Development Of Cancer In Ulcerative Colitis Research Articles

A systematic review of the role of DNA methylation on inflammatory genes in ulcerative colitis.

Ulcerative colitis (UC) is an idiopathic disease of the large intestine with evidence pointing to the role of epigenetic changes. Searches were performed in three databases (EMBASE, MEDLINE and Web of Science), following PRISMA protocol. DNA methylation was the only epigenetic mechanism affecting genes linked to inflammatory response in UC. A total of 25 differentially methylated inflammatory genes were identified. Hypermethylation of miR-1247 significantly correlates (p = 0.0006) with refractory UC while PAR2 hypermethylation correlates (p = 0.007) with corticosteroid dependence. Evidence points to a step-wise increase in methylation status of the genome between a healthy colon, quiescent UC and when inflamed. Inflammatory genes (which are aberrantly methylated), have also been implicated in cancer development in UC.

Effect of PLCε gene silencing on inhibiting the cancerous transformation of ulcerative colitis.

The aim of the present study was to investigate the effect of phosphoinositide-specific phospholipase Cε (PLCε) gene silencing on the inhibition of cancer development in ulcerative colitis (UC) and to explore the pathogenesis and carcinogenic mechanism of UC, in order to facilitate the establishment of novel strategies for the treatment of UC, prevent the cancerous transformation of UC and discern the association between inflammation and cancer. A pGenesil-PLCε RNA interference vector was constructed and transfected into HEK293 cells (pGenesil-PLCε group). HEK293 cells transfected with pGenesil empty plasmid were set as the negative control (pGenesil-NC group). The expression of PLCε was observed, and molecules associated with the PLC signaling pathway were detected using a reverse transcription-quantitative polymerase chain reaction and western blotting. ELISA was used to determine the expression of serum interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) of mice in which the PLCε gene had been silenced. Compared with the pGenesil-NC group, the mRNA and protein levels of PLCε were significantly decreased in the pGenesil-PLCε group. In addition, the mRNA levels of K-ras, NF-κB, Fas and Bcl-2 were markedly reduced, while P53 mRNA level was notably enhanced, in the pGenesil-PLCε group, and these changes were accompanied by similar changes in the corresponding protein levels. The serum IL-1 and TNF-α expression in the PLCε gene-silenced mice was significantly reduced compared with that in the control mice. In conclusion, PLCε RNA silencing can effectively inhibit the cancerous transformation of UC by regulating the colorectal cancer-related cell proliferation and cell cycle in vivo. In addition, PLCε RNA silencing can suppress the expression of inflammatory factors in vitro.

ERK controls epithelial cell death receptor signalling and cellular FLICE-like inhibitory protein (c-FLIP) in ulcerative colitis

Intestinal epithelial cell (IEC) death signalling through the Fas receptor is impaired in active ulcerative colitis (UC). This is possibly due to the activation of cytoprotective pathways resulting in limitation of the tissue injury secondary to inflammation. We hypothesized that inflammatory signalling like the nuclear factor (NF)-κB or mitogen activated protein kinase (MAPK) pathways could be involved in (a) the modification of Fas mediated apoptosis responses and (b) the regulation of the Fas receptor inhibitor cellular FLICE-like inhibitory protein (c-FLIP). Phospho-ERK was upregulated in IECs in active UC as well as IECs exposed to pro-inflammatory cytokines in vitro. Similarly, the short form of c-FLIP (c-FLIPS) was found to be upregulated in IECs from patients with active UC. c-FLIPS was the main splice variant found in both HT-29 cells and primary human IECs. Both splice variants were induced by TNF-α, IL-1β and IFN-γ, while IL-10 induced c-FLIPL expression; TNF-α also induced c-FLIPS in primary IECs. Inhibition of NF-κB, JNK and p38 pathways did not affect c-FLIP expression, whereas ERK inhibition by MEK1 RNA silencing and pharmacologic inhibitors decreased c-FLIPS expression. Similarly, ERK - but not NF-κB - inhibited Fas ligand and TNF-α-mediated apoptosis responses in both cell line experiments and primary IECs. The present study identifies the MEK-ERK pathway as a major regulator of apoptosis in IECs during flares of UC and an inducer of c-FLIPS. The results explain the resistance to receptor mediated epithelial apoptosis in active UC. Oncogenic c-FLIP could promote propagation of DNA-damaged IECs and contribute to cancer development in UC.

