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PubMed1997

Intestinal-type fibroblasts selectively influence proliferation rate and peptide synthesis in the murine entero-endocrine cell line STC-1.

The intestinal epithelium consists of enterocytes, endocrine cells, goblet cells and Paneth cells, which differentiate from pluripotent stem cells located at the crypt bases. The role of the epithelial-mesenchymal inter-actions has been well documented for the differentiation of enterocytes, but the mechanisms that control endocrine cell differentiation are poorly understood. We have cultured the intestinal endocrine cell line STC-1, which synthesizes most of the intestinal peptide hormones, in media conditioned by several subepithelial fibroblast cell lines from three distinct sites of intestine. The fibroblast Swiss 3T3 cell line was used as a non-intestinal control. Our results show that culture media from intestinal fibroblasts inhibit the proliferation rate of STC-1 cells, while those from Swiss 3T3 fibroblasts do not. As regards peptide hormone gene expression, Swiss 3T3-conditioned media have no effect, whereas media from intestinal fibroblasts variably affect cholecystokinin, glucagon, secretin and somatostatin mRNA levels. In particular, clonal subepithelial myofibroblasts do not exert the same effects as mixed subepithelial fibroblasts from homologous intestinal segment. Taken together, these results suggest that cultured fibroblasts of intestinal origin release soluble factors that inhibit STC-1 cell proliferation and modulate, in a region-specific manner, the expression of hormonal peptide genes in this nonspecialized endocrine cell line.

Animals↗
PubMed2005

Gene expression profiling of intestinal epithelial cell maturation along the crypt-villus axis.

BACKGROUND & AIMS: To define the genetic reprogramming that drives intestinal epithelial cell maturation along the crypt-villus axis, enterocytes were sequentially isolated from the villus tip to the crypts of mouse small intestine. METHODS: Changes in gene expression were assessed using 27,405-element complementary DNA microarrays (14,685 unique genes) and specific changes validated by Western blotting. RESULTS: A total of 1113 genes differentially expressed between the crypt and villus were identified. Among these, established markers of absorptive and goblet cell differentiation were up-regulated in villus cells, whereas Paneth cell markers were maximally expressed in crypt cells. The 1113 differentially expressed genes were significantly enriched for genes involved in cell cycle progression, RNA processing, and translation (all predominantly down-regulated during maturation) and genes involved in cytoskeleton assembly and lipid uptake (predominantly up-regulated during maturation). No enrichment for apoptosis-regulating genes was observed. We confirmed that Wnt signaling was maximal in the proliferative compartment and observed a decrease in MYC and an increase in MAD and MAX expression during the maturation program. Consistent with these changes, the 1113 genes were enriched for MYC targets, establishing the importance of this network in intestinal cell maturation. CONCLUSIONS: This database serves as a resource for understanding the molecular mechanisms of intestinal cell maturation and for dissection of how perturbations in the maturation process can lead to changes in gastrointestinal physiology and pathology, particularly intestinal tumorigenesis.

Animals↗
PubMed1981

The site of incorporation of sialic acid residues into glycoproteins and the subsequent fates of these molecules in various rat and mouse cell types as shown by radioautography after injection of [3H]N-acetylmannosamine. II. Observations in tissues other than liver.

