Katia Lofano

Estrogens, phytoestrogens and colorectal neoproliferative lesions

Epidemiological and experimental studies suggest a protective role of estrogens against colorectal cancer. This effect seems to be mediated by their binding to estrogen receptor beta (ER-β), one of the two estrogen receptors with high affinity for these hormones. Very recently, the demonstration of an involvement of ER-β in the development of adenomatous polyps of the colon has also been documented, suggesting the use of selective ER-β agonists in primary colorectal cancer prevention. Phytoestrogens are plant-derived compounds that structurally and functionally act as estrogen-agonists in mammals. They are characterized by a higher binding affinity to ER-β as compared to estrogen receptor alpha (ER-α), the other estrogen receptor subtype. These biological characteristics explain why the administration of phytoestrogens does not produce the classical side effects associated to estrogen administration (cerebro- and cardio-vascular accidents, higher incidence of endometrial and breast cancer) and makes these substances ideal candidates for the prevention of colorectal cancer.

Dietary-induced ERβ upregulation counteracts intestinal neoplasia development in intact male ApcMin/+ mice

Most sporadic colorectal cancers (CRCs) develop through the adenoma-carcinoma sequence pathway and are initiated by adenomatous polyposis coli (APC) gene mutations. Estrogen receptor beta (ERbeta) is recognized to progressively reduce its expression in adenomatous and carcinomatous tissues in humans. Moreover, ERbeta deficiency enhances small intestinal tumorigenesis in rodents. In the Apc(Min/+) mouse model, we evaluated intestinal polyp development and ERbeta expression plus other biological parameters influencing tumor growth (epithelial cell proliferation, apoptosis and migration) following the addition of a combination of the ERbeta-selective agonist silymarin (SIL) and/or lignin (LIG) to a high-fat/low-fiber diet. Forty-five Apc(Min/+) mice were divided in four groups: animals fed on the tumorigenic high-fat/low-fiber diet, the tumorigenic diet supplemented with SIL (0.02%) or purified LIG (6.24%) or SIL (0.005%) + LIG (6.24%). In these animals, we assessed polyp number and volume and their degree of dysplasia together with ERbeta messenger RNA (mRNA) and protein levels and epithelial cell proliferation, migration and apoptosis. The latter group of parameters was evaluated in normal and adenomatous mucosa and the results compared with those found in wild-type (WT) mice fed on the control diet. The addition of SIL or LIG to the diet and even more the specific combination of the two significantly counteracted intestinal tumorigenesis and increased ERbeta mRNA and protein levels. Cell proliferation and apoptosis were rebalanced and cell migration accelerated, restoring values similar to those observed in WT animals. Our results further support a protective effect of ERbeta in CRC suggesting the use of the combination of SIL-LIG as a potential approach against CRC development.

Dietary, Endocrine, and Metabolic Factors in the Development of Colorectal Cancer

IntroductionColorectal cancer is the third cause of death in industrialized countries. Genetic susceptibility and diet are determinant of cancer risk and tumor behavior. Variation in cancer incidence among and within populations with similar dietary patterns suggests that an individual response may reflect interactions with genetic factors, which may modify gene, protein, and metabolite expression patterns. Nutrigenomics, defined as the interaction between nutrition and an individual genome, will likely provide important clues about responders and non-responders to nutritional intervention.DiscussionEpidemiological and experimental studies suggest a protective role of some normal components of daily diet (fish oil, milk, and vegetables), estrogens, and phytoestrogens in colorectal cancer. The effect of estrogen seems to be mediated by their binding to estrogen receptor beta (ER-β), one of the two estrogen receptors with high affinity for these hormones. Very recently, the demonstration of an involvement of ER-β in the development of adenomatous polyps of the colon has also been documented, suggesting the use of selective ER-β agonists in primary colorectal cancer prevention. Phytoestrogens are plant-derived compounds that structurally and functionally act as estrogen agonists in mammals. They are characterized by a higher binding affinity to ER-β as compared to estrogen receptor alpha (ER-α), the other estrogen receptor subtype. These biological characteristics explain why the administration of phytoestrogens does not produce the classical side effects associated to estrogen administration (cerebro- and cardiovascular accidents, higher incidence of endometrial and breast cancer) and makes these substances potential candidates for colorectal cancer prevention.

Dietary lifestyle and colorectal cancer onset, recurrence, and survival: myth or reality?

Background and PurposeInterest in the possibility that diet might help to reduce the risk of colorectal cancer dates back to 1970 based on both the large variation in rates of specific cancers in different countries and the impressive changes observed in the incidence of cancer in migrants from low- to high-risk areas. Here, we report the state of art of literature data about this topic.MethodsThree sections have been separately considered: chemoprevention of first tumor onset, chemoprevention of recurrence after surgery, and chemoprevention of polyp recurrence in the course of the follow-up of subjects with elevated risk. A particular attention has been pointed to dietary factors and survival, whose relevance is showing a growing interest.ResultsThe relationship between diet and colorectal cancer has been extensively studied about the onset, sometimes with controversial results. Its influence on recurrence and survival has been examined in only few studies.ConclusionsLiterature data are convincing for a protective role on the onset of preneoplastic and neoplastic lesions for some foods such as fibers, vitamin A and D, folic acid, calcium, antioxidants, and promising perspectives for some substances such as phyto-estrogens. Less evidence-based data are available on the possibility to avoid the recurrence of the disease or to affect its mortality with dietary habits. Future perspectives will be directed be not only to identify new dietary style able to prevent the onset of neoplastic lesion of the colon but also to realize an effective chemoprevention.

