Abstract:
BACKGROUND & AIMS:Resistance of metastatic human colorectal cancer cells to drugs that block epidermal growth factor (EGF) receptor signaling could be caused by aberrant activity of other receptor tyrosine kinases, activating overlapping signaling pathways. One of these receptor tyrosine kinases could be MET, the receptor for hepatocyte growth factor (HGF). We investigated how MET signaling, and its interaction with CD44 (a putative MET coreceptor regulated by Wnt signaling and highly expressed by intestinal stem cells [ISCs] and adenomas) affects intestinal homeostasis, regeneration, and adenoma formation in mini-gut organoids and mice. METHODS:We established organoid cultures from ISCs stimulated with HGF or EGF and assessed intestinal differentiation by immunohistochemistry. Mice with total epithelial disruption of MET (AhCre/Metfl/fl/LacZ) or ISC-specific disruption of MET (Lgr5Creert2/Metfl/fl/LacZ) and control mice (AhCre/Met+/+/LacZ, Lgr5Creert2/Met+/+/LacZ) were exposed to 10 Gy total body irradiation; intestinal tissues were collected, and homeostasis and regeneration were assessed by immunohistochemistry. We investigated adenoma organoid expansion stimulated by HGF or EGF using adenomas derived from Lgr5Creert2/Metfl/fl/Apcfl/fl and Lgr5Creert2/Met+/+/Apcfl/fl mice. The same mice were evaluated for adenoma prevalence and size. We also quantified adenomas in AhCre/Metfl/fl/Apcfl/+ mice compared with AhCre/Met+/+/Apcfl/+ control mice. We studied expansion of organoids generated from crypts and adenomas, stimulated by HGF or EGF, that were derived from mice expressing different CD44 splice variants (Cd44+/+, Cd44-/-, Cd44s/s, or Cd44v4-10/v4-10 mice). RESULTS:Crypts incubated with EGF or HGF expanded into self-organizing mini-guts with similar levels of efficacy and contained all differentiated cell lineages. MET-deficient mice did not have defects in intestinal homeostasis. Total body irradiation reduced numbers of proliferating crypts in AhCre/Metfl/fl/LacZ mice. Lgr5Creert2/Metfl/fl/LacZ mice had impaired regeneration of MET-deficient ISCs. Adenoma organoids stimulated with EGF or HGF expanded to almost twice the size of nonstimulated organoids. MET-deficient adenoma organoids did not respond to HGF stimulation, but did respond to EGF. ISC-specific disruption of Met (Lgr5Creert2/Metfl/fl/Apcfl/fl mice) caused a twofold increase in apoptosis in microadenomas, resulting in an approximately 50% reduction of microadenoma numbers and significantly reduced average adenoma size. Total epithelial disruption of Met (AhCre/Metfl/fl/Apcfl/+ mice) resulted in an approximate 50% reduction in (micro)adenoma numbers. Intestinal crypts from Cd44-/- mice did not expand to the same extent as crypts from Cd44+/+ mice on stimulation with HGF, but had the same response to EGF. The negative effect on HGF-mediated growth was overcome by expression of CD44v4-10, but not by CD44s. Similarly, HGF-mediated expansion of adenoma organoids required CD44v4-10. CONCLUSIONS:In studies of intestinal organoid cultures and mice with inducible deletion of MET, we found HGF receptor signaling to regulate intestinal homeostasis and regeneration, as well as adenoma formation. These activities of MET are promoted by the stem cell CD44 isoform CD44v4-10. Our findings provide rationale for targeting signaling via MET and CD44 during anti-EGF receptor therapy of patients with colorectal cancer or in patients resistant to EGF receptor inhibitors.
