Polyps of colon and small intestine [keywords]
- GLP-1R agonists promote normal and neoplastic intestinal growth through mechanisms requiring Fgf7. [Journal Article, Research Support, Non-U.S. Gov't]
- Cell Metab 2015 Mar 3; 21(3):379-91.
Glucagon-like peptide-1 (GLP-1) secreted from enteroendocrine L cells promotes nutrient disposal via the incretin effect. However, the majority of L cells are localized to the distal gut, suggesting additional biological roles for GLP-1. Here, we demonstrate that GLP-1 receptor (GLP-1R) signaling controls mucosal expansion of the small bowel (SB) and colon. These actions did not require the epidermal growth factor (EGF) or intestinal epithelial insulin-like growth factor (IGF1) receptors but were absent in Glp1r(-/-) mice. Polyp number and size were increased in SB of exendin-4-treated Apc(Min/+) mice, whereas polyp number was reduced in SB and colon of Glp1r(-/-):Apc(Min/+) mice. Exendin-4 increased fibroblast growth factor 7 (Fgf7) expression in colonic polyps of Apc(Min/+) mice and failed to increase intestinal growth in mice lacking Fgf7. Exogenous exendin-4 and Fgf7 regulated an overlapping set of genes important for intestinal growth. Thus, gain and loss of GLP-1R signaling regulates gut growth and intestinal tumorigenesis.
- Paediatric surgical pathology - a profile of cases from Western India and review of literature. [Journal Article]
- J Clin Diagn Res 2015 Jan; 9(1):EC08-11.
The paediatric surgical pathology specimens manifest a wide spectrum of morphological and histological features. The present work has been undertaken to know the prevalence and to describe the profile of paediatric surgical pathology specimens from western India as seen in Ahmedabad, India from 2008 to 2010.We reviewed 140 paediatric surgical specimens, 118 specimens rendered definitive diagnosis were included for the analysis. Cases were divided in two groups, one of developmental and congenital conditions and another of acquired lesions.This study included 118 patients of which 79.3 % were male and 20.7 % were female. Age range of the patients was one day to twelve years. Children of one month to one year age group (infants) were the most vulnerable (31.3% cases). Group of developmental and congenital conditions consisted of 45.7% cases where as 55.3 % cases were of acquired lesions. Gastrointestinal tract was most frequently affected organ (43.2%) followed by head and neck region (14.4%) and testis (7.6%). Hirschsprung's disease (HD) cases (6.7%) were commonest among the group of developmental and congenital conditions followed by juvenile polyps of colon (5%), Meckel's diverticulum of small intestine (5%) and neural tube defect (5%). In acquired lesions, Appendicitis was the most frequent lesion (21.2%) followed by haemorrhagic infarct of testis due to torsion (5%) and intussuception of intestine (5%). Malignant cases were (4.2%) and the most common cancer was yolk sac tumour.Paediatric surgical specimens, unlike adults, represent significant number of developmental and congenital conditions in addition to acquired lesions; accounting for wide spectrum of morphological and histological features. Study provides insight into the trends of paediatric surgical lesions in the western region of India.
- Characterization of LGR5 stem cells in colorectal adenomas and carcinomas. [Journal Article, Research Support, Non-U.S. Gov't]
- Sci Rep 2015.:8654.
LGR5 is known to be a stem cell marker in the murine small intestine and colon, however the localization of LGR5 in human adenoma samples has not been examined in detail, and previous studies have been limited by the lack of specific antibodies. Here we used in situ hybridization to specifically examine LGR5 mRNA expression in a panel of human adenoma and carcinoma samples (n = 66). We found that a small number of cells express LGR5 at the base of normal colonic crypts. We then showed that conventional adenomas widely express high levels of LGR5, and there is no evidence of stereotypic cellular hierarchy. In contrast, serrated lesions display basal localization of LGR5, and the cellular hierarchy resembles that of a normal crypt. Moreover, ectopic crypts found in traditional serrated adenomas show basal LGR5 mRNA, indicating that they replicate the stem cell organization of normal crypts with the development of a cellular hierarchy. These data imply differences in the stem cell dynamics between the serrated and conventional pathways of colorectal carcinogenesis. Furthermore we noted high LGR5 expression in invading cells, with later development of a stem cell niche in adenocarcinomas of all stages.
- Evaluation of preventive and therapeutic activity of novel non-steroidal anti-inflammatory drug, CG100649, in colon cancer: Increased expression of TNF-related apoptosis-inducing ligand receptors enhance the apoptotic response to combination treatment with TRAIL. [Journal Article, Research Support, Non-U.S. Gov't]
- Oncol Rep 2015 Apr; 33(4):1947-55.
