Guanylyl cyclase C is a marker of intestinal metaplasia, dysplasia and neoplasia of the gastrointestinal tract

Department of Medicine, Fox Chase Cancer Center, Filadelfia, Pennsylvania, United States
Human Pathlogy (Impact Factor: 2.77). 03/2005; 36(2):170-9. DOI: 10.1016/j.humpath.2004.12.002
Source: PubMed


Gastrointestinal (GI) tumors continue to be major causes of cancer-related mortality, in part, reflecting metastases that escape detection by histopathology. Moreover, although approximately 10% of carcinomas arise from unknown locations, these tumors frequently originate in the GI tract. Guanylyl cyclase C (GC-C) is a receptor selectively expressed by intestinal epithelial cells whose persistent expression by colorectal carcinomas and ectopic expression by adenocarcinomas of the upper GI tract suggest its use as a marker for GI malignancies. Here, expression of GC-C protein, identified by immunohistochemistry, was examined in tissues and tumors arising from the human GI tract. Guanylyl cyclase C protein was expressed by epithelial cells from the duodenum to the rectum, but not by those in normal esophagus and stomach. Expression was retained in tubular adenomas, inflammatory bowel disease, premalignant lesions, and in primary and metastatic adenocarcinomas from the colon, including metastases to lymph nodes and liver. Moreover, GC-C was ectopically expressed in all cases of dysplasia and adenocarcinomas arising from intestinal metaplasia in esophagus and stomach. Thus, GC-C appears to be an immunohistochemical marker for identifying adenocarcinomas of unknown origin, metastases in patients undergoing staging for GI adenocarcinomas, and intestinal metaplasia, dysplasia, and tumors arising therein in the upper GI tract.

