1,898 research outputs found

    Mesenchymal adenomatous polyposis coli plays critical and diverse roles in regulating lung development.

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    BackgroundAdenomatous polyposis coli (Apc) is a tumor suppressor that inhibits Wnt/Ctnnb1. Mutations of Apc will not only lead to familial adenomatous polyposis with associated epithelial lesions, but will also cause aggressive fibromatosis in mesenchymal cells. However, the roles of Apc in regulating mesenchymal cell biology and organogenesis during development are unknown.ResultsWe have specifically deleted the Apc gene in lung mesenchymal cells during early lung development in mice. Loss of Apc function resulted in immediate mesenchymal cell hyperproliferation through abnormal activation of Wnt/Ctnnb1, followed by a subsequent inhibition of cell proliferation due to cell cycle arrest at G0/G1, which was caused by a mechanism independent of Wnt/Ctnnb1. Meanwhile, abrogation of Apc also disrupted lung mesenchymal cell differentiation, including decreased airway and vascular smooth muscle cells, the presence of Sox9-positive mesenchymal cells in the peripheral lung, and excessive versican production. Moreover, lung epithelial branching morphogenesis was drastically inhibited due to disrupted Bmp4-Fgf10 morphogen production and regulation in surrounding lung mesenchyme. Lastly, lung mesenchyme-specific Apc conditional knockout also resulted in altered lung vasculogenesis and disrupted pulmonary vascular continuity through a paracrine mechanism, leading to massive pulmonary hemorrhage and lethality at mid-gestation when the pulmonary circulation should have started.ConclusionsOur study suggests that Apc in lung mesenchyme plays central roles in coordinating the proper development of several quite different cellular compartments including lung epithelial branching and pulmonary vascular circulation during lung organogenesis

    Hereditary Colorectal Cancer in China

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    The purpose of this article is to review basic research as well as clinical studies on Chinese hereditary colorectal cancer. Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) accounts for 2.2% of all colorectal cancer, and Chinese criteria for suspected HNPCC have been developed. Germline mutations as well as large genomic rearrangements of mismatch repair (MMR) genes are responsible for this syndrome. Gastric cancer is the second most common cancer in Chinese HNPCC patients. Contrary to sporadic colorectal cancer in the Chinese population, HNPCC does not typically present with rectal cancer. Incidence of familial adenomatous polyposis (FAP) in China is approximately 1.5/100,000. Polyps in Chinese FAP patients can emerge as early as 16 months old, but malignant transformation usually occurs in the third and fourth decade. Total resection of the colon and rectum is necessary in FAP patients. For unresectable duodenal polyps, chemopreventive agents may be used

    Wnt/beta-catenin/Tcf signaling: A critical pathway in gastrointestinal tumorigenesis

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    Cancers of the gastrointestinal tract, including the liver, bile ducts, and pancreas, constitute the largest group of malignant tumors. Colorectal cancer is one of the most common neoplastic diseases in Western countries and one of the leading causes of cancer-related deaths. Inactivation of the adenomatous polyposis coli (APC) tumor-suppressor gene during early adenoma formation is thought to be the first genetic event in the process of colorectal carcinogenesis followed by mutations in oncogenes like K-Ras and tumor-suppressor genes like p53. Identification of the interaction of APC with the proto-oncogene beta-catenin has linked colorectal carcinogenesis to the Wnt-signal transduction pathway. The main function of APC is thought to be the regulation of free beta-catenin in concert with the glycogen synthase kinase 3beta (GSK-3beta) and Axin proteins. Loss of APC function, inactivation of Axin or activating beta-catenin mutations result in the cellular accumulation of beta-catenin. Upon translocation to the nucleus beta-catenin serves as an activator of T-cell factor (Tcf)-dependent transcription leading to an increased expression of several specific target genes including c-Myc, cyclin D1, MMP-7, and ITF-2. While APC mutations are almost exclusively found in colorectal cancers, deregulation of Wnt/beta-catenin/Tcf signaling is also common in other gastrointestinal and extra-gastrointestinal human cancers. In a fraction of hepatocellular carcinomas the Writ pathway is deregulated by inactivation of Axin or stabilizing mutations of beta-catenin. The majority of hepatoblastomas and a group of gastric cancers also carry beta-catenin mutations. Clearly, this pathway harbors great potential for future applications in cancer diagnostics, staging, and therapy. Copyright (C) 2002 S. Karger AG, Basel

