Colitis-related Colorectal Cancer Research Articles

MiR-597-5p inhibits carcinogenesis and macrophage recruitment in colitis-related colorectal cancer via reducing the expression of CXCL5

ABSTRACT Despite being the subject of multiple cancer studies, nothing is known about miR-597-5p’s role in colitis-associated colorectal cancer (CAC). We intend to explore how miR-597-5p influences the growth and development of CAC. In order to construct a CAC model, mice were stimulated with azoxymethane (AOM)/dextran sulfate sodium (DSS). The in situ hybridization (ISH) and quantitative real-time polymerase chain reaction (qRT-PCR) was used for the detection of miR-597-5p expression. The protein expression of CXCL5 was determined by western blotting, immunohistochemistry and enzyme-linked immuno sorbent assay (ELISA). The histologic colitis score and hematoxylin and eosin (HE) staining were used to evaluate degree of damage to colonic tissues. The proportion of macrophages detected in colon tumors was also measured using flow cytometry. The transwell test was employed to assess macrophage migration. It was found that the miR-597-5p and its target CXCL5 had a negative correlation. MiR-597-5p expression was decreased, while CXCL5 expression was raised in CAC tissues. In AOM/DSS-induced mice, miR-597-5p deficiency in intestinal epithelial cells resulted in decreasing colon length as well as increasing tumor numbers and histologic colitis score, which was reversed by CXCL5 inhibition. MiR-597-5p deficiency facilitated macrophage recruitment in AOM/DSS-induced mice and promoted macrophage migration in vitro, which were reversed by CXCL5 inhibition. Deficiency of miR-597-5p aggravated macrophage recruitment and tumorigenesis in a mouse CAC model, suggesting that miR-597-5p agonists may have an anti-inflammatory therapeutic effect in inflammatory bowel diseases and reduce the risk of developing CAC.

Feasibility of Laparoscopic and Robotic Total Proctocolectomy for Ulcerative Colitis-related Colorectal Cancer.

To evaluate the feasibility of laparoscopic and robotic total proctocolectomy (TPC) for ulcerative colitis-associated colorectal cancer (UC-CRC). We retrospectively analyzed the postoperative outcomes of TPC in 13 patients with UC-CRC between January 2011 and December 2021. Laparoscopic TPC was performed in 10 patients. TPC consisted of two procedures: ileal pouch-anal anastomosis (IAA) and TPC with end ileostomy. Using the da Vinci Xi platform with six ports, robotic TPC and abdominal perineal resection (APR) were performed in two and one patients, respectively. Transanal total mesorectal excision (TaTME) was performed using the perineal approach in five patients. UC-CRC was located in the transverse colon, sigmoid colon, rectum, and anal canal in 1, 1, 10, and 1 patients, respectively. IAA, TPC with end ileostomy, and APR were performed in nine, three, and one patients, respectively. Postoperative complications included colitis, portal vein thrombosis, and liver dysfunction, without mortality. The pathological stages were 0, I, IIa, IIIb, and IIIc in five, four, one, two, and one patients, respectively. The tumors were completely resected in all cases. Eleven patients with pStages 0, I, and II survived without recurrence; however, two patients with pStage III died of cancer recurrence. This study demonstrated the feasibility of laparoscopic and robotic TPC in patients with UC-CRC. However, long-term outcomes in terms of oncology and patient quality of life must be investigated in future large-scale studies.

Establishment of a Novel Colitis-Associated Cancer Mouse Model Showing Flat Invasive Neoplasia.

Chronic inflammation, such as ulcerative colitis, increases the risk of developing colitis-associated cancers. Currently, mice administered with azoxymethane/dextran sodium sulfate are well-known models for colitis-associated cancers. Although human colitis-associated cancers are often flat lesions, most azoxymethane/dextran sodium sulfate mouse cancers are raised lesions. To establish a novel mouse model for colitis-associated cancers and evaluate its characteristics. A single dose of azoxymethane was intraperitoneally administered to CD4-dnTGFβRII mice,which are genetically modified mice that spontaneously develop inflammatory bowel disease at different doses and timings. The morphological and biological characteristics of cancers was assessed in these mice. Colorectal cancer developed with different proportions in each group. In particular, a high rate of cancer was observed at 10 and 20weeks after administration in 12-week-old CD4-dnTGFβRII mice dosed at 15mg/kg. Immunohistochemical staining of tumors was positive for β-catenin, ki67, and Sox9 but not for p53. Grade of inflammation was significantly higher in mice with cancer than in those without cancer (p < 0.001). In CD4-dnTGFβRII/azoxymethane mice, adenocarcinomas with flat lesions were observed, with moderate-to-severe inflammation in the non-tumor area. In comparison, non-tumor areas of azoxymethane/dextran sodium sulfate mice had less inflammation than those of CD4-dnTGFβRII/azoxymethane mice, and most macroscopic characteristics of tumors were pedunculated or sessile lesions in azoxymethane/dextran sodium sulfate mice. Although feasibility and reproducibility of azoxymethane/CD4-dbTGFβRII appear to be disadvantages compared to the azoxymethane/dextran sodium sulfate model, this is the first report to demonstrate that the chronic inflammatory colitis model, CD4-dnTGFβRII also develops colitis-related colorectal cancer.

