Cell proliferation in developing human stomach

Ménard, Daniel; Arsenault, Pierre

doi:10.1007/bf00178918

Cited by 32 publications

(23 citation statements)

References 24 publications

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“…27 In our series of cases, the co-expression of P-gp and Bcl-x L suggests that, during stomach development, P-gp may have a physiological role, that is, to warrant survival of specific cellular populations, which characterizes the histological architecture and function of the mature organ. 28,29 In contrast, in the adult, the co-expression of P-gp and Bcl-x L , during Hp-related gastric carcinogenesis, could result in prolonged survival of abnormal cells in which the sequential accumulation of molecular alterations can ultimately lead to tumor promotion and progression. Hp is the most important single factor responsible for inflammatory and neoplastic gastric diseases.…”

Section: Discussionmentioning

confidence: 99%

MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells

Rocco

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Liguori

et al. 2012

Laboratory Investigation

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P-glycoprotein (P-gp), traditionally linked to cancer poor prognosis and multidrug resistance, is undetectable in normal gastric mucosa and overexpressed in gastric cancer (GC). We propose that P-gp may be involved in Helicobacter pylori (Hp)-related gastric carcinogenesis by inhibiting apoptosis. Aim of the study was to evaluate the expression of P-gp in fetal stomach and in Hp-related gastric carcinogenesis, the epigenetic control of the multi-drug resistance-1 (MDR1) gene, the localization and interaction between P-gp and Bcl-x L and the effect of the selective silencing of P-gp on cell survival. P-gp and Bcl-xl expression was evaluated by immunohistochemistry on 28 spontaneously abortive human fetuses, 66 Hp-negative subjects, 138 Hp-positive chronic gastritis (CG) of whom 28 with intestinal metaplasia (IM) and 45 intestinal type GCs. P-gp/Bcl-x L colocalization was investigated by confocal immunofluorescence microscopy and protein-protein interaction by co-immunoprecipitation, in basal conditions and after stress-induced apoptosis, in GC cell lines AGS and MKN-28 and hepatocellular carcinoma cell line Hep-G2. The role of P-gp in controlling apoptosis was evaluated by knocking down its expression with a specific small interfering RNAs in stressed AGS and MKN-28 cell lines. P-gp is expressed in the gastric mucosa of all human fetuses while, it is undetectable in adult normal mucosa and re-expressed in 30/110 Hp-positive non-IM-CG, 28/28 IM-CG and 40/45 GCs. P-gp expression directly correlates with that of Bcl-x L and with the promoter hypomethylation of the MDR1 gene. In GC cell lines, P-gp is localized on the plasma membrane and mitochondria where it colocalizes with Bcl-x L . Co-immunoprecipitation confirms the physical interaction between P-gp and Bcl-x L in AGS, MKN-28 and Hep-G2, at both basal level and after stress-induced apoptosis. The selective silencing of P-gp sensitizes GC cells to stress-induced apoptosis. P-gp behaves as an oncofetal protein that, by cross-talking with Bcl-x L , acts as an anti-apoptotic agent in Hp-related gastric carcinogenesis.Laboratory Investigation (2012) 92, 1407-1418; doi:10.1038/labinvest.2012.100; published online 2 July 2012 KEYWORDS: apoptosis; gastric carcinogenesis; H. pylori; P-glycoprotein; stomach morphogenesis P-glycoprotein (P-gp), the main product of the multi-drug resistance-1 (MDR1) gene, is a membrane-associated glycoprotein, normally expressed on the apical membrane of various cell types, 1 where it extrudes drugs and other toxic agents by acting as an energy-dependent efflux pump. 2 P-gp has been related to the intrinsic and acquired drug resistance in several neoplasms and represents one of the leading cause of the failure of chemotherapeutic treatments and poor prognosis of cancer. 3