- Peutz-Jeghers syndrome: early clinical expression of a new STK11 gene variant. [Case Reports]
- BCBMJ Case Rep 2015; 2015
- Genetic heterogeneity has been recognised in Peutz-Jeghers syndrome (PJS) (over 230 STK11 gene mutations reported). We report a rare PJS phenotype with early extensive gastrointestinal (GI) presentat...
Genetic heterogeneity has been recognised in Peutz-Jeghers syndrome (PJS) (over 230 STK11 gene mutations reported). We report a rare PJS phenotype with early extensive gastrointestinal (GI) presentation and a new genetic variant. The case presented as haematochezia and mucocutaneous pigmentation (the patient was 3 years of age). Endoscopy showed several polyps throughout the stomach/colon (PJ-type hamartomas); the larger polyps were resected. Small bowel imaging detected multiple jejunum/ileum small polyps. During 8 years of follow-up of this asymptomatic patient, an increasing number of diffusely distributed polyps was observed and polypectomies were performed. Subsequently, the patient failed consultations; when the patient was 13 years of age, emergency surgery was required due to small bowel intussusception (ileal polyp). A STK11 gene study identified two missense variants in heterozygous (yet unknown significance but probably pathogenic): c.854T>A (exon 6) and c.446C>T* (exon 2) (*not previously reported). We report two STK11 gene variants (one not previously described) of yet undetermined causality in a paediatric patient presenting with extensive GI involvement at a very early age, with no family medical history. Structural and functional repercussion of the newly described variants should be further investigated.
- Increased catabolism and decreased unsaturation of ganglioside in patients with inflammatory bowel disease. [Journal Article]
- WJWorld J Gastroenterol 2015 Sep 21; 21(35):10080-90
- CONCLUSIONS: This study suggests a new paradigm by proposing that IBD occurs as a consequence of increased metabolism of specific gangliosides.
- Apc Restoration Promotes Cellular Differentiation and Reestablishes Crypt Homeostasis in Colorectal Cancer. [Journal Article]
- CellCell 2015 Jun 18; 161(7):1539-52
- The adenomatous polyposis coli (APC) tumor suppressor is mutated in the vast majority of human colorectal cancers (CRC) and leads to deregulated Wnt signaling. To determine whether Apc disruption is ...
The adenomatous polyposis coli (APC) tumor suppressor is mutated in the vast majority of human colorectal cancers (CRC) and leads to deregulated Wnt signaling. To determine whether Apc disruption is required for tumor maintenance, we developed a mouse model of CRC whereby Apc can be conditionally suppressed using a doxycycline-regulated shRNA. Apc suppression produces adenomas in both the small intestine and colon that, in the presence of Kras and p53 mutations, can progress to invasive carcinoma. In established tumors, Apc restoration drives rapid and widespread tumor-cell differentiation and sustained regression without relapse. Tumor regression is accompanied by the re-establishment of normal crypt-villus homeostasis, such that once aberrantly proliferating cells reacquire self-renewal and multi-lineage differentiation capability. Our study reveals that CRC cells can revert to functioning normal cells given appropriate signals and provide compelling in vivo validation of the Wnt pathway as a therapeutic target for treatment of CRC.
- Peutz-jeghers syndrome with synchronous adenocarcinoma arising from ileal polyps. [Journal Article]
- IJIndian J Surg 2015; 77(Suppl 1):100-2
- Peutz-Jeghers syndrome is a rare inherited autosomal disease characterized by mucocutaneous pigmentation and multiple polyps in the gastrointestinal tract. The clinical picture is characterized by re...
Peutz-Jeghers syndrome is a rare inherited autosomal disease characterized by mucocutaneous pigmentation and multiple polyps in the gastrointestinal tract. The clinical picture is characterized by repeated episodes of polyp-induced intestinal obstruction, abdominal pain, and bleeding per rectum. Predisposition to both gastrointestinal and nongastrointestinal malignancies is increased in a patient with Peutz-Jeghers syndrome. This is a case report of a 29-year-old male with Peutz-Jeghers syndrome who presented with a complaint of recurrent abdominal pain. CT scan revealed a single obstructing ileal polyp. However, preoperatively, another large ileal polyp with multiple small jejunal polyps was seen. Histopathology of both ileal polyps was identified as a mucinous adenocarcinoma infiltrating up to the serosa. The follow-up endoscopies showed small multiple polyps in the stomach, duodenum, and colon. Histopathology of all endoscopically removed polyps was consistent with the diagnosis of hamartomatous polyps. Very few cases of intestinal intussusception combined with synchronous malignant small intestine polyps have been reported until to date.
- T-cell Expression of IL10 Is Essential for Tumor Immune Surveillance in the Small Intestine. [Journal Article]
- CICancer Immunol Res 2015; 3(7):806-14
- IL10 is attributed with immune-suppressive and anti-inflammatory properties, which could promote or suppress cancer in the gastrointestinal tract. Loss of IL10 exacerbates colonic inflammation, leadi...
IL10 is attributed with immune-suppressive and anti-inflammatory properties, which could promote or suppress cancer in the gastrointestinal tract. Loss of IL10 exacerbates colonic inflammation, leading to colitis and cancer. Consistent with this, transfer of IL10-competent regulatory T cells (Treg) into mice with colitis or hereditary polyposis protects against disease, while IL10-deficient mice are predisposed to polyposis with increased colon polyp load. Little is known about the protective or pathogenic function of IL10 in cancers of the small intestine. We found CD4(+) T cells and CD4(+) Foxp3(+) Tregs to be the major sources of IL10 in the small intestine and responsible for the increase in IL10 during polyposis in the APC(Δ468) mouse model of hereditary polyposis. Targeted ablation of IL10 in T cells caused severe IL10 deficiency and delayed polyp growth. However, these polyps progressively lost cytotoxic activity and eventually progressed to cancer. Several observations suggested that the effect was due to the loss of IFNγ-dependent immune surveillance. IL10-incompetent CD4(+) T cells failed to secrete IFNγ when stimulated with polyp antigens and were inefficient in T-helper-1 (TH1) commitment. By contrast, the TH17 commitment was unaffected. These findings were validated using mice whose T cells overexpress IL10. In these mice, we observed high intra-polyp cytotoxic activity and attenuation of polyposis. Thus, expression of IL10 by T cells is protective and required for immune surveillance in the small intestine.
- GLP-1R agonists promote normal and neoplastic intestinal growth through mechanisms requiring Fgf7. [Journal Article]
- CMCell 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 ...
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]
- JCJ Clin Diagn Res 2015; 9(1):EC08-11
- CONCLUSIONS: 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]
- SRSci Rep 2015; 5:8654
- 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 be...
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]
- OROncol Rep 2015; 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...
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.
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- NKD1 marks intestinal and liver tumors linked to aberrant Wnt signaling. [Journal Article]
- CSCell Signal 2015; 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 severa...
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.