MiR-370-3p Alleviates Ulcerative Colitis-Related Colorectal Cancer in Mice Through Inhibiting the Inflammatory Response and Epithelial-Mesenchymal Transition.

IntroductionUlcerative colitis (UC) is a chronic and inflammatory bowel disease. UC-associated colorectal cancer (UC-CRC) is one of the most severe complications of long-standing UC. In the present study, we explored the effects of miR-370-3p on UC-CRC in vivo and investigated its underlying mechanisms in vivo and in vitro.MethodsAzoxymethane (AOM) and dextran sodium sulfate (DSS) were used to induce UC-CRC in C57BL/6 mice. AOM/DSS-induced mice were treated with 5×108 pfu miR-370-3p overexpressing-adenovirus via tail-vein injection every two weeks.ResultsWe found that miR-370-3p significantly improved the body weights and survival rates and inhibited the tumorigenesis of UC-CRC in AOM/DSS mice. Mechanically, miR-370-3p inhibited AOM/DSS-induced inflammatory response by decreasing tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) through targeting toll-like receptor 4 (TLR4), as demonstrated by down-regulation of TLR4, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and phosphorylated epidermal growth factor receptor (pEGFR). miR-370-3p decreased the expression of tumor-associated proteins, including p53, β-catenin, and ki67 in AOM/DSS-treated mice. Additionally, miR-370-3p remarkably inhibited epithelial-mesenchymal transition (EMT) via increasing E-cadherin expression and reducing N-cadherin and Vimentin expression in vivo. Further studies showed that miR-370-3p repressed proliferation and EMT of colon cancer cells in vitro. Moreover, we proved that miR-370-3p decreased the expression of tumor-associated proteins and reversed EMT by regulating β-catenin in colon cancer cells.ConclusionTaken together, miR-370-3p alleviated UC-CRC by inhibiting the inflammatory response and EMT in mice, which suggested miR-370-3p as a novel potential target for UC-CRC therapy.

Feng-Liao-Chang-Wei-Kang Combined with 5-Fluorouracil Synergistically Suppresses Colitis-Associated Colorectal Cancer via the IL-6/STAT3 Signalling Pathway.

Background Colitis-associated colorectal cancer (CAC) develops from active colonic inflammation, which is characterized by the production of proinflammatory cytokines that can induce mutations. IL-6 is produced by multiple cell types located within the tumor microenvironment including tumor-infiltrating immune cells, stromal cells, and the tumor cells themselves. The aim of our study was to explore the mechanism of Feng-Liao-Chang-Wei-Kang (FLCWK) and 5-fluorouracil (5-FU) in treating CAC. Method HCT116 cells were treated with 5-FU in the absence or presence of FLCWK. Cell proliferation was assayed by MTT assays. Apoptosis and the cell cycle phases were detected by flow cytometry. Western blotting and Q-PCR assays were used to detect the expression levels of proteins and genes related to the IL-6/STAT3 signalling pathway. A mouse model for CAC was established by treating animals with 12.5 mg/kg azoxymethane (AOM) followed by 3 cycles of 2.5% dextran sodium sulphate (DSS). The associated pathological changes were determined after haematoxylin and eosin (H&E) staining. The expression of related proteins and genes in various tissues was examined using immunofluorescence techniques. Results FLCWK enhanced the ability of 5-FU to promote apoptosis by inhibiting the proliferation of HCT116 cells and blocking the IL-6/STAT3 pathway. FLCWK combined with 5-FU reduced the number and size of colon tumors in mice with CAC and significantly increased their survival rate. In the CAC model, FLCWK synergized with 5-FU to inhibit the phosphorylation of STAT3, preventing IL-6/STAT3 signal transduction and thus further inducing apoptosis and inhibition of colon cancer cell proliferation. Conclusion FLCWK can inhibit the activation of STAT3 by reducing the production of IL-6, thereby increasing the occurrence of colitis-related colorectal cancer with 5-FU.