Biochemical evidence from the preceding paper indicated that [3H]N-acetylmannosamine may be used as a fairly specific precursor for the sialic acid residues of glycoproteins (and perhaps glycolipids) in radioautographs of rat liver and duodenum. In order to study the site of incorporation of this label in cell types of various tissues, we gave 40-g rats and 15-g Swiss albino mice a single intravenous injection of 8 mCi of [3H]N-acetylmannosamine and sacrificed them after 2 and 10 min. To trace the subsequent migration of the labeled glycoproteins, we injected 40-g rats with 4 mCi of [3H]N-acetylmannosamine and sacrificed them after 20 and 30 min, 1, 4, and 24 h, and 3 and 9 d. Light microscope radioautographic analysis revealed that in a great variety of cell types the label was initially localized to the Golgi region. Electron microscope radioautographic analysis of duodenal villous columnar and goblet cells, pancreatic acinar cells and Paneth cells, from rats and mice sacrificed 10 min after injection, showed that the silver grains were localized over Golgi saccules (and adjacent secretion granules). In kidney proximal and distal tubule cells reaction was initially localized to the Golgi apparatus in some areas of the kidney cortex whereas in other areas it was more diffuse. In all cells, the proportion of silver grains over the Golgi apparatus decreased with time after injection while an increasing number of grains appeared over secretion products in secretory cells or over the plasma membrane in other cell types. Lysosomes also became increasingly labeled at later time intervals. The above results suggest that in most cell types sialic acid residues are incorporated into glycoproteins (and perhaps glycolipids), primarily in the Golgi apparatus. With time, these newly synthesized molecules migrate to secretion products, to the plasma membrane, or to the lysosomes.

Animals↗
PubMed2000

Microcystic endocervical adenocarcinomas: a report of eight cases.

Eight endocervical adenocarcinomas with a prominent cystic component that resulted in a resemblance, in part, to certain benign lesions are described. The patients ranged in age from 34 to 78 years (average age, 48.6 years), and three women were postmenopausal. Presentations included abnormal cervical cytology smears (n = 4) and vaginal bleeding (n = 3). One patient was pregnant at the time of diagnosis. Six tumors were typical endocervical-type and two tumors were intestinal-type adenocarcinomas. The cysts occupied 50% to approximately 90% of the tumor and ranged from 1 to 8 mm in diameter. They were lined by flattened to low cuboidal to pseudostratified epithelium with focal goblet cells and Paneth cells in the two intestinal-type tumors, and the epithelial lining of the cysts was denuded occasionally. Seven tumors contained luminal mucin, which was brightly eosinophilic in one patient and resembled the contents of mesonephric tubules, but was mucin positive on special stains. A desmoplastic stroma was identified in two patients; the remainder had no stromal reaction. The features that resulted in mimicry of benign lesions were the cystic glands, their sometimes orderly distribution, and focal, deceptively bland cytology. All tumors contained, at least focally however, architecturally abnormal glands lined by cytologically malignant cells.

Adenocarcinoma↗
PubMed2002

Gastric adenomas: intestinal-type and gastric-type adenomas differ in the risk of adenocarcinoma and presence of background mucosal pathology.

Gastric adenomas are neoplastic growths characterized by localized, polypoid proliferations of dysplastic epithelium. They frequently arise in stomachs with a background of mucosal atrophy and intestinal metaplasia, and a higher risk of adenocarcinoma elsewhere in the stomach has been reported in patients with gastric adenomas. Additionally, some gastric adenomas themselves demonstrate neoplastic progression to infiltrating adenocarcinoma. However, previous studies have not comprehensively evaluated the background gastric mucosa and risk of adenocarcinoma, particularly in relation to the histologic classification of adenomas as either intestinal-type or gastric-type. We studied 61 gastric adenomas from 51 patients between 1985 and 2001. The adenomas were classified as intestinal-type (containing at least focal goblet cells and/or Paneth cells), gastric-type (lined entirely by gastric mucin cells on PAS/alcian blue stain), or indeterminate. We evaluated the histologic features of both the adenomas (location, multiplicity, degree of dysplasia, presence of adenocarcinoma within the polyp) and the surrounding gastric mucosa (presence of gastritis, intestinal metaplasia, and adenocarcinoma). Gastric adenomas were distributed equally throughout the stomach, were most frequently solitary (82%), and contained adenocarcinoma in nine cases (14.8%). There were 34 intestinal-type adenomas (56%) in 31 patients, 25 gastric-type adenomas (41%) in 18 patients (including 10 patients with familial adenomatous polyposis), and 2 of indeterminate type (3%). Intestinal-type adenomas were significantly more likely than gastric-type adenomas to show high-grade dysplasia (p <0.0001), adenocarcinoma within the polyp (p = 0.016), intestinal metaplasia in the surrounding stomach (p <0.000001), and gastritis (p = 0.002). Patients with intestinal-type adenomas were also more likely to have separate adenocarcinomas (five cases vs 0 cases), although this did not reach statistical significance. Gastric adenomas are rarely truly "sporadic" lesions. In any individual patient complete removal of the adenoma should be performed, and thorough biopsy of the surrounding gastric mucosa is essential to understand the clinicopathologic context of the adenoma.