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    • "In accordance with this, an increased number of intestinal crypts and proliferation of epithelial cells as well as increased tumorigenesis and attenuated apoptosis has been observed in Gucy2c À/À mice and cell lines [30] [31] [32], supporting the concept that reduced GC-C signaling may be favorable for growth and regeneration of a damaged intestinal epithelium. Moreover, GUCY2C is expressed in colonic adenoma and cancer [33]. The GC-C ligand GN, abundantly expressed in the colonic epithelium, however, is lost in colon cancer, leading to reduced GC-C stimulation and oncogenesis [34]. "
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    ABSTRACT: Activation of membrane receptor guanylate cyclase-C (GC-C) is implicated in gastrointestinal fluid and electrolyte balance, preservation of intestinal barrier integrity, anti-trophic effects and inhibition of pain sensation. To evaluate GC-C signaling, we examined the regulation of GC-C (GUCY2C/Gucy2c) and its endogenous ligands guanylin (GN/GUCA2A/Guca2a) and uroguanylin (UGN/GUCA2B/Guca2b) in colonic Crohn's disease (CD), ulcerative colitis (UC) and in rats with 2,4,6-Trinitrobenzene sulphonic acid (TNBS) colitis. Correlation analyses between expression of GUCA2A and GUCY2C and expression of inflammatory cytokines (IL1A, IL1B, TNFA and IFNG) were conducted. Additionally, expression of transcription factors for GUCA2A and GUCY2C, and the GC-C signaling pathway, were examined. Biopsies from active UC/CD, un-inflamed UC/CD and healthy controls, and inflamed and healthy rat colon were investigated with gene expression microarray, immunohistochemistry (IHC) and in situ hybridization (ISH). GUCA2A/Guca2a, GUCA2B, GUCY2C/Gucy2c, transcription factors, as well as several cyclic guanosine-3',5'-monophosphate downstream mediators were all significantly down-regulated in both inflamed colonic inflammatory bowel disease (IBD) mucosa and TNBS colitis. Expression of GUCA2A and GUCY2C negatively correlated to expression of inflammatory cytokines. IHC and ISH confirmed microarray results for GUCA2A/Guca2a and GUCY2C/Gucy2c in inflamed samples. We identified a highly significant positive correlation between the expression of the transcription factor caudal type homeobox 2 (CDX2) and the expression of the downstream target gene GUCY2C. GUCA2A, GUCA2B and GUCY2C as well as several steps of the GC-C signaling pathway are down-regulated in IBD. This may have implications in IBD pathogenesis.
    Full-text · Article · May 2015 · Scandinavian Journal of Gastroenterology
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    • "There is reasonable hope and further evidence emerging that the presence of CRC could be detected by specific changes in the composition of serum proteins or mRNA expression levels [4]. Different markers are overexpressed in CRC compared with matched normal adjacent mucosa [5]. These observations suggest a model wherein as a key regulator of epithelial cell proliferation along the associated with neoplastic transformation. "
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    ABSTRACT: Colorectal cancer (CRC) is the second most common cause of death from cancer in both men and women in the majority of developed countries. Molecular tests of blood could potentially provide this ideal screening tool. Our objective was to assess the usefulness of serum markers and mRNA expression levels in the diagnosis of CRC. In a prospective study, we measured mRNA expression levels of 13 markers (carbonic anhydrase, guanylyl cyclase C, plasminogen activator inhibitor, matrix metalloproteinase 7 (MMP7), urokinase-type plasminogen activator receptor (uPAR), urokinase-type plasminogen activator, survivin, tetranectin, vascular endothelial growth factor (VEGF), cytokeratin 20, thymidylate synthase, cyclooxygenase 2 (COX-2), and CD44) and three proteins in serum (alpha 1 antitrypsin, carcinoembryonic antigen (CEA) and activated C3 in 42 patients with CRC and 33 with normal colonoscopy results. Alpha 1-antitrypsin was the serum marker that was most useful for CRC diagnosis (1.79±0.25 in the CRC group vs 1.27±0.25 in the control group, P<0.0005). The area under the ROC curve for alpha 1-antitrypsin was 0.88 (0.79-0.96). The mRNA expression levels of five markers were statistically different between CRC cases and controls: those for which the ROC area was over 75% were MMP7 (0.81) and tetranectin (0.80), COX-2 (0.78), uPAR (0.78) and carbonic anhydrase (0.77). The markers which identified early stage CRC (Stages I and II) were alpha 1-antitrypsin, uPAR, COX-2 and MMP7. Serum alpha 1-antitrypsin and the levels of mRNA expression of MMP7, COX-2 and uPAR have good diagnostic accuracy for CRC, even in the early stages.
    Full-text · Article · Jan 2013 · PLoS ONE
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    ABSTRACT: Colorectal cancer (CRC) is the third most common cancer and a leading cause of death for both men and women in North America. The staging of the CRC at the time of diagnosis is the single most important prognostic factor in determining recurrence and survival. Until 2008, accurate evaluation of CRC stages I and II was based on examination of regional lymph nodes (LNs) under a microscope to identify cancer cells. This method can detect one cancer cell in 200 normal cells, but analyzes only a fraction of the available tissue from the LN (less than 0.1%). Up to 30% of patients assessed by traditional histopathology methods as having stage II disease (negative LNs) experience a recurrence of their cancer. Previstage™ GCC Colorectal Cancer Staging Test, a new molecular diagnostic test, is able to identify patients at high risk of recurrence by examining their LNs for guanylyl cyclase C (GCC). GCC is a marker found in cells lining the lumen of the gastrointestinal tract. The expression of GCC is conserved in CRC and metastatic disease. Using an ultrasensitive quantitative reverse transcription (RT)-PCR, the test interrogates a patient’s LN tissues to identify GCC levels consistent with metastatic (stage III) disease. The technology employed in Previstage™ GCC is nearly 100 000 times more sensitive than microscopic staging methods. This molecular diagnostic test allows a more thorough examination of LNs and has an analytic sensitivity of 92% and a specificity of 98%. Such a test can be used to overcome the limitations of staging by traditional histopathology alone.
    No preview · Article · Mar 2012 · Molecular Diagnosis & Therapy
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