Uncovering the Anticancer Mechanism of Compound Sophorae Decoction against Ulcerative Colitis-Related Colorectal Cancer in Mice.

Compound sophorae decoction (CSD), a traditional Chinese medicine (TCM) formula, has been voluminously used in China to deal with ulcerative colitis and gained significant therapeutic effect. Tremendous explorations have unraveled a contributory role of inflammatory bowel disease (IBD) like ulcerative colitis (UC) and Crohn's disease (CD) at the onset of colorectal cancer, scilicet, and colitis-related cancer (CRC). In light of the anti-inflammatory properties of CSD in UC, we appraised its chemoprevention capacity and underlying mechanism in ulcerative colitis-related colorectal cancer (UCRCC), employing a model of azoxymethane (AOM) plus dextran sulfate sodium- (DSS-) induced colorectal cancer (CRC) in C57BL/6 mice. Rapturously, our results illuminated the ameliorative effect of CSD against UCRCC in mice portrayed by lesser polyps or adenomas, attenuated colonic xenograft tumor growth in company with the preferable well-being of mice in contrast to the Model Group. We examined significant downregulation of proinflammatory cytokines such as TNF-α, NF-κB, IL-6, STAT3, and IL-17 after exposure to CSD, with the concomitant repression of inflammation-associated proteins, including COX-2 and iNOS. Independent of this, treatment with CSD declined the proportion of T helper 17 cells (Th17) and protein level of matrix metallopeptidase 9 (MMP-9). Moreover, transmission electron microscopy (TEM) detected observably suppressed mitophagy in mice administered with CSD and that was paralleled by the pro-apoptotic effect as indicated by upregulating caspase-3 together with caspase-9 and deregulating B-cell lymphoma 2 (Bcl-2). In closing, these findings suggest CSD executes the UCRCC-inhibitory activity through counteracting inflammatory responses and rescuing detuning of apoptosis as well as neutralizing overactive mitophagy, concurring to build up an oncosuppressive microenvironment.

Over-expressed miRNA-200b ameliorates ulcerative colitis-related colorectal cancer in mice through orchestrating epithelial-mesenchymal transition and inflammatory responses by channel of AKT2

Our study was to explore the potential role of miRNA-200b in modulating tumorigenesis in the model of ulcerative colitis-related colorectal cancer (UCRCC) and, further, to decipher the underlying mechanisms associated with this effect. In this study, we examined a greater number of polyps or adenomas, a higher grade of epithelial dysplasia accompanied with a decrease in survival ratio in azoxymethane (AOM)/dextran sulfate sodium (DSS) model mice compared to mice treated with over-expressed miRNA-200b. Surprisingly, enforced miRNA-200b expression significantly suppressed AOM/DSS-induced up-regulation of oncologic markers including β-catenin and CD133. Independent of this, treatment with miRNA-200b obviously attenuated inflammatory responses, as indicated by down-regulating tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β) and blockade of AKT2-mediated NF-κB/IL-6/STAT3 signaling pathway. Furthermore, a simultaneous shift in epithelial-mesenchymal transition (EMT) markers such as E-cadherin and N-cadherin were observed to be increased and decreased, respectively. Coupled with the associated influence of over-expressed miRNA-200b were change in colorectal cell morphology shown by Transmission electron microscope (TEM) and a decrease in expression of rho-kinase2 (ROCK2) together with AKT2 phosphorylation (p-AKT2). Moreover, mice which were transfected with negative control of miRNA-200b possessed results that were in line with that obtained from AOM/DSS model mice. Additionally, we demonstrated that the 3′untranslated region (UTR) of AKT2 was a direct target of miRNA-200b through bioinformatics analysis and dual-luciferase assay. Collectively, these findings suggest that miRNA-200b's contribution to tumor-suppressing program was correlated with EMT and inflammatory responses in a AKT2-dependent manner.

