目的:探讨双气囊小肠镜在小肠恶性肿瘤诊断中的作用。方法:76例怀疑小肠疾病者,行操作方式包括经口和经肛检查,对未检出病灶者建议择期改换方式再行检查,分析双气囊小肠镜检查对小肠疾病,尤其是小肠恶性肿瘤的检出率、诊断准确性、患者依从性和不良反应发生率等。结果:76例中,2例操作失败,小肠病变总检出率为45.9%(34/74),小肠恶性肿瘤检出率为13.5%(10/74),占所有检出病变的29.4%(10/34)。11例双气囊小肠镜检查判断为恶性肿瘤者中,10例经手术证实,1例明确为良性病变,诊断准确率为90.9%(10/11)。结论:双气囊小肠镜检查是一项针对小肠疾病安全、有效的检查方法,可作为疑似小肠恶性肿瘤者的首选检查方法或作为胶囊内镜检查后的补充检测手段。     

Modulation of intestinal environment by prebiotic germinated barley foodstuff prevents chemo-induced colonic carcinogenesis in rats

Butyrate was shown to have a preventive effect on colon cancer in vivo. Germinated barley foodstuff (GBF) was in a prebiotic stage and had the potency to attenuate mucosal inflammation and to increase fecal butyrate production in colitis. This study aimed to determine whether the GBF treatment in a colon cancer model had the potency to suppress colon cancer. After a pre-feeding of either a control or a GBF diet for two weeks, male F344 rats received subcutaneous injections of azoxymethane twice, at a dose level of 15 mg/kg body weight. The injections were administered once a week for 2 weeks (n=10/group). Four weeks after that, the number of aberrant crypt foci (ACF) and heat shock protein (HSP) 25-positive cells in colonic mucosa were observed histologically. The mRNA level of slc5a8 was evaluated by in situ hybridization. Colonic mucosal beta-catenin was determined by Western blotting. Cecal short chain fatty acids, beta-glucosidase and beta-glucuronidase were also determined. The results showed that GBF treatment significantly decreased the number of ACF and beta-catenin formations in the colonic mucosa. GBF significantly increased the production of slc5a8, which is a tumor suppressor gene, as well as the cecal butyrate content and beta-glucosidase activity. beta-glucuronidase activity remained at the same level in GBF and control subjects. The number of HSP25-positive cells in GBF was higher than that in the control group, although it did not reach significant difference. In conclusion, GBF showed anti-tumorigenicity in the AOM rat model. Changes in the colonic environment featured through the increase of butyrate production were found. Although a more detailed study is required, this study showed the promising anti-neoplastic effects of prebiotic treatment.     

The dual role of the novel Wnt receptor tyrosine kinase,ROR2, in human carcinogenesis

The Wnt signaling pathway is involved in the development and progression of many human cancers, yet attempts to target the pathway therapeutically have been disappointing to date. The recent discovery that the ROR2 receptor tyrosine kinase (RTK) is a novel Wnt receptor provides the potential to target the non‐canonical Wnt pathway for cancer treatments. As a member of the RTK superfamily of surface receptors ROR2 appears to possess dual roles as a tumor suppressor or activator depending on tumor type. This review will explore the dual role of ROR2 in tumorigenesis and provide an up to date analysis of current literature in this rapidly expanding field.     