journal_name
Gastroenterologyjournal_title
Gastroenterologyauthors
Joosten SPJ,Zeilstra J,van Andel H,Mijnals RC,Zaunbrecher J,Duivenvoorden AAM,van de Wetering M,Clevers H,Spaargaren M,Pals STdoi
10.1053/j.gastro.2017.07.008subject
Has Abstractpub_date
2017-10-01 00:00:00pages
1040-1053.e4issue
4eissn
0016-5085issn
1528-0012pii
S0016-5085(17)35909-7journal_volume
153pub_type
杂志文章相关文献
GASTROENTEROLOGY文献大全abstract::A 14-yr-old girl presented with long-standing symptoms of partial gastric outlet obstruction due to an antral mucosal diaphragm that had a central aperture of 4-5 mm. The literature of this congenital malformation is reviewed with respect to diagnostic criteria and feasibility of endoscopic transection. The procedure ...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:10.1016/0016-5085(85)90222-7
更新日期:1985-11-01 00:00:00
abstract::To define a potential role for the angiotensin system in Crohn's colitis, the colonic mucosal levels of angiotensin I and II were measured in endoscopic biopsy samples from patients with active Crohn's colitis (n = 20), ulcerative colitis (n = 13), other forms of colitis (n = 3), and normal controls (n = 17). Colonic ...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:10.1016/0016-5085(90)91088-n
更新日期:1990-06-01 00:00:00
abstract:BACKGROUND & AIMS:Pancreatic mucinous cystic neoplasm (MCN), a cystic tumor of the pancreas that develops most frequently in women, is a potential precursor to pancreatic ductal adenocarcinoma. MCNs develop primarily in the body and tail of the pancreas and are characterized by the presence of a mucinous epithelium and...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:10.1053/j.gastro.2013.09.044
更新日期:2014-01-01 00:00:00
abstract:BACKGROUND & AIMS:Hepatic bile salt secretion is an essential function of vertebrate liver. Rat and mouse bile salt export pump (Bsep) are adenosine triphosphate (ATP)-dependent bile salt transporters. Mutations in human BSEP were identified as the cause of progressive familial intrahepatic cholestasis type 2. BSEP pro...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:10.1053/gast.2002.36587
更新日期:2002-11-01 00:00:00
abstract::Microsatellite instability (MSI) caused by mismatch repair deficiency (dMMR) is detected in a small proportion of pancreatic ductal adenocarcinomas (PDACs). dMMR and MSI have been associated with responses of metastatic tumors, including PDACs, to immune checkpoint inhibitor therapy. We performed immunohistochemical a...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:10.1053/j.gastro.2017.11.009
更新日期:2018-03-01 00:00:00
abstract:BACKGROUND/AIMS:The yeast Saccharomyces boulardii inhibits the secretion induced by cholera toxin (CT) in rat jejunum. The present study was aimed at unraveling the mechanism by which S. boulardii protects intestinal cells against CT. METHODS:CT-induced adenosine 3',5'-cyclic monophosphate (cAMP) levels were measured ...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:10.1016/s0016-5085(94)94403-2
更新日期:1994-01-01 00:00:00
abstract::In seven healthy volunteers pure pancreatic juice was obtained by endoscopic cannulation of the papilla of Vater. Synthetic secretin was intravenously infused in doses doubled every 20 min. The volume of pancreatic juice was proportional to the log of the secretin dose. A significant rise (P less than 0.05) in pancrea...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:
更新日期:1976-04-01 00:00:00
abstract:BACKGROUND & AIMS:Patients with irritable bowel syndrome with diarrhea (IBS-D) have increased mucosal serotonin (5-hydroxytryptamine [5-HT]) availability, possibly because immune activation reduces activity of the 5-HT transporter (SERT). We investigated the relationship between mucosal and platelet SERT and immune act...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:10.1053/j.gastro.2011.01.052
更新日期:2011-05-01 00:00:00
abstract::This study is an examination of the association between Crohn's disease and psychiatric illness using careful gastrointestinal evaluation, a structured psychiatric interview of known reliability and validity, and explicit diagnostic criteria for psychiatric illness. A proband sample of 50 subjects with Crohn's disease...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:
更新日期:1984-02-01 00:00:00
abstract:BACKGROUND & AIMS:Small intestinal carcinomas are rare but occur with increased incidence in Crohn's disease. The aim of this study was to elucidate the genetic alterations. METHODS:Mutations and deletions involved in colorectal carcinoma were studied in sporadic and Crohn's-associated intestinal carcinomas and precur...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:10.1016/s0016-5085(97)70087-8