Sa1675 - Periostin Attenuates Tumor Growth by Inducing Apoptosis in Colitis-Related Colorectal Cancer

Sa1675 - Periostin Attenuates Tumor Growth by Inducing Apoptosis in Colitis-Related Colorectal Cancer

Periostin attenuates tumor growth by inducing apoptosis in colitis-related colorectal cancer.

Inflammatory bowel diseases, which are multifactorial autoimmune colitis diseases, are occurring with increasing prevalence. One of the most serious complications of these diseases is colorectal cancer. Here we investigated the role of periostin (Postn), a matricellular protein that interacts with various integrin molecules on the cell surface, in colitis-induced colorectal cancer. Immunohistochemistry of mouse and human colorectal cancer samples revealed that Postn was expressed in the stroma and was upregulated in close proximity to the cancer cells. The colonic tumorigenesis in an inflammation-related colon carcinogenesis mouse model was increased in Postn knock-out (Postn−/−) mice compared to Postn+/+ mice. Although no difference was found in the degree of colitis between Postn+/+ and Postn−/− mice, Postn inhibited tumor growth and induced the apoptosis of mouse rectal cancer cells in vitro. Furthermore, fewer apoptotic colorectal cancer cells were observed in Postn−/− than in Postn+/+ mice. These data suggested that Postn has an anti-tumor effect on colitis-induced colorectal cancer.

Prevention of ulcerative colitis-related colorectal cancer

Prevention of ulcerative colitis-related colorectal cancer

Clinical characteristics of ulcerative colitis-related colorectal cancer in Chinese patients.

The prevalence of ulcerative colitis (UC) in China has been increasing, together with the incidence of ulcerative colitis-related colorectal cancer (UCRCC). In this study we aimed to investigate the clinical features of UCRCC in Chinese UC patients. Clinical data of patients with UCRCC during January 2003 to December 2016 were retrieved from the Peking Union Medical College Hospital registration database and compared with that of sporadic colorectal cancer (CRC). During the study period, among the 10 110 patients with CRC 25 were found to have UCRCC, with an average age of 51 years and a median disease duration of 15 years. The cumulative prevalence of UCRCC was 0.25% in all CRC patients, with a significant increase from 2003-2007 to 2013-2016 (P < 0.01). Altogether 14 (56.0%) patients with UCRCC were men, and 5 (20.0%) had a family history of UC or cancer. Four (16.0%) patients had concurrent high-grade intraepithelial neoplasia with variable differentiated adenocarcinoma at other sites and 19 (59.4%) tumors were moderately or poorly differentiated. Twenty-three (92.0%) patients underwent surgery, of whom 10 (40%) were at stage III and IV according to the TNM staging system. Compared with the 10 085 patients with sporadic CRC, UCRCC patients were younger (P < 0.01) and were more likely to have descending colon involvement and multifocal lesions (P < 0.01). UCRCC patients have been increasing in recent years. Compared with patients with sporadic CRC, those with UCRCC are younger and are more likely to have descending colon involvement and multifocality.

Changing Paradigms in Detection of Dysplasia and Management of Patients With Inflammatory Bowel Disease: Is Colectomy Still Necessary?

This review chronicles the evolution of dysplasia detection and management in inflammatory bowel disease since 1925, the year the first case report of colitis-related colorectal cancer was published. We conclude that colorectal cancer prevention and dysplasia management for patients with inflammatory bowel disease has changed since this first case report, from somewhat hopeless to hopeful.

Celastrol Ameliorates Ulcerative Colitis-Related Colorectal Cancer in Mice via Suppressing Inflammatory Responses and Epithelial-Mesenchymal Transition.

Celastrol, also named as tripterine, is a pharmacologically active ingredient extracted from the root of traditional Chinese herb Tripterygium wilfordii Hook F with potent anti-inflammatory and anti-tumor activities. In the present study, we investigated the effects of celastrol on ulcerative colitis-related colorectal cancer (UC-CRC) as well as CRC in vivo and in vitro and explored its underlying mechanisms. UC-CRC model was induced in C57BL/6 mice by administration of azoxymethane (AOM) and dextran sodium sulfate (DSS). Colonic tumor xenograft models were developed in BALB/c-nu mice by subcutaneous injection with HCT116 and HT-29 cells. Intragastric administration of celastrol (2 mg/kg/d) for 14 weeks significantly increased the survival ratio and reduced the multiplicity of colonic neoplasms compared with AOM/DSS model mice. Mechanically, celastrol treatment significantly prevented AOM/DSS-induced up-regulation of expression levels of oncologic markers including mutated p53 and phospho-p53, β-catenin and proliferating cell nuclear antigen (PCNA). In addition, treatment with celastrol inhibited inflammatory responses, as indicated by the decrease of serum tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6, down-regulation of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), and inactivation of nuclear factor κB (NF-κB). Moreover, celastrol obviously suppressed epithelial-mesenchymal transition (EMT) through up-regulating E-cadherin and down-regulating N-cadherin, Vimentin and Snail. Additionally, we also demonstrated that celastrol inhibited human CRC cell proliferation and attenuated colonic xenograft tumor growth via reversing EMT. Taken together, celastrol could effectively ameliorate UC-CRC by suppressing inflammatory responses and EMT, suggesting a potential drug candidate for UC-CRC therapy.