Non-steroidal anti-inflammatory drugs (NSAIDs) have been suggested as the potential new class of preventive or therapeutic antitumor agents. The aim of the present study was to evaluate the antitumor activity of the novel NSAID, CG100649. CG100649 is a novel NSAID dual inhibitor for COX-2 and carbonic anhydrase (CA)-I/-II. In the present study, we investigated the alternative mechanism by which CG100649 mediated suppression of the colon cancer growth and development. The anchorage‑dependent and -independent clonogenic assay showed that CG100649 inhibited the clonogenicity of human colon cancer cells. The flow cytometric analysis showed that CG100649 induced the G2/M cell cycle arrest in colon cancer cells. Animal studies showed that CG100649 inhibited the tumor growth in colon cancer xenograft in nude mice. Furthermore, quantitative PCR and FACS analysis demonstrated that CG100649 upregulated the expression of TNF-related apoptosis-inducing ligand (TRAIL) receptors (DR4 and DR5) but decreased the expression of decoy receptors (DcR1 and DcR2) in colon cancer cells. The results showed that CG100649 treatment sensitized TRAIL‑mediated growth suppression and apoptotic cell death. The combination treatment resulted in significant repression of the intestinal polyp formation in APCmin/+ mice. Our data clearly demonstrated that CG100649 contains preventive and therapeutic activity for colon cancer. The present study may be useful for identification of the potential benefit of the NSAID CG100649, for the achievement of a better treatment response in colon cancer.
- NKD1 marks intestinal and liver tumors linked to aberrant Wnt signaling. [Journal Article, Research Support, Non-U.S. Gov't]
- Cell Signal 2015 Feb; 27(2):245-56.
The activity of the Wnt pathway undergoes complex regulation to ensure proper functioning of this principal signaling mechanism during development of adult tissues. The regulation may occur at several levels and includes both positive and negative feedback loops. In the present study we employed one of such negative feedback regulators, naked cuticle homolog 1 (Nkd1), to follow the Wnt pathway activity in the intestine and liver and in neoplasia originated in these organs. Using lineage tracing in transgenic mice we localized Nkd1 mRNA to the bottom parts of the small intestinal crypts and hepatocytes surrounding the central vein of the hepatic lobule. Furthermore, in two mouse models of intestinal tumorigenesis, Nkd1 expression levels were elevated in tumors when compared to healthy tissue. We utilized a collection of human intestinal polyps and carcinomas to confirm that NKD1 represents a robust marker of neoplastic growth. In addition, expression analysis of NKD1 in liver cancer showed that high expression levels of the gene distinguish a subclass of hepatocellular carcinomas related to aberrant Wnt signaling. Finally, our results were confirmed by bioinformatic analysis of large publicly available datasets that included gene expression profiling and high-throughput sequencing data of human colon and liver cancer specimens.
- Multilabel region classification and semantic linking for colon segmentation in CT colonography. [Journal Article]
- IEEE Trans Biomed Eng 2015 Mar; 62(3):948-59.
Accurate and automatic colon segmentation from CT images is a crucial step of many clinical applications in CT colonography, including computer-aided detection (CAD) of colon polyps, 3-D virtual flythrough of the colon, and prone/supine registration. However, the existence of adjacent air-filled organs such as the lung, stomach, and small intestine, and the collapse of the colon due to poor insufflation, render accurate segmentation of the colon a difficult problem. Extra-colonic components can be categorized into two types based on their 3-D connection to the colon: detached and attached extracolonic components (DEC and AEC, respectively). In this paper, we propose graph inference methods to remove extracolonic components to achieve a high quality segmentation. We first decompose each 3-D air-filled object into a set of 3-D regions. A classifier trained with region-level features can be used to identify the colon regions from noncolon regions. After removing obvious DEC, we remove the remaining DEC by modeling the global anatomic structure with an a priori topological constraint and solving a graph inference problem using semantic information provided by a multiclass classifier. Finally, we remove AEC by modeling regions within each 3-D object with a hierarchical conditional random field, solved by graph cut. Experimental results demonstrate that our method outperforms a purely discriminative learning method in detecting true colon regions, while decreasing extra-colonic components in challenging clinical data that includes collapsed cases.
- Cdx1 and Cdx2 function as tumor suppressors. [Journal Article]
- J Biol Chem 2014 Nov 28; 289(48):33343-54.
In humans, colorectal cancer is often initiated through APC loss of function, which leads to crypt hyperplasia and polyposis driven by unrestricted canonical Wnt signaling. Such polyps typically arise in the colorectal region and are at risk of transforming to invasive adenocarcinomas. Although colorectal cancer is the third most common cause of cancer-related death worldwide, the processes impacting initiation, transformation, and invasion are incompletely understood. Murine APC(Min/+) mutants are often used to model colorectal cancers; however, they develop nonmetastatic tumors confined largely to the small intestine and are thus not entirely representative of the human disease. APC(Min/+) alleles can collaborate with mutations impacting other pathways to recapitulate some aspects of human colorectal cancer. To this end, we assessed APC(Min/+)-induced polyposis following somatic loss of the homeodomain transcription factor Cdx2, alone or with a Cdx1 null allele, in the adult gastrointestinal tract. APC(Min/+)-Cdx2 mutants recapitulated several aspects of human colorectal cancer, including an invasive phenotype. Notably, the concomitant loss of Cdx1 led to a significant increase in the incidence of tumors in the distal colon, relative to APC(Min/+)-Cdx2 offspring, demonstrating a previously unrecognized role for this transcription factor in colorectal tumorigenesis. These findings underscore previously unrecognized roles for Cdx members in intestinal tumorigenesis.