Adenoma↗
PubMed2003

Hepatocyte antigen as a marker of intestinal metaplasia.

Intestinal metaplasia is a histologic hallmark of Barrett's esophagus and chronic gastritis. Intestinal metaplasia may progress to dysplasia or carcinomas without proper treatment. Most cases of intestinal metaplasia are easily recognized on hematoxylin and eosin-stained sections. However, some cases of intestinal metaplasia may be hard to recognize if they lack the characteristic mucin-producing cells and Paneth cells, or if they are small in size. Recently, keratin 7, keratin 20, and MUC2 expression patterns were reported to be useful in confirming the diagnosis of intestinal metaplasia. We studied hepatocyte (Hep) antigen (a hepatocellular antigen mainly expressing in normal and neoplastic hepatic tissues) in 33 cases of Barrett's esophagus (9 cases associated with esophageal adenocarcinoma) and 13 cases of chronic gastritis associated with intestinal metaplasia and gastric adenocarcinoma. Hep monoclonal antibody recognizes intestinal metaplasia in all cases. We also compared expression of Hep with that of keratin 7, keratin 20, and MUC2 in intestinal metaplasia. The specificity and sensitivity of Hep for intestinal metaplasia were higher than that of keratin 7 and keratin 20, or MUC2. We conclude that Hep may be used as a single diagnostic marker for intestinal metaplasia.

Adenocarcinoma↗
PubMed1995

Enteric differentiation in endometrial adenocarcinomas: a mucin histochemical study.

A histochemical study revealed focal intracytoplasmic mucin within 50% of a series of adenocarcinomas arising within the endometrium. Seventeen percent of the adenocarcinomas studied contained intracytoplasmic O-acetylated sialomucins, as demonstrated by the PB/KOH/PAS technique. The presence of O-acetylated sialomucin, indicating enteric or intestinal differentiation, has not previously been demonstrated within endometrial adenocarcinomas, although it is well described in endocervical adenocarcinomas and in mucinous tumors of the ovary. In none of the cases in which enteric-type mucins were identified was there morphological evidence of intestinal differentiation in the form of goblet cells or Paneth cells. No correlation was found between the presence of enteric mucins and the grade of the adenocarcinoma. The results of the study provide further confirmation of the ability of the epithelial lining of the female genital tract to undergo various forms of metaplasia, along both Mullerian and non-Mullerian pathways. The demonstration of specific mucins is more sensitive than morphology in establishing enteric differentiation.

Adenocarcinoma↗
PubMed2003

Genetic alterations in gastric adenomas of intestinal and foveolar phenotypes.

