Aisling M. Hogan

Oestrogen and the colon: potential mechanisms for cancer prevention

The role of oestrogen in oncogenesis has been examined extensively, especially in the context of breast cancer, and receptor modulators are an integral part of targeted treatment in this disease. The role of oestrogen signalling in colonic carcinoma is poorly understood. Men are more susceptible than women to colon cancer. Furthermore, hormone-replacement therapy affords an additive protective effect for postmenopausal women, and when these women do develop cancer, they typically have less aggressive disease. The discovery of a second oestrogen receptor (ERbeta) and its over expression in healthy human colon coupled with reduced expression in colon cancer suggests that this receptor might be involved. The underlying mechanism, however, remains largely unknown. In this Review, we discuss the various hypotheses presented in the published literature. We examine the cellular and molecular mechanisms through which oestrogen is purported to exert its protective influence, and we review the evidence available to support these claims.

Microbial and viral pathogens in colorectal cancer.

The heterogenetic and sporadic nature of colorectal cancer has led to many epidemiological associations with causes of this disease. As our understanding of the underlying molecular processes in colorectal-cancer develops, the concept of microbial-epithelial interactions as an oncogenic trigger might provide a plausible hypothesis for the pathogenesis of colorectal cancer. By contrast with other cancers of the gastrointestinal tract (gastric carcinoma, mucosa-associated lymphoid-tissue lymphoma), a direct causal link between microbial infection (bacteria and viruses) and colorectal carcinoma has not been established. Studies support the involvement of these organisms in oncogenesis, however, in colorectal cancer, clinical data are lacking. Here, we discuss current evidence (both in vitro and clinical studies), and focus on a putative role for bacterial and viral pathogens as a cause of colorectal cancer.

Estrogen and gastrointestinal malignancy

The concept that E2 exerts an effect on the gastrointestinal tract is not new and its actions on intestinal mucosa have been investigated for at least three decades. An attempt to consolidate results of these investigations generates more questions than answers, thus suggesting that many unexplored avenues remain and that the full capabilities of this steroid hormone are far from understood. Evidence of its role in esophageal, gastric and gallbladder cancers is confusing and often equivocal. The most compelling evidence regards the protective role conferred by estrogen (or perhaps ERbeta) against the development and proliferation of colon cancer. Not only has the effect been described but also many mechanisms of action have been explored. It is likely that, along with surgery, chemotherapy and radiotherapy, hormonal manipulation will play an integral role in colon cancer management in the very near future.

Differential protein abundance and function of UT-B urea transporters in human colon

Facilitative UT-B urea transporters enable the passage of urea across cell membranes. Gastrointestinal urea transporters are thought to play a significant role in the urea nitrogen salvaging process that occurs between mammalian hosts and their gut bacteria. This study investigated the expression of UT-B urea transporters in different segments of human colon. Immunoblot analysis showed that human colon expressed a 35-kDa glycosylated UT-B protein in the colonic mucosa. The 35-kDa UT-B transporter was predominantly located in plasma membrane-enriched samples (P < 0.001; n = 6), and its expression was greater in the ascending colon compared with the descending colon (P < 0.01; n = 3). At the cellular level, UT-B transporters were located throughout colonocytes situated in the upper portion of the colonic crypts. Bidirectional trans-epithelial urea transport was significantly greater in the ascending colon than the descending colon (P < 0.05; n = 6). In addition, the facilitative urea transporter inhibitor 1,3,dimethylurea significantly reduced urea transport in the ascending colon (P < 0.05; n = 6) but had no effect in the descending colon (NS; n = 6). These results illustrate differential protein abundance of functional UT-B protein in different sections of the human colon, strongly correlating to regions that contain the largest populations of intestinal bacteria. This study suggests an important role for UT-B urea transporters in maintaining the symbiotic relationship between humans and their gut bacteria.

Oestrogen inhibits human colonic motility by a non-genomic cell membrane receptor-dependent mechanism

Classical effects of oestrogen involve activation of target genes after binding nuclear receptors. Oestrogenic effects too rapid for DNA transcription (non‐genomic) are known to occur. The effect of oestrogen on colonic motility is unknown despite the prevalence of gastrointestinal symptoms in pregnant and premenopausal women.

Estrogen and its role in gastrointestinal health and disease

IntroductionWhile the concept of a role of estrogen in gastrointestinal (in particular, colonic) malignancy has generated excitement in recent years, no review has examined the role of this potent and omnipresent steroid hormone in physiological states or its contribution to the development of benign pathological processes. Understanding these effects (and mechanisms therein) may provide a platform for a deeper understanding of more complex disease processes.MethodsA literature search was conducted using the PubMed database and the search terms were “estrogen,” “estrogen AND gastrointestinal tract,” “estrogen AND colon,” “estrogen AND esophagus,” “estrogen AND small intestine,” “estrogen AND stomach,” “estrogen AND gallbladder,” and “estrogen AND motility.” Bibliographies of extracted studies were further cross-referenced. In all, 136 full-text articles were selected for review. A logical organ-based approach was taken to enable extraction of data of clinical relevance and meaningful interpretation thereof. Insight is provided into the hypotheses, theories, controversies, and contradictions generated over the last five decades by extensive investigation of estrogen in human, animal, and cell models using techniques as diverse as autoradiographic studies of baboons to human population analysis.ConclusionsEffects from esophagus through to the colon and rectum are summarized in this first concise collection of data pertaining to estrogenic actions in gastrointestinal health and disease. Mechanisms of these actions are discussed where possible. Undoubtedly, this hormone exerts many actions yet to be elucidated, and its potential therapeutic applications remain, as yet, largely unexplored.