更新日期:1997-07-01 00:00:00
abstract::Motor abnormalities of the small bowel that occur only during the waking state have been reported in the irritable bowel syndrome (IBS), suggesting that central nervous system arousal is a necessary condition for expression of the disorder and that it may reflect inappropriate brain-gut interaction. This possible rela...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:10.1016/0016-5085(92)91089-m
更新日期:1992-07-01 00:00:00
abstract::It is generally accepted that the intestinal phase of pancreatic secretion is initiated by the stimulation of chemoreceptors sensitive to fat and protein degradation products and hydrogen ions. The effect of the volume and osmolality of food emptied by the stomach into the duodenum has received less attention. We inve...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:
更新日期:1984-01-01 00:00:00
abstract:BACKGROUND AND AIMS:Cholestasis is one of the principal manifestations of liver disease and often results from disorders involving bile duct epithelia rather than hepatocytes. A range of disorders affects biliary epithelia, and no unifying pathophysiologic event in these cells has been identified as the cause of choles...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:10.1016/s0016-5085(03)01201-0
更新日期:2003-10-01 00:00:00
abstract::The incidence of celiac disease is increasing, partly because of improved recognition of, and testing for, the disease. The rise in incidence is also due to a real increase of this immune-based disorder, independent of disease detection. The reasons for this true rise in recent decades are unknown but may be related t...
journal_title:Gastroenterology
pub_type: 杂志文章,评审
doi:10.1053/j.gastro.2020.06.098
更新日期:2021-01-01 00:00:00
abstract::In humans and most other species, a decline in pH of gallbladder contents occurs during the concentration of bile. Recent in vitro studies in rabbit, guinea pig, and Necturus gallbladders have strongly suggested mucosal H+ secretion during sodium reabsorption, presumably representing a Na+/H+ exchange. The present in ...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:10.1016/0016-5085(87)90118-1
更新日期:1987-02-01 00:00:00
abstract::We studied the influence of morphine on intestinal secretion induced by three different secretogogues in an attempt to elucidate the mechanism for its antisecretory activity. In rabbit ileal mucosa in vitro morphine (10(-4) M) did not influence the electrical response to the subsequent administration of prostaglandin ...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:
更新日期:1982-02-01 00:00:00
abstract::Fluorescent periodic acid-Schiff reaction (FPR) was used in the study of the normal rabbit ileal epithelium and its changes after injection of living cultures or enterotoxins of enterotoxigenic Escherichia coli. This reaction, with the use of auramine OO-SO2 complex as a Schiff-type reagent, demonstrates gut epitheliu...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:
更新日期:1980-04-01 00:00:00
abstract:BACKGROUND & AIMS:Feeding intolerance because of functional gastrointestinal dysmotility and parenteral nutrition-associated cholestasis (PNAC) are common problems in preterm, very-low-birth-weight (VLBW) infants. This double-blind, randomized, placebo-controlled study aimed to assess the effectiveness of "high-dose" o...
journal_title:Gastroenterology
pub_type: 杂志文章,随机对照试验
doi:10.1053/j.gastro.2007.03.043
更新日期:2007-05-01 00:00:00
abstract:BACKGROUND & AIMS:Mutational inactivation of adenomatous polyposis coli (APC) is an early event in colorectal cancer (CRC) progression that affects the stability and increases the activity of β-catenin, a mediator of Wnt signaling. Progression of CRC also involves inactivation of signaling via transforming growth facto...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:10.1053/j.gastro.2011.11.026
更新日期:2012-03-01 00:00:00
abstract::The role of adrenal medullary discharge of catecholamines on inhibition of gastric emptying and small intestinal propulsion after laparotomy was examined in rats. The rate of movement of a 51Cr-labeled liquid test meal, which had been introduced by gastric intubation, out of the stomach and through the small intestine...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:
更新日期:1975-03-01 00:00:00
abstract:BACKGROUND & AIMS:Risk factors for cardiovascular disease, such as obesity and hypertension, have been associated with nonalcoholic fatty liver disease. Psychological distress (symptoms of anxiety and depression) is a risk factor for cardiovascular disease, so it might also be associated, directly or indirectly, with l...