    Colorectal Cancer: Epidemiological Trends, Screening, and Inheritability

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    Colorectal cancer is one of the most common cancer worldwide. The incidence and mortality trend in different areas of the world varies. Colorectal cancer incidence and mortality are increasing in some countries. There are also epidemiological shift towards younger age  (below 40). Most common non-invasive screening tests are fecal immunochemistry test (FIT) and fecal occult blood test (FOBT). Both have good sensitivity. The best invasive method for colorectal screening is still colonoscopy. Hereditary colorectal cancer is an important factor in younger age colorectal cancer. Familial adenomatous polyposis and Lynch syndrome are most common hereditary CRC. In familial or hereditary CRC, the chance of developing the cancerous form of the disease is nearly inevitable. Genetic testing may benefit the patients and their future progenies

    Mutation Analysis of the APC Gene in a Chinese FAP Pedigree with Unusual Phenotype

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    Background and Aim. Germline mutations of the adenomatous polyposis coli (APC) gene cause familial adenomatous polyposis (FAP), an autosomal dominant inherited disease mainly characterized by colorectal adenomatous polyposis. Genetic studies of FAP have shown that somatic APC mutations are dependent on the position of the germline APC mutation. However, the molecular mechanism underlying these genotype-phenotype associations for APC in Chinese remain largely unknown. Patients and Methods. In this study, we investigated the APC gene mutation in a Chinese FAP family by systematic screening with multiplex ligation-dependent probe amplification (MLPA), denaturing high-performance liquid chromatography (dHPLC), and DNA sequencing. Promoter methylation was detected by methylation-specific PCR. Results. The identical germline mutation c.1999 C>T (Q667X) of APC was identified in 5 affected members, among which 2 members carried somatic mutations of APC, one with promoter hypermethylation and the other with loss of wild-type allele in their adenomas. The somatic mutations were shown connected with the disease severity, demonstrating a unique genotype-phenotype association in this FAP pedigree. Conclusion. The study revealed the existence of novel pathogenic mutations in Chinese patients with FAP. Somatic mutations are of particular interest because of the unusual phenotypic features shown by patients

    Idiopathic desmoid-type fibromatosis of the pancreatic head: case report and literature review

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    Desmoid-type fibromatosis (DTF) is an uncommon nonmetastatic fibrous neoplasm. Sporadic intraperitoneal DTF is rarely described in current literature. We herein report a case of DTF of unknown cause involving the pancreatic head. A 41-year-old man presented with recurrent epigastric pain and weight loss. An abdominal computed tomography scan showed a well-delineated solid cystic mass inside the pancreatic head. Pylorus-preserving pancreaticoduodenectomy was performed due to the patient’s debilitating symptoms and suspected malignancy. The pathological examination revealed massive fibroblastic proliferation arising from the musculoaponeurotic tissues, consistent with a diagnosis of DTF. Immunohistochemical phenotyping determined positive immunoreactivity to vimentin and β-catenin, but negative immunoreactivity to smooth muscle actin, CD117, CD34, or S-100, confirming the diagnosis of DTF. No local recurrence or distant metastasis was found during a 24-month follow-up. Radical resection is recommended as first-line treatment for pancreatic DTF. Long-term follow-up studies are required to establish the prognosis of pancreatic DTF

    Hereditary Colorectal Cancer Syndromes in Hong Kong: a Registry's Perspective

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    Established in 1995, the Hereditary Gastrointestinal Cancer Registry aimed at cancer prevention due to hereditary colorectal cancer syndromes in Hong Kong through early detection, timely treatment, education and ongoing research. This article details the history, structure and work of the Registry. A summary is also provided on the results of various research work conducted by the Registry which facilitates the clinical management of hereditary colorectal cancer syndromes in Hong Kong Chinese families
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