Estrogen receptors expression in long-lasting ulcerative pancolitis with and without dysplasia: A preliminary report

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P085 Effect of phytoestrogenic dietary supplementation on the progression of chronic intestinal inflammation to cancer in an animal model

Background and aim : Colorectal cancer (CRC) is increased in inflammatory bowel diseases (IBD). Chemopreventive agents could minimize this risk. Estrogens exert prevention against CRC throught Estrogen Receptor β (ERβ) with an inverse relation with the tumor. ER β induction may be a target in CRC prevention. Phytoestrogens are dietary compounds with higher binding affinity for ERβ than Erα. A blend of the dietary phytoestrogens (silymarin and lignan) and non-starch insoluble fibers (Eviendep, CM&D Pharma) has been tested in an experimental mouse model of AOM/DSS induced colitis, to assess the anti-inflammatory and anti-carcinogenetic properties and to verify whether such effect is related to an increased ERβ expression. Material and methods : A known model of dextran sodium sulfate/azoxymethane induced CRC was used to obtain the best simulation of IBD-related CRC pathogenesis. Seventy-six C57BL/6J male mice were divided into three groups: 35 mice fed a Eviendepmodified diet during the whole carcinogenetic process, 35 fed a standard diet (positive control) and 6 mice with no treatment or modified diet (negative control). Monitoring of colitis and tumorigenesis was performed by a specific video-endoscopic system (Coloview Miniendoscopic System) at 21 weeks. Animals were sacrificed at 22 weeks for histogical and ERs immunohistochemical evaluation. Histological score was: 0 (no dysplasia), 1 (low grade dysplasia), 2 (high grade dysplasia) and 3 (carcinoma). Results : Mortality rate was of 40-50%. At sacrifice, treated animals showed a decrease in number/volume of polyps and in histological score (p,0.05 ANOVA-Bonferroni post hoc test). Only 30% of Eviendepsupplemented mice showed at least 1 CRC compared with the 100% of the positive controls. ERα expression was higher in neoplastic tissue than in normal mucosa both in treated and positive control groups, while ERβ labeling index (LI%) showed a higher value in nonneoplastic tissue of the Eviendep-supplemented group (63.8±4.7) than in positive control (46.6±6.4), resulting similar to the ERβ LI value of negative controls (54.9±7.9) (p,0.05 Fisher Exact Test) Conclusions : Our results suggest a chemopreventive effect of Eviendep on colonic carcinogenesis arising from inflamed tissue, and such an effect associates with an increase ERβ content in the tissue.

Sa1260 Non Invasive Evaluation of Endothelial Function in Inflammatory Bowel Diseases

In the last decades an ever-growing body of evidence has suggested the involvement of intestinal microvascular endothelial cells in development and maintenance of inflammatory bowel diseases (IBD). Changes in structure and function of endothelium, mediated by a multifaceted network of chemokines, cytokines and inflammatory growth factors, are a distinctive feature of active disease. In addition, human intestinal microvessels taken from inflamed mucosa exhibit consistent degrees of endothelial dysfunction, with significant impairment of acetylcholine-induced vasodilation based on decreased endothelial nitric oxide (NO) synthase (eNOS) activity. By “endothelial dysfunction” is comprehensively meant a condition in which the varied homeostatic functions of endothelium are impaired. Endothelial function can be measured through the flow-mediated dilation (FMD) technique, a wellestablished non invasive procedure in which changes in the calibre of the brachial artery induced by an increased vessel wall shear stress are measured ultrasonographically. AIM: The present study was designed to evaluate whether FMD at the brachial artery was impaired in a sample of patients with Crohns disease (CD) and ulcerative colitis (UC) in comparison to healthy control subjects. As a secondary measure of interest, intima-media thickness at the common carotid artery (ccIMT) was also calculated. MATERIALS AND METHOD: 49 patients (25 males; mean age, 41 yrs ± 16) with CD (26) and UC (23) in moderate-severe activity phase were included. Endothelial function was assessed through FMD and shear stress reactive hyperemia determination; moreover, ccIMT was measured ultrasonographically. Statistical analyses were made by using Statistica 6.1 software (StatSoft Inc.. Tulsa. OK. USA). RESULTS: In IBD patients FMD% values were significantly lower than in controls (6.3±3.3 vs 8.1±3.4, p=0.013). Such difference was not related to age, sex, disease duration, or comorbidity (such as, hypertension or diabetes). On the contrary, ccIMT measurements did not differ consistently between cases and controls. CONCLUSIONS: IBD group showed significant levels of endothelium dysfunction compared with controls. In our view, this result was more likely related to systemic inflammation than to traditional risk factors. By contrast, the lack of significant differences in ccIMT was possibly related to the low mean age and disease duration in our study population. Future studies of endothelial function are warranted comparing case series before and after remission obtained under elective treatments.