- Capsule endoscopy followed by single balloon enteroscopy in children with obscure gastrointestinal bleeding: a combined approach. [Journal Article]
- Dig Liver Dis 2015 Feb; 47(2):125-30.
This prospective single-centre study aims to evaluate a new diagnostic algorithm using capsule endoscopy, colon capsule endoscopy and single-balloon enteroscopy in the work-up of obscure gastrointestinal bleeding in children.The usefulness of a new diagnostic algorithm was assessed comparing the clinically relevant findings revealed by each technique, and evaluating the clinical outcomes during the follow-up.A total of 22 paediatric patients were evaluated (14 male; mean age 12.5 years ± 3.9). Capsule endoscopies were positive in 14 (63.6%), suspicious in 5 (22.7%) and negative in 3 (13.6%). A second look with colon capsule identified new lesions in 2/3 (67%) of previous negative cases. Enteroscopies were able to reach the positive and suspicious findings in all but 2, in which an intraoperative enteroscopy was needed. This combined approach showed positive findings in 21/22 of cases with a diagnostic yield of 95%. Eighteen patients (82%) had a complete resolution after therapy. One patient resolved his symptoms spontaneously. Despite diagnosis, in three patients (13.6%) the gastrointestinal bleeding was not resolved after therapy.This algorithm achieves optimal levels of diagnostic yield (95%) and therapeutic outcome (82%). This approach deserves to be studied in a larger multicentre cohort of patients and for a longer follow-up period.
- Multiple mucin depleted foci, high proliferation and low apoptotic response in the onset of colon carcinogenesis of the PIRC rat, mutated in Apc. [Journal Article, Research Support, Non-U.S. Gov't]
- Int J Cancer 2015 Mar 15; 136(6):E488-95.
PIRC rats (F344/NTac-Apc (am1137) ) mutated in the Apc gene spontaneously develop colon tumors thus mimicking familial adenomatous polyposis (FAP) and sporadic colorectal cancer (CRC) more closely than Apc-based rodent models developing tumors mostly in the small intestine. To understand whether microscopic dysplastic lesions precede the development of macroscopic tumors, PIRC rat colon was examined for the presence of mucin depleted foci (MDF), microadenomas of the rodent and human colon. Few MDF (about 4/animal) were already present in 1-month-old rats and their number rapidly increases to about 250 in 8-month-old rats. These lesions showed Wnt signaling activation (nuclear β-catenin accumulation) and were dramatically decreased by sulindac (320 ppm), a drug with chemopreventive activity (MDF/rat at 4 months: 156 ± 8 and 38 ± 6 in controls and sulindac-treated rats, respectively, means ± SE, p < 0.001). Since altered proliferation and apoptosis could underlie the early phases of carcinogenesis, we studied these processes in the apparently normal colon mucosa (NM) of 1-month-old PIRC and wt rats. Colon proliferation (PCNA expression) was significantly higher in PIRC rats. Notably, PIRC rat NM showed resistance to apoptosis since it sustained proliferation and had lower apoptosis after a cytotoxic insult with 1,2 dimethylhydrazine. Gene expression of Myc, p21, Birc5, Ogg1, Apex1 and Sod2 were significantly up-regulated in the NM of PIRC rat. The overall results put forward PIRC rat as useful model of colon carcinogenesis, either to study the process itself or to test in vivo chemopreventive agents in both short- and long-term studies.
- The concentrations of EGFR, LRG1, ITIH4, and F5 in serum correlate with the number of colonic adenomas in ApcPirc/+ rats. [Journal Article, Research Support, N.I.H., Extramural]
- Cancer Prev Res (Phila) 2014 Nov; 7(11):1160-9.
The development of noninvasive methods for early detection of colon cancer is critical for the successful management of this disease. Using a targeted quantitative proteomics technique, we assessed the ability of 12 serum proteins to detect the presence of colonic polyps in the Apc(Pirc) (/+) rat model of familial colon cancer. Serum protein candidates were selected from gene transcripts upregulated in colonic tumors of Apc(Pirc) (/+) rats and from a prior study of serum proteins differentially expressed in mice carrying intestinal adenomas. Proteins were quantified at early stages of polyp formation in a rat cohort monitored longitudinally by colonoscopy over a period of 75 days. Of the 12 proteins monitored at three distinct time points, seven showed differential expression in at least one time point in the serum from Apc(Pirc) (/+) rats compared with wild-type rats. Tumor multiplicity correlated with protein expression changes, and most tumors grew during the study. EGFR, LRG1, ITIH4, and F5 displayed the most robust tumor-associated protein expression changes over time. Receiver operator characteristic analysis using these four proteins resulted in a sensitivity of 100%, a specificity of 80%, and an area under the curve of 0.93 at 135 days of age, when the Pirc rats bore an average of 19 tumors in the colon and seven in the small intestine. The results of this study demonstrate that the quantitative analysis of a panel of serum proteins can detect the presence of early intestinal tumors in a rat model, and provides support for future measurements in humans.