Gastric adenomas are unusual neoplasms that can constitute one of the direct precursors to gastric adenocarcinoma. Most gastric adenomas are comprised of polypoid projections of dysplastic epithelium with at least focal intestinal-type differentiation (containing goblet cells and/or Paneth cells), whereas adenomas comprised entirely of dysplastic foveolar-type epithelium are rare. It has been shown that nearly all intestinal-type adenomas arise in association with background intestinal metaplasia and gastric atrophy, approximately 40% harbor high-grade dysplasia, and nearly one fourth progress to adenocarcinoma. In contrast, foveolar-type adenomas tend to occur in otherwise normal, nonatrophic gastric mucosa and rarely harbor high-grade dysplasia or carcinoma. Potential differences in the genetic alterations between intestinal-type and foveolar-type gastric adenomas have not been systematically studied. We investigated 11 intestinal-type and 7 foveolar-type gastric adenomas (all from patients without familial adenomatous polyposis) for alterations in APC (using 5q allelic loss assays and direct DNA sequencing of the mutation cluster region), beta-catenin (using direct DNA sequencing of the phosphorylation region in exon 3), K-ras (using direct DNA sequencing of codons 12 and 13), and microsatellite instability (MSI; using fluorescent-based PCR amplification of a standard panel of 5 microsatellite markers). Overall, 10 of 11 (91%) intestinal-type adenomas harbored at least one detectable genetic alteration, whereas only 3 of 7 (43%) of foveolar-type adenomas did (P =.047). However, no statistically significant differences in any particular genetic alteration were found. Among intestinal-type adenomas, APC alterations were present in seven (64%), high-level MSI in three (27%), and K-ras mutations in two (18%). Among foveolar-type adenomas, APC alterations were present in three (43%) and a K-ras mutation in one of six amplifiable polyps (17%). Neither APC nor MSI correlated with the size of the adenoma, but K-ras mutations were found only in lesions of > or = 1 cm. beta-catenin mutations were not present in any gastric adenoma, irrespective of the presence or absence of APC alterations. These results suggest that the types and frequencies of genetic alterations occurring in gastric and colorectal adenomas are similar. Although intestinal-type and foveolar-type gastric adenomas display divergent biologic behavior, the specific genetic events accounting for these differences in morphology and biologic behavior are unclear.

Adenoma↗
PubMed1986

High-level expression of the 32.5-kilodalton calelectrin in ductal epithelia as revealed by immunocytochemistry.

Calelectrins are a family of antigenically related Ca2+-binding proteins that have only recently been described. They have the important property of binding to membranes only in the presence of Ca2+. We systematically studied the tissue localization of one calelectrin, the 32.5-kilodalton species, in rats using immunocytochemistry. We found that high levels were exclusively present in the epithelial cells of bile and pancreatic ducts, renal collecting ducts, bronchial epithelia, and brain ependyma. In all of these organs, the other cells were not immunoreactive. In addition, strong immunoreactivity was found in the intercalated disks of myocardial cells, and mild immunoreactivity was observed in several endocrine tissues. In contrast, the cellular distribution of the 67-kilodalton calelectrin was more diffuse, involving most parenchymal cells in addition to the already-mentioned cells. Due to the presence of high levels of 32.5-kilodalton calelectrin in some cell types, this protein may be used as a histochemical marker for differentiated ductal epithelial cells, some specialized epithelia, myocardial cells, and Paneth cells.

Animals↗
PubMed1993

Human Caco-2 cells transfected with c-Ha-Ras as a model for endocrine differentiation in the large intestine.

Endocrine cells occur in approximately 30% of all colorectal adenocarcinomas, and this feature appears to correlate with a relatively poor prognosis. To study the factors regulating endocrine differentiation in colorectal cancer, which may bear resemblance to the regulation of endocrine differentiation in normal intestinal mucosa, models in which differentiation can be manipulated are essential. However, endocrine features in colorectal cancer cell lines are scarce and are almost exclusively observed in xenografts, presumably as a result of differentiation induction by stromal components. We attempted to demonstrate endocrine differentiation in the colonic adenocarcinoma cell line Caco-2, which is frequently used as a model for enterocytic differentiation. In vitro endocrine tumor cells were not encountered. In vivo studies were cumbersome, because of the low take rate of Caco-2 cells. We did manage to establish nude mouse xenografts of Caco-2 cells by inoculating cells in collagen gel and by suppressing natural killer cell activity. In an attempt to induce a better take rate and to investigate the effect of Ras oncoprotein overexpression on endocrine differentiation, Caco-2 cells were transfected with a point-mutated c-Ha-Ras gene. The cell line Caco-2 EJ6, generated from these experiments, could be xenografted in nude mice with a high take rate, yielding a moderately well differentiated adenocarcinoma, morphologically identical to the tumors derived from untransfected Caco-2 cells. The xenografts displayed goblet cell, enterocytic, Paneth cell and endocrine differentiation. In vitro endocrine differentiation was observed neither under standard conditions nor with extracellular matrix components as differentiation inducers. We conclude that the Caco-2 cell line and its c-Ha-Ras transfected subline Caco-2 EJ6 in vivo display endocrine differentiation. Ras overexpression does not enhance endocrine differentiation. Due to its favorable growth properties in vivo, Caco-2 EJ6 is a suitable model for studies on endocrine differentiation in colorectal cancer.