A Rare Finding of Dysplasia Associated Mass or Lesion 6 Months after Diagnosis of Ulcerative Colitis

Purpose: A 19-year-old female was evaluated for loose stools of several years duration. Lab work revealed a normal hematocrit, c-reactive protein, albumin, and erythrocyte sedimentation rate. Stool studies were negative for infection. A colonoscopy found severe pancolitis consistent with ulcerative colitis (UC). Systemic steroids and a 5-aminosalicylic acid derivative were initiated. Repeat colonoscopy 6 months later was significant for a carpet like lesion at 25 cm from the anal verge in an otherwise normal appearing colon. Biopsies contained low grade dysplasia within the lesion and the surrounding mucosa, consistent with a dysplasia associated non-adenoma like lesion or mass (DALM). The patient underwent a total proctocolectomy with J pouch formation and ileoanal anastomosis. Upon follow up she was doing well. In inflammatory bowel disease (IBD), dysplasia is defined as unequivocal neoplastic epithelium that is confined to the basement membrane without invasion into the lamina propria. The rate at which colitic mucosa progresses to dysplasia, and ultimately to colorectal cancer (CRC) is unknown. The molecular biology of cancer in IBD is unique in that the accumulation of molecular and genetic alterations may occur more rapidly or in an unconventional sequence when compared to sporadic CRC. The duration and extent of colitis, early age of onset of colitis, family history of CRC, coexistent primary sclerosing cholangitis, and severity of microscopic inflammation are risk factors for the development of cancer in UC. Elevated lesions that are endoscopically visible, but not amenable to endoscopic resection are referred to as dysplasia associated lesion or mass (DALM). In a series of 12 patients with a DALM who underwent colectomy, 7 were found to have invasive carcinoma. One in 8 patients with UC will have dysplasia or cancer found on their initial screening colonoscopy. Patients with greater than 10 years of disease and those with extensive disease (pancolitis) are at highest risk for cancer. The incidence rate increases with each successive decade of disease activity, with cumulative probabilities of 2% at 10 years, 8% at 20 years, and 18% at 30 years. More recent data suggests that the risk may be on the decline with 0.6% after 10 years, 5.4% after 20 years, and 7.5% after 30 years of chronic UC. We present a case of UC with findings of a DALM that led to proctocolectomy only 6 months after the diagnosis of pancolitis in a 19-year-old patient. This presentation of a DALM is unusual because of the short duration of known UC and the patient's young age.

Serrated neoplasias and de novo carcinomas in ulcerative colitis: A histological study in colectomy specimens

Cancer in ulcerative colitis (UC) originates in dysplastic crypts, adenomatous growths (UCAG), and UC-associated adenomas (UCAD). The aim of the present study was to compare the histological phenotypes between UCAG, UCAD, and sporadic colorectal adenomas in non-colitics (non-UCAD), as well as between UC-associated carcinomas (UCC) and carcinomas in non-colitic patients (non-UCC). Three thousand and forty nine sections from 96 colectomy specimens in patients with UC-pancolitis and carcinoma were reviewed. Villous phenotypes were more frequent in UCAG (48%) than in UCAD (26%) and non-UCAD (11%), and serrated phenotypes more frequent in UCAD (29%) than in UCAG (12%) and non-UCAD (8%). Tubular phenotypes were far less frequent in UCAG (14%) than in UCAD (45%) and non-UCAD (80%). Villous and signet ring cell cancer phenotypes were more frequent in UCC (22% and 8%, respectively) than in non-UCC (9% and 0.8%, respectively). Six UCC (5.6%) were de novo carcinomas. Invasive carcinomas were found in one-half of the UCAG and in one-third of the UCAD, indicating that both lesions are important in cancer development in UC. The different proportions of histological phenotypes found in UCAG, UCAD, and non-UCAD on the one hand, and UCC and non-UCC on the other, suggest that chronic protracted inflammation might have modified the stem cell receptors that receive the molecular signals that program structural configurations in neoplastic glands. This is the first study reporting the occurrence of serrated and microtubular UCAG and of de novo carcinomas in UC.

Gene Expression Signature and the Prediction of Ulcerative Colitis–Associated Colorectal Cancer by DNA Microarray

Ulcerative colitis (UC) is associated with a high risk of colorectal cancer. To identify genes that could predict the development of cancer in UC, we conducted a DNA microarray analysis using nonneoplastic rectal mucosa of UC patients. Gene expression in nonneoplastic mucosa of 53 UC patients were examined. Gene expression profiles were examined using human Genome U133 Plus 2.0 gene chip array (Affymetrix). Among 53 UC patients, 10 had UC-associated cancer (UC-Ca group) whereas 43 did not (UC-NonCa group). By comparing gene expression profiles of nonneoplastic rectal mucosae between the UC-Ca and UC-NonCa groups, we could identify 40 genes that were differentially expressed between two groups. The list of discriminating genes included low-density lipoprotein receptor-related protein (LRP5 and LRP6). Previous studies suggested that LRP5 and LRP6 expression promotes cancer cell proliferation and tumorigenesis and are considered as candidate oncogenes. In the present study, both LRP5 and LRP6 showed significantly higher expression in the UC-Ca group, which suggests the importance of these genes in the development of UC-associated colorectal cancers. With the 40 selected discriminating genes, we did class prediction of the development of colorectal neoplasms in UC patients. Using the k-nearest neighbor method and the support vector machine, we could predict the development of UC-associated neoplasms with an accuracy of 86.8% and 98.1%, respectively. These findings have important implications for the early detection of malignant lesions in UC and may provide directions for future research into the molecular mechanisms of UC-associated cancer.

Adenocarcinoma of the ileoanal pouch for ulcerative colitis—a complication of severe chronic atrophic pouchitis?