Anti-inflammatory and Antitumor Activity of a Triple Therapy for a Colitis-Related Colorectal Cancer.

Colorectal cancer (CRC) is an important health issue worldwide, accounting for the third place of cancer incidence. Chronic inflammation, as seen in Crohn's disease and ulcerative colitis, is the most important risk factor for developing CRC, as it favours neoplastic transformation by enhancing epithelial cell turnover in the colonic mucosa. Treatments for CRC need to be improved; currently they are not specific and have several secondary effects in patients. The main objective of this work was to evaluate a new therapeutic strategy against a colitis-related colorectal cancer in vivo and in vitro by targeting mTOR-signaling and lactate dehydrogenase A. Together, these mechanisms directly affect tumor energetics. In this study we evaluated a better and more efficient triple therapy against a chronic inflammation-associated CRC in vivo and in vitro. After the development of tumors, mice were treated intraperitoneally during a forty-day period with single drugs or different combinations of Metformin, Sodium Oxamate and Doxorubicin.Targeted inhibition of the mTOR pathway, lactate dehydrogenase A and the concurrent use of Doxorubicin (called in this work as triple therapy), leaded to a notable reduction in the number and size of tumors in mice, and, a significant pro-inflammatory cytokines reduction Besides, we showed that treated cells were induced to early autophagy, and apoptosis cell death.Our results represent a novel and robust therapeutic strategy for overcoming CRC by means of targeting central molecular pathways in cancer by the combination of Metformin, Oxamate, and Doxorubicin leading to a rapid tumor growth inhibition and a dramatic colorectal crypt restoration. Besides, drug combination resulted in a notable reduction of anti-inflammatory cytokines.

Small bowel adenocarcinomas complicating Crohn's disease are associated with dysplasia: a pathological and molecular study.

Crohn's disease (CD) is associated with an increased risk of small bowel adenocarcinoma (SBA). However, there are no guidelines for the screening and early diagnosis of SBA. Colorectal cancer associated with chronic colitis arises from dysplasia. High-risk patients benefit from surveillance colonoscopies aimed to detect dysplasia. The dysplasia-carcinoma sequence remains poorly documented in CD-associated SBA. Moreover, molecular data about SBA complicating CD and associated dysplasia are very limited. We therefore assessed dysplasia and several key molecular markers of carcinogenesis in SBA and dysplasia developed in patients with CD. Forty-five SBA complicating CD and 4 specimens with dysplasia without SBA were screened. In SBA, we looked for dysplasia and determined their pathological characteristics (type, grade, distribution). We also stained for mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), p53, β-catenin, and p16 and looked for KRAS, BRAF and PIK3CA mutations. All neoplastic lesions, except 1 lesion, were found in inflamed mucosal areas. Dysplasia was found in 20 of 41 patients with SBA (49%). Dysplasia was flat or raised, low grade or high grade, and adjacent or distant to concomitant SBA. Molecular markers of SBA carcinogenesis complicating CD were similar to those observed in chronic colitis-related colorectal cancer (KRAS, BRAF, p53, MSI), although differences were observed for β-catenin and p16. No PIK3CA mutations were observed. These results suggest that there is an inflammation-dysplasia-adenocarcinoma sequence in at least half of CD-related SBA, similar to what is observed in chronic colitis-related colorectal cancer and may have implications for the prevention and treatment of this cancer.

Implications of the colonic deposition of free hemoglobin-α chain: a previously unknown tissue by-product in inflammatory bowel disease.