Animals↗
PubMedDate not supplied

'Metaplastic lesions' in intrahepatic bile ducts in hepatolithiasis: a histochemical and immunohistochemical study.

Pathology of the intrahepatic bile ducts bearing calculi was examined with an emphasis on metaplasia in 22 cases of hepatolithiasis and in seven cases of normal livers. Normal livers contained few glandular elements within the bile duct walls and no metaplastic lesions or endocrine cells. In hepatolithiasis, a number of mucous glands resembling pyloric glands (pseudopyloric gland metaplasia) were seen within duct walls in all cases. The epithelial cells of the glands were positive for class III mucin with paradoxical concanavalin A staining which is known to be specific for pyloric glands. These cells were also positive for neutral, sialo- and sulfomucin to a variable extent. Intestinal metaplasia, including goblet cell and Paneth cell metaplasia, was found within duct walls and in covering epithelia in five (23%) cases. Endocrine cells, including argyrophil, argentaffin and gut hormone-containing cells were present in these metaplastic lesions in 13 (59%) cases. The occurrence of endocrine cells was closely associated with intestinal metaplasia, although there were a few endocrine cells in metaplastic pseudopyloric glands. These findings suggest that metaplastic lesions similar to the well-known metaplastic lesions in the gallbladder occur in the intrahepatic bile duct walls in hepatolithiasis. The appearance of metaplastic lesions and endocrine cells may be causally related to chronic inflammatory processes associated with hepatolithiasis.

Bile Ducts, Intrahepatic↗
PubMed1983

Carbonic anhydrase in the monkey stomach and intestine.

The distribution of carbonic anhydrase in the stomach and intestine of the cynomolgus monkey (Macaca fascicularis) was studied by the histochemical method of Hansson. In the gastric surface epithelium high enzyme activity was found in the cytoplasm and at the lateral cell borders. The parietal cells in the gastric glands also showed high enzyme activity, while the chief cells were less active. The mucous cells in the pyloric glands and in the Brunner's glands demonstrated a staining pattern similar to that of gastric surface cells. The mucosa of the duodenum and the jejunum was less intensely stained than the gastric mucosa. The enzyme activity was located at the lateral cell borders of the enterocytes, with weak or no cytoplasmic activity. Goblet cells and Paneth cells were unstained. In the ileum a small number of epithelial cells displayed high enzyme activity; their identity is not clear at present. In the cecum and colon large amounts of cytoplasmic carbonic anhydrase were found in the surface epithelium and in the upper part of the glands. Capillaries showing clear enzyme staining were found in the mucosa of all tissues; they were often located close to the surface epithelium and the glands. In the stomach, cecum and colon the distribution of the enzyme in the monkey appears very similar to that reported for other mammalian species, but in the small intestine clear differences exist. The functional role of carbonic anhydrase at the various sites in the gastrointestinal tract is only partly understood.

Animals↗
PubMed1990

Pancreatic secretory trypsin inhibitor in gastrointestinal mucosa and gastric juice.