The role of nitric oxide synthases and nitrotyrosine in retinoblastoma

BACKGROUND: To investigate the potential involvement of the nitric oxide (NO) pathway in retinoblastoma, the authors correlated immunoreactivity for endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and nitrotyrosine (NT) with the degree of tumor invasiveness in retinoblastoma. METHODS: eNOS, iNOS, and NT reactivity was evaluated by immunohistochemistry in 34 archival retinoblastoma specimens and in a human Y79 retinoblastoma cell line. The tumors were divided into 2 groups: Group A tumors (n = 17 tumors) with no invasion and Group B tumors (n = 17 tumors) with invasion of the choroid, optic nerve, and/or orbit. The expression levels of eNOS, iNOS, and NT were correlated with invasiveness of the tumors. RESULTS: In Group A tumors (n = 17 tumors) without invasion, eNOS was positive in 17 of 17 tumors (100%), iNOS was positive in 14 of 17 tumors (82%), and NT was positive in 17 of 17 tumors (100%). In Group B tumors (n = 17 tumors) with invasion, eNOS was positive in 17 of 17 tumors (100%), iNOS was positive in 16 of 17 tumors (94%), and NT was positive in 17 of 17 tumors (100%). The invasive cohort showed significantly higher expression of iNOS (P < 0.0001) and NT (P < 0.020) compared with the noninvasive cohort. Y79 cells also expressed eNOS, iNOS, and NT; and nonneoplastic retina was positive for eNOS, iNOS, and NT. CONCLUSIONS: Taken together, the results suggested that retinoblastomas can produce NO. The roles of NO in the biology of retinoblastoma and in the prognosis for patients with retinoblastoma remain to be established.     

The role of aspirin in carcinogenesis

British Journal of Cancer (2002) 87, 1337–1338. doi:10.1038/sj.bjc.6600670 www.bjcancer.com© 2002 Cancer Research UKSirWe read with interest the excellent paper by Akhmedkhanov et al (2002) regarding aspirin use and the incidence of lung cancer. We would like to offer another possible anti-cancer property of aspirin, namely, the inhibition of phenolsulphotransferase (PST) activity.PSTs are found throughout the body, but the bowel, liver and platelets are known to contain particularly high activities of this enzyme. PSTs are cytosolic and exist in two forms: (i) P-PST, which selectively sulphates micromolar concentrations of phenols; and (ii) M-PST, which is similarly selective for aromatic amines.The main function of this sulphation is to scavenge low concentrations of endogenous and exogenous toxins from the body, but the lability of the phenolic sulphate-ester bond means it is liable to cause the formation of electrophilic free radicals. These react chemically with DNA which may cause mutations leading to neoplasia (Coughtrie, 1996).Food cooking can result in a wide variety of mutagenic compounds, including polyaromatic hydrocarbons and heterocyclic amines, especially if the food becomes charred when grilled or barbequed. Certainly, several polyaromatic hydrocarbons have been shown to be activated by hydroxylation to phenols followed by sulphation via P-PST to the final mutagenic form (Grover, 1986). P-PST has also been found to be responsible for the activation of heterocyclic amines by N-sulphation, for example, the bladder carcinogen 2-napthylamine (Hernandez et al, 1991) and a wide variety of carcinogenic N-hydroxy arylamines (Chou et al, 1995).Thus, inhibition of P-PST would block one route of activation for both main groups of carcinogen found in food. Indeed, Rao and Duffel (1991) have shown that salicylic acid, the initial breakdown product of aspirin, is a potent inhibitor of aryl sulphotransferase IV (AST IV), at least in the rat – and AST IV is the rat equivalent of human PST enzymes. Other studies (Boberg et al, 1983; Tsutumi et al, 1995) have also shown that sulphotransferase inhibitors dramatically reduces the potency of sulphation activated carcinogens in both mice and hamsters.We would therefore suggest that the action of salicylic acid on P-PST, by preventing the excessive activation of carcinogens, may represent another possible pathway by which aspirin may reduce cancer risk.     

Sister chromatid exchange analysis in the colonic and small intestinal epithelium of the mouse

This report describes a method which produces high quality chromosome preparations from the colon and the small intestine of the mouse. These preparations are suitable for sister chromatid exchange (SCE) analysis because the pretreatment used to dissociate the cells does not prevent sister chromatid differentiation and because very little tissue handling is required at the time of killing, thus allowing sampling from several animals within a short period of time. Since the procedure used to make chromosome preparations from the tissue samples is very simple, no cytogenetic experience is required to make excellent chromosome preparations using this method. To demonstrate the utility of this method, the induction of SCEs by cyclophosphamide was measured in small intestine and colon samples collected from the same animals. The results indicate that this method can be used to determine dose responses in both tissues.     