Volume-outcome analysis in rectal cancer: A plea for enquiry, evidence and evolution

In the last three decades, since Luft suggested a link between hospital volume and patient outcome, little has changed. Despite great efforts to formally quantify the relationship between volume and cancer survival, much uncertainty remains. It is intuitive that increased experience (of the surgeon, the hospital or the ancillary staff) translates to better patient care but closer analysis of the literature uncovers widespread inconsistency in study design questioning validity of conclusions. Although centralisation of cancer services would seem beneficial, definitive evidence is only available regarding pancreatic and oesophageal disease and that pertaining to rectal cancer is heterogeneous and often flawed. A majority of evidence suggests better outcome for patients with rectal cancer managed in high volume centres. There are, however, many variables in data collection and interpretation rendering comparison between studies challenging. Definitions of the rectum range from distance from the anal verge (inherent disagreement e range 10e16 cm), to relationship to sacral promontory (subject to interpreter variation), and location of peritoneal reflection (cannot be interpreted endoscopically). Many authors fail to differentiate between sigmoid colon and rectum 3 and, those that do demonstrate wide variation. One of the largest studies, (more than 7000 patients) from the Californian Cancer Registry offered no description of tumour location. It concluded that patients undergoing surgery at high volume hospitals were less likely to have permanent colostomies and had better survival rates. The diagnosis of rectal cancer was, however, questionable as it was based only on a discharge letter, often written by the most junior team member with no reference to true anatomical location. Most US studies are published from a few high volume institutions with a select patient cohort and are based on retrospective analysis of large databases which, themselves are notoriously inaccurate. The European experience was recently explored by Ptok in a prospective trial of almost 7000 patients undergoing resection for rectal cancer. This is arguably the most complete data set available to date and great effort was made to overcome common biases. A clear definition of the rectum was provided, hospital volume was classified

Cyclic AMP‐mediated chloride secretion is induced by prostaglandin F2α in human isolated colon

Background and purpose:  Prostaglandin F2α (PGF2α) is implicated in the pathogenesis of inflammatory bowel disease and colorectal cancer. This study investigates the effects of PGF2α on electrophysiological parameters in isolated human colonic mucosa.

Rapid effects of phytoestrogens on human colonic smooth muscle are mediated by oestrogen receptor β

Epidemiological studies have correlated consumption of dietary phytoestrogens with beneficial effects on colon, breast and prostate cancers. Genomic and non-genomic mechanisms are responsible for anti-carcinogenic effects but, until now, the effect on human colon was assumed to be passive and remote. No direct effect on human colonic smooth muscle has previously been described. Institutional research board approval was granted. Histologically normal colon was obtained from the proximal resection margin of colorectal carcinoma specimens. Circular smooth muscle strips were microdissected and suspended under 1g of tension in organ baths containing oxygenated Krebs solution at 37 degrees C. After an equilibration period, tissues were exposed to diarylpropionitrile (DPN) (ER beta agonist) and 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) (ER alpha agonist) or to the synthetic phytoestrogen compounds genistein (n=8), daidzein (n=8), fisetin (n=8) and quercetin (n=8) in the presence or absence of fulvestrant (oestrogen receptor antagonist). Mechanism of action was investigated by inhibition of downstream pathways. The cholinergic agonist carbachol was used to induce contractile activity. Tension was recorded isometrically. Phytoestrogens inhibit carbachol-induced colonic contractility. In keeping with a non-genomic, rapid onset direct action, the effect was within minutes, reversible and similar to previously described actions of 17 beta oestradiol. No effect was seen in the presence of fulvestrant indicating receptor modulation. While the DPN exerted inhibitory effects, PPT did not. The effect appears to be reliant on a p38/mitogen activated protein kinase mediated induction of nitric oxide production in colonic smooth muscle. The present data set provides the first description of a direct effect of genistein, daidzein, fisetin and quercetin on human colonic smooth muscle. The presence of ER in colonic smooth muscle has been functionally proven and the beta isoform appears to play a predominant role in exerting non-genomic effects.

Gastric applications of electrical field stimulation.

Advances in clinical applications of electricity have been vast since the launch of Haymans first cardiac pacemaker more than 70 years ago. Gastric electrical stimulation devices have been recently licensed for treatment of gastroparesis and preliminary studies examining their potential for use in refractory obesity yield promising results.