We analyzed inflamed mucosal/submucosal layers of ulcerative colitis (UC = 63) and Crohn's colitis (CC = 50), and unexpectedly, we unveiled a pool of free hemoglobin alpha (Hb-α) chain. Patients with colitides have increased reactive oxidative stress (ROS), DNA oxidation products, free iron in mucosa, in preneoplastic, and in colitis-cancers and increased risks of developing colorectal cancer. All inflammatory bowel disease-related colorectal cancer lesions are found in segments with colitis. Linking this information, we investigated whether free Hb-α is key transformational stepping that increases colitis-related colorectal cancer vulnerability. UC/CC samples were profiled using matrix-assisted laser desorption/ionization mass spectrometry; protein identification was made by liquid chromatography. Diverticulitis was used as control (Ctrl). The presence of Hb(n) (n = α, β, or hemin)/Hb was validated by Western blotting and immunohistochemistry. We tested for DNA damage (DNAD) by exposing normal colonic epithelial cell line, NCM460, to 10 μM and 100 μM of Hb(n)/Hb, individually for 2, 6, and 12 hours. Quantification of Hb-α staining was done by Nikon Elements Advance Research Analysis software. ROS was measured by the production of 8-OHdG. DNAD was assessed by Comet assay. Colonic tissue homogenate antioxidants Nrf2-, CAT-, SOD-, and GPx-expressions were analyzed densitometrically/normalized by β-actin. Immunohistochemistry of CC/UC mucosal/submucosal compartments stained strongly positive for Hb-α and significantly higher versus Ctrl. NCM460 exposed to Hb(n)/Hb exhibited steadily increasing ROS and subsequent DNAD. DNAD was higher in 10 μM than 100 μM in Hb-β/hemin the first 2 hours then plateaued followed by DNAD repair. This may be likely due to apoptosis in the later concentration. Nrf2 enzyme activities among UC, CC, and ulcerative colitis-associated colon cancer (UCAC) were observed impaired in all inflammatory bowel disease subjects. Decreased levels of Nrf2 among patients with UC versus patients with CC with active disease were insignificant as well as versus Ctrls but significantly lower in UCAC versus Ctrl. SOD was decreased in UC and UCAC and GPx in CC but statistically not significant. Comparing CC versus UC, SOD was significantly lower in CC (P < 0.05). CAT was observed increased among patients with CC/UC/UCAC and GPx in UC and UCAC versus Ctrl, respectively, and significantly increased in CC versus Ctrl (P < 0.01). In the colitides, mucosal/submucosal tissue microenvironments demonstrated pool of free Hb-α chain. In vitro exposure of NCM460 cells to Hb(n)/Hb induced ROS and DNAD. Toxic effect of free Hb-α, in colonic epithelial cells, is therefore through production of ROS formation modulated by impairment of antioxidant effects. Targeting reduction-oxidation-sensitive pathways and transcription factors may offer options for inflammatory bowel disease-management and colitis-related cancer prevention.

IL-6-induced DNMT1 activity mediates SOCS3 promoter hypermethylation in ulcerative colitis-related colorectal cancer

Ulcerative colitis (UC) is associated with a high risk of developing colorectal cancer (CRC). The mechanisms by which chronic inflammatory responses in the colon may promote CRC remain only partially understood, but may involve reduced negative regulation of interleukin (IL)-6 signaling towards signal transducer and activator of transcription 3 activation through the loss of SOCS3 expression, unleashing the full carcinogenic potential of this transcription factor. Thus, we analyzed SOCS3 expression in the colon of healthy controls, as well as in a cohort of UC patients with varying degrees of dysplasia. We observe that the loss of epithelial SOCS3 expression delimits the areas subject to dysplasia in UC, suggesting an important tumour-suppressive role of SOCS3 downregulation, early in the transformation process. Importantly, methylation of the SOCS3 promotor appears to constitute an important regulatory mechanism for colonic SOCS3 expression as SOCS3 methylation status in CRC cells correlates with a disability to upregulate SOCS3 upon IL-6 stimulation, whereas forced demethylation using 5-aza-2'-deoxycytidine restores SOCS3 expression and inhibits IL-6-induced p-signal transducer and activator of transcription 3 activation and proliferation. Expression of the DNA methyltransferase gene DMNT1 is prominent in dysplastic cells and correlates with low or absent SOCS3 expression. Thus, induction of DNMT1 expression in the chronically inflamed colon may release IL-6 signaling towards signal transducer and activator of transcription 3 from inhibition through SOCS3 increasing the propensity to malignant transformation. Hence, DNMT1 emerges as a rational target in preventive strategies aimed at counteracting UC-CRC.