As2O3抑制人乳腺癌裸鼠移植瘤淋巴管生成相关基因表达的研究

目的：探讨As2O3抑制乳腺癌淋巴管生成的机制。方法：24只裸鼠复制成人乳腺浸润性导管癌模型,随机分成4组：阴性对照组（NS）、阳性对照组（5-FU30mg/kg）,实验组1（As2O31.5mg/kg）和实验组2（As2O33.0mg/kg）,采用免疫组织化学、RT-PCR技术分别检测COX-2、VEGF-C基因、蛋白的表达。结果：阴性对照组COX-2、VEGF-C基因、蛋白呈强阳性表达,实验组1、实验组2的COX-2、VEGF-C阳性表达随着As2O3用量的增加而下降（P〈0.05）,与阳性和阴性对照组的表达比较呈明显下降趋势（P〈0.05）。各组中COX-2与VEGF-C的基因、蛋白表达水平呈明显相关关系（r=0.725,r=0.915）。结论：As2O3可降低乳腺癌裸鼠移植瘤组织中VEGF-C和COX-2的表达,有可能减少肿瘤中淋巴管生成,抑制肿瘤生长及淋巴转移。     

The role of senescence and immortalization in carcinogenesis

Normal somatic cells are able to divide only a limited number of times before they become senescent. The occurrence of intratumoral cell death and the need for clonal evolution mean that many more cell divisions are required for tumorigenesis than is possible unless cells breach the senescence proliferation barrier and become immortalized. Senescence may therefore be a major tumor suppressor mechanism. During the past decade the study of senescence and immortalization has entered the mainstream of cancer research. A major reason for the current interest in this subject is the observation that most cancers have an activated telomere maintenance mechanism, a marker of immortalization. It has also been found that some of the most common genetic changes known to occur in cancer have a key role in the immortalization process.     

Inhibitory Effects of Low-Dose Aloe-Emodin on the Development of Colorectal Tumors in Min Mice

Aloe-emodin (AE), a natural anthraquinone compound, has been reported to exhibit anticancer activityin various cancer cell lines and anti-inflammatory effects in murine macrophages. In the present study, weinvestigated the cancer chemopreventive effects of AE in an Apc-deficient Min mouse model. In the firstexperiment, male Min mice were fed a basal diet or diets containing 5 ppm AE and 10 ppm AE for 12 weeks.The dietary administration of 5 ppm AE significantly reduced the number of colorectal tumors. In a secondexperiment, we investigated the effects of AE on colitis-related colon carcinogenesis in Min mouse treated withdextran sodium sulfate (DSS). Female Min mice were administered 1% DSS in their drinking water for 7 days.AE was given to mice in their diet at a dose of 5 or 50 ppm for 5 weeks. Feeding with AE significantly reducedthe number of colorectal tumors. When proliferation of cells in normal-appearing colonic mucosa was assessedby monoclonal anti-rat Ki-67 antibody (MIB-5) immunohistochemistry in experiments 1 and 2, the AE treatmentsignificantly decreased the mean MIB-5-labeling index. These results suggest that the dietary administration oflow-dose AE may have chemopreventive effects against development of colorectal tumors in Min mice, possiblyin part by reducing cell proliferation in colorectal mucosa.     

The role of macrophages in asbestos-induced carcinogenesis

Data available on the pathways of asbestos (fibrous) carcinogenesis still leaves much to be desired. Asbestos is regarded as a non-genotoxic substance by most researchers. There is insufficient evidence on the interaction of fibres, target-cells and macrophages. Macrophages secreted proteins (ca. 450 kD) to inhibit proliferation of intact mesothelium and cytoxine (3-5 kD) which stimulated the cellular sensitivity of intact mesothelium and mesotheliomas to the toxic influence of asbestos. It was suggested that the effect was due to the triggering of intrinsic causation of cell death. Like any other fibres, carcinogenic effect of asbestos could be accounted for by such significant factor as active oxygen radicals. When exposed to asbestos, both intact mesothelial and mesothelioma cells and macrophages synthesized those substances. Free radical-like substances in conjunction with macrophage-conditioned media produced toxic effect on mesothelial cells. The role of active oxygen radicals in fibre-induced carcinogenesis is discussed.