We studied the distribution of pancreatic secretory trypsin inhibitor (PSTI) in the epithelia of the gastrointestinal tract and determined whether PSTI is secreted into gastric juice. PSTI was measured by a specific radioimmunoassay in biopsy specimens taken from the upper (n = 8) and lower (n = 7) gastrointestinal tract of patients with normal endoscopies. PSTI was present in the stomach, small intestine, and colon. Concentrations (micrograms/g protein) were highest in the stomach, and significantly higher in the antrum (1240, 670-1700, median and range) than in the gastric body (370, 350-570) (p less than 0.01). Concentrations were similar in the duodenum (180, 80-210) and colon (160, 130-360). PSTI determined by immunohistochemistry was present in mucus secreting gastric foveolar cells, duodenal Paneth cells, and colonic non mucus cells. PSTI was present in gastric juice. The median (range) concentration of PSTI in basal gastric juice from 13 patients with duodenal ulcers was 9 (3-21) micrograms/l and did not change during stimulation with pentagastrin. The rate of secretion, however, did increase significantly (p less than 0.05) from 1430 (180-2810) ng/h to 4500 (1250-12,770) ng/h during pentagastrin stimulation. PSTI was labile in acid pepsin but stable in the neutral conditions present in the mucus layer. The presence of pancreatic secretory trypsin inhibitor throughout the gut and its secretion into the lumen suggests a hitherto unrecognised mechanism protecting gastrointestinal epithelia against luminal proteases.

Adult↗
PubMed1998

Stress stimulates transepithelial macromolecular uptake in rat jejunum.

Evidence suggests that stress may be a contributing factor in intestinal inflammatory disease; however, the involved mechanisms have not been elucidated. We previously reported that acute stress alters epithelial physiology of rat intestine. In this study, we documented stress-induced macromolecular transport across intestinal epithelium. After exposure of Wistar-Kyoto rats to acute restraint stress, transport of a model protein, horseradish peroxidase (HRP), was assessed in isolated segments of jejunum. The flux of intact HRP was significantly enhanced across intestine from stressed rats compared with controls. Electron microscopy revealed HRP-containing endosomes within enterocytes, goblet cells, and Paneth cells of stressed rats. The number and area of HRP endosomes within enterocytes were found to be significantly increased by stress. HRP was also visualized in paracellular spaces between adjacent epithelial cells only in intestine from stressed rats. Atropine treatment of rats prevented the stress-induced abnormalities of protein transport. Our results suggest that stress, via a mechanism that involves release of acetylcholine, causes epithelial dysfunction that includes enhanced uptake of macromolecular protein antigens. We speculate that immune reactions to such foreign proteins may initiate or exacerbate inflammation.

Animals↗
PubMed2001

Interposed colon between remnants of the small intestine exhibits small bowel features in a patient with short bowel syndrome.

We describe herein the case of a 48-year-old man who underwent emergency massive resection of the small intestine due to a strangulated ileus, which led to short bowel syndrome (SBS), as he was left with only 7 cm of jejunum and 8 cm of ileum with ileocecal valve. He then received interposition of a colon segment between the jejunum and ileum remnants isoperistaltically. For 24 months after the operation, he has been able to tolerate oral intake, but still requires partial home parenteral nutritional support during the night on a bimonthly basis. Biochemical and nutritional parameters, including the analysis of minerals and trace elements, indicated that the patient was in relatively good health. Histological examination revealed that the mucosa of the interposed colon showed hypertrophy and hyperplasia of the crypt glands, and cells resembling Paneth cells which are usually seen in the small intestine, suggesting that the colon segment exhibits adaptive changes to the small intestine. Colon interposition may be a useful technique in patients with SBS when the small bowel is too short for the other surgical considerations.

Anastomosis, Surgical↗
PubMed1985

Long-term effect of somatostatin 14 on mouse stomach, antrum, intestine and exocrine pancreas.

Mice were injected 3 times a day for 12 days with 8 micrograms/kg of somatostatin 14 which caused a hypoplasia of parietal and goblet cells, a hypotrophy and hypofunctionality of pancreatic acinar cells with a decrease in lipase and chymotrypsin activities, a decrease in the secretory fuction of the Brunner gland and in the number of dark granules of G cells. Neither villous and microvillous areas nor brush border hydrolase activities were affected. The number of peptic cells and Paneth cells increase as the level of pepsin and lysozyme. Mice were injected 4 times per hour with 2 micrograms/kg of somatostatin. 2 h after the first injection of somatostatin and 90 min after a single injection of tritiated thymidine, fundic, antral, jejunal and ileal labelling indexes strongly decrease (maximal effect in ileum). The inhibitory effect of somatostatin on the digestive epithelial cell proliferation compared to its long-term action only directed on specific cell types evokes probable compensatory mechanisms induced to maintain the equilibrium of the digestive epithelia.