The appearance of a carcinoma in the ileal pouch after restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative proctocolitis is rare. Most of these adenocarcinomas previously described in literature develop from residual viable rectal mucosa. We report a case of an adenocarcinoma arising in all probability from the ileal pouch after malignant transformation of the ileal pouch mucosa based on a chronic atrophic pouchitis. A 34-year-old man developed an adenocarcinoma after a double-stapled ileorectal J-pouch for ulcerative colitis (UC) proceeded from malignant ileal transformation. Before surgery, he had a 20-year history of UC refractory to medical therapy, but no occurrence of backwash ileitis, dysplasia or colitis-associated illness. He experienced severe pouchitis after IPAA since the ileostomy closure. Carcinoma was ensured by endoscopy, and the patient underwent an abdominoperineal pouch extirpation combined with excision of perirectal tissues and anal canal. Histology after surgery showed a pT4,pN2(4/16)pM0,G3 adenocarcinoma with global severe chronic atrophic pouchitis (CAP), villous atrophy and malignant ileal transformation. No metaplasia of the rectal mucosa was found, not even malignant epithelial transformation of the anal canal. This case suggests that a malignant transformation of the ileal pouch mucosa may occur as a pure complication of severe CAP, even in the absence of backwash ileitis or a previous history of cancer. The absence of metaplasia of the rectal mucosa revealed the passage from CAP to dysplastic epithelium and to cancer. A multifactorial development of carcinogenesis is supposed, but we emphasize the importance of severe CAP, and that careful surveillance is needed in patients after IPAA. We must submit that this is just a case report and cannot stand for general cancer development in ulcerative colitis, but it may point out the risk factor of chronic inflammation and leads the surgeon to skillful working when building the pouch.

Ulcerative colitis with low-grade dysplasia

37-year-old woman with a 17-year history of ulerative colitis that extends up to the mid-descendng colon undergoes routine surveillance colonosopy. Her disease is quiescent at the time of the rocedure (and has been for 5 years) and no lesions r masses are identified. Thirty-six biopsies are aken from 10-cm intervals up to the cecum. Histoogical exam reveals findings consistent with idioathic inflammatory bowel disease in the rectum, igmoid colon, and descending colon. Three biopies from her sigmoid colon are reported as lowrade dysplasia. The biopsies are sent to a local niversity pathologist with a special interest in GI athology, and she suggests that the biopsies are ndeterminate for dysplasia. The patient returns for repeat dysplasia surveillance endoscopy 3 months ater and 8 extra biopsies are obtained from the igmoid and descending colon. Four biopsies from er sigmoid colon are identified as containing lowrade dysplasia, and there is agreement between the pathologists.

Microsatellite instability in inflamed and neoplastic epithelium in ulcerative colitis

Background—Several genetic alterations have been documented in dysplasia and cancer developing in ulcerative colitis (UC). However, the microsatellite instability (MSI) status has rarely been described, especially in the inflamed epithelium...

Histochemical study of colonic cancer in experimental colitis of rats.

A reliable test for premalignant lesions in the development of colonic cancer in chronic ulcerative colitis has been needed. Thus, we designed this cytochemical study, using a model of experimental colitis and colonic tumors induced in Wistar male rats by the feeding of dextran sulfate sodium. The colitis had histologic similarities to ulcerative colitis in man. The percent frequency of polypoid lesions (dysplasia or dysplasia with carcinoma in situ) in the cecum and ascending colon was about 25% at three months and 90% at six months of dextran sulfate feeding. The cytochemical findings by high-iron diamine-Alcian blue staining and Ulex europeus agglutinin binding were chronologically paralleled by histological changes in the colonic mucosa, and the binding pattern of peanut agglutinin was not different between normal and dextran-treated animals. Moreover, some cytochemical changes that occurred during the inflammatory responses were not present in dysplastic or malignant lesions. Thus, the histochemical tests were not useful for detecting of premalignant lesions earlier than by conventional histology. Nevertheless, the dextran sulfate model of colitis in the rat appears suitable for study of cancer development in ulcerative colitis.

ILEORECTAL ANASTOMOSIS—FRIEND OR FOE?*

Ileorectal anastomosis is a controversial operation. Its use has been promoted for the management of colonic cancer, familial polyposis, Crohn's disease, ulcerative colitis and in several rarer conditions. In the treatment of ulcerative colitis controversy has centered on the risk of malignant change in the retained rectum and on the long term quality of function. E. S. R. Hughes has been a proponent of this procedure and is one of those able to report a major series with long term follow-up of function and cancer development in ulcerative colitis. Of 364 colitics treated by resection, 43% were selected for this operation. This group showed a success rate of 72% and after 15 years 57% remained functional. The probability of malignant change has reached 14% at 27 years with 8% of the series developing rectal carcinoma. The probability of this development following a diagnosis of moderate or severe mucosal dysplasia reached 42% at 13 years from histological assessment. Ileorectal anastomosis has a high degree of acceptability in appropriately selected ulcerative colitics; its continuing use is dependent on surveillance of sufficient quality to predict cancerous change or to detect it earlier enough to effect cure by proctectomy.