Abstract LB-285: Blocking Dll4/Notch signaling inhibits development of chronic colitis-associated colorectal cancer in mice

Abstract Colorectal cancer (CRC) is one of the most frequent cancers worldwide, often developing as a complication of inflammatory bowel diseases. The Notch pathway plays a central role in intestinal homeostasia and its deregulation contributes to tumor development. Inhibition of Notch signaling through the Dll4 ligand shows anti-tumor activity against a variety of human and rodent tumors grafted in mice. The aim of this work was to analyze Dll4 expression in both normal intestine and intestinal tumors, and determine the effect of Dll4 inhibition by using Dll4 heterozygous mice or administering a pharmacological inhibitor (soluble Dll4-Fc) in the mouse model of chemically induced colo-rectal cancer (CRC). To induce chronic colitis and CRC we combined the administration of azoxymethane, and repeated cycles of the proinflammatory dextran sodium sulfate in the drinking water, as previously described (Neufert et al. Nat Protoc 2: 1998) in either Dll4+/− mice or wild type mice treated with sDll4-Fc at a dose of 5mg/Kg/day, IP, 3x/wk from week 10 of AOM plus DSS treatment to week 14. Dll4 expression was detected in the vascular endothelium as well as in both absorptive and secretive epithelium of the normal intestine and colorectal (CR) polyps. Both genetical (Dll4 allelic deletion, Dll4+/−) and pharmacological inhibition by the soluble extracellular domain of Dll4 (Dll4-Fc) led to significant reductions in the average number (12.5-fold in mutants, 3.7-fold in Dll4-Fc treated), average volume (1.6-fold in mutants, 2.3-fold in Dll4-Fc treated) and overall burden (15.2-fold in mutants, 6.3-fold in Dll4-Fc treated) of CR polyps, by inducing intratumoral apoptosis and disrupting proper tumor angiogenesis., leading to the formation of immature and non-functional blood vessels. Dll4 heterozygous mutants shown a 42.5% increase in tumor vascular density and a 13.9 % decrease in smooth muscle cell vascular recruitment, displaying increased vascular permeability and reduce vascular perfusion. Dll4-Fc treated mice displayed more proeminent vascular disruption, with a 127.5% increase in tumor vascular density and a 53.2% decrease in smooth muscle cell vascular recruitment, showing extensive vascular extravasation and poor perfusion of the tumor blood vessels. In conclusion, Dll4Fc administration in chronic colitis-related CRC appears to constitute a promising therapeutical approach, capable of inhibiting the tumorigenic events as well as targeting the tumour vasculature and preventing tumor development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-285. doi:10.1158/1538-7445.AM2011-LB-285

5-Aminosalicylic Acid Therapy and the Risk of Colorectal Cancer Among Patients with Inflammatory Bowel Disease

Patients with inflammatory bowel disease (IBD) affecting the colon are at increased risk of developing colorectal cancer (CRC). Published data are conflicting about whether 5-aminosalicylic acid (5-ASA) has chemopreventive properties against IBD-related carcinogenesis. The objective of this observational study was to determine if an association between 5-ASA therapy and CRC risk exists in IBD patients. Adult patients with a new CRC diagnosis (n = 18,440) were identified from 2 large administrative claims databases. For each case, 20 control patients with no record of CRC diagnosis or bowel surgery (n = 368,800) were identified. An IBD diagnosis was associated with a 6- to 7-fold increased risk of CRC (ulcerative colitis, crude odds ratio [OR] = 6.72, 95% CI, 5.79-7.81; Crohn's disease, crude OR = 6.60, 95% CI, 5.56-7.82). Among patients with IBD (364 CRC cases, 1172 controls), exposure to 5-ASA therapy of any dose or duration during the 12 months before CRC diagnosis was not associated with a reduced risk of CRC (OR = 0.97; 95% CI, 0.77-1.23). However, there was a trend toward a decreased risk of CRC with increasing number of mesalamine prescriptions in the previous year, though statistical significance was not achieved (trend P = 0.08). Treating IBD patients with 5-ASA medications was not found to have a protective effect against colitis-related CRC when assessed over a short period of exposure.

Mesalamine in IBD: Multiple hats?

Mesalamine in IBD: Multiple hats?