Animals↗
PubMedDate not supplied

Dissimilar frequency of hepatoblastomas and hepatic cystadenomas and adenocarcinomas arising in hepatocellular neoplasms of D2B6F1 mice initiated with N-nitrosodiethylamine and subsequently given Aroclor-1254, dichlorodiphenyltrichloroethane, or phenobarbital.

Aroclor-1254 (Ar-1254) and dichlorodiphenyltrichloroethane (DDT) were compared to phenobarbital (PB) for their ability to promote hepatocellular proliferative lesions to hepatocellular adenomas and carcinomas and to hepatoblastomas in D2B6F1 male mice initiated with N-nitrosodiethylamine (NDEA). Hepatocellular neoplasms developed in all mice given NDEA and were more numerous in mice fed promoters. Multiplicities decreased in the order Ar-1254 > PB > DDT, indicating that Ar-1254 was more potent than either PB or DDT at the dosage levels used. PB was the most effective of the 3 agents in stimulating the evolution of hepatocellular neoplasms to hepatoblastoma. The incidence of hepatoblastomas in the NDEA.PB group was 72% but was only 27% in NDEA-initiated, DDT-promoted mice and 33% in low-dose and only 9% in high-dose Ar-1254-promoted mice. In contrast, lesions resembling benign and malignant cholangiocellular neoplasms were frequently found within hepatocellular tumors in Ar-1254-promoted mice but not in mice fed PB or DDT, either alone or after NDEA. Some cystic glandular structures in Ar-1254-promoted mice contained mucous cells, argentaffin cells, and Paneth cells and thus constituted intestinal metaplasia. Hepatoblastoma and intestinal metaplasia/cholangiocellular tumor morphology appear to constitute different patterns of genetic programming induced by certain promoters in expanding clones of initiated hepatocytes, on favorable genetic backgrounds such as that of D2B6F1 male mice.

Adenocarcinoma↗
PubMed1999

Targeted ablation of secretin-producing cells in transgenic mice reveals a common differentiation pathway with multiple enteroendocrine cell lineages in the small intestine.

The four cell types of gut epithelium, enteroendocrine cells, enterocytes, Paneth cells and goblet cells, arise from a common totipotent stem cell located in the mid portion of the intestinal gland. The secretin-producing (S) cell is one of at least ten cell types belonging to the diffuse neuroendocrine system of the gut. We have examined the developmental relationship between secretin cells and other enteroendocrine cell types by conditional ablation of secretin cells in transgenic mice expressing herpes simplex virus 1 thymidine kinase (HSVTK). Ganciclovir-treated mice showed markedly increased numbers of apoptotic cells at the crypt-villus junction. Unexpectedly, ganciclovir treatment induced nearly complete ablation of enteroendocrine cells expressing cholecystokinin and peptide YY/glucagon (L cells) as well as secretin cells, suggesting a close developmental relationship between these three cell types. In addition, ganciclovir reduced the number of enteroendocrine cells producing gastric inhibitory polypeptide, substance-P, somatostatin and serotonin. During recovery from ganciclovir treatment, the enteroendocrine cells repopulated the intestine in normal numbers, suggesting that a common early endocrine progenitor was spared. Expression of BETA2, a basic helix-loop-helix protein essential for differentiation of secretin and cholecystokinin cells was examined in the proximal small intestine. BETA2 expression was seen in all enteroendocrine cells and not seen in nonendocrine cells. These results suggest that most small intestinal endocrine cells are developmentally related and that a close developmental relationship exists between secretin-producing S cells and cholecystokinin-producing and L type enteroendocrine cells. In addition, our work shows the existence of a multipotent endocrine-committed cell type and locates this hybrid multipotent cell type to a region of the intestine populated by relatively immature cells.

Animals↗