journal_title:Gastroenterology
pub_type: 杂志文章,meta分析
doi:10.1053/j.gastro.2015.02.004
更新日期:2015-05-01 00:00:00
abstract::By speeding the fragmentation of meat, peptic digestion might accelerate gastric emptying. To examine this possibility, mongrel dogs prepared with chronic duodenal fistulas were fed steak and 99mTc-labeled chicken liver, measuring 99mTc in all chyme exiting from the stomach out the duodenal fistula allowed quantitatio...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:
更新日期:1980-08-01 00:00:00
abstract:BACKGROUND & AIMS:Weight loss in response to sibutramine is highly variable. We assessed the association of specific markers of polymorphisms of candidate alpha2A adrenoreceptor, 5-HT transporter, and GNbeta3 genes and weight loss with sibutramine. METHODS:We conducted a randomized, double-blind, pharmacogenetic study...
journal_title:Gastroenterology
pub_type: 杂志文章,随机对照试验
doi:10.1053/j.gastro.2008.07.009
更新日期:2008-10-01 00:00:00
abstract:BACKGROUND & AIMS:Hepcidin is an antimicrobial peptide thought to be involved in the regulation of intestinal iron absorption. To further investigate its role in this process, we examined hepatic and duodenal gene expression in rats after the switch from a control diet to an iron-deficient diet. METHODS:Adult rats on ...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:10.1053/gast.2002.35353
更新日期:2002-09-01 00:00:00
abstract:BACKGROUND & AIMS:Liver disease has been associated with cardiovascular disorders, but little is known about the relationship between serum levels of alanine aminotransferase (ALT) and markers of atherogenesis. We investigated the relationship between low-normal and high-normal levels of ALT and an extended panel of ca...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:10.1053/j.gastro.2013.08.036
更新日期:2013-12-01 00:00:00
abstract::A 61-yr-old woman was found to have multicentric hepatocellular carcinoma associated with clinical hyperthyroidism. Marked elevations in serum thyroid-stimulating hormone, T4, T3, and free T4 were documented. These values increased with tumor progression. It is postulated that this patient's hepatoma produced a substa...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:10.1016/s0016-5085(85)80152-9
更新日期:1985-01-01 00:00:00
abstract::A prospective study of 22 patients with antibiotic-associated pseudomembranous colitis demonstrated that the most distal location of the pseudomembranes was noted from 0 to 25 cm from the anus in 17 patients, from 25 to 60 cm from the anus in 3 patients, and greater than 60 cm from the anus in only 2 patients. These d...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:
更新日期:1982-12-01 00:00:00
abstract:BACKGROUND & AIMS:Corticofugal pathways to the human esophagus have been recently identified in humans using transcranial magnetic stimulation. The aim of this study was to determine the topographic representation of the esophagus on the cerebral cortex. METHODS:Focal magnetic stimulation of 1-cm areas was performed o...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:10.1016/s0016-5085(96)70053-7
更新日期:1996-10-01 00:00:00
abstract:BACKGROUND AND AIMS:We set out to test the hypothesis that irritable bowel syndrome (IBS) is characterized by an augmented cellular immune response with enhanced production of proinflammatory cytokines. We further aimed to explore whether symptoms and psychiatric comorbidity in IBS are linked to the release of proinfla...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:10.1053/j.gastro.2007.01.046
更新日期:2007-03-01 00:00:00
abstract:BACKGROUND & AIMS:Apart from its importance as an acid secretogogue, the role of histamine as a downstream target of gastrin has not been fully explored. Previous studies have shown that the combination of hypergastrinemia and Helicobacter infection resulted in accelerated gastric cancer in mice. We used this model to ...
journal_title:Gastroenterology
pub_type: 杂志文章
doi:10.1053/j.gastro.2005.03.027
更新日期:2005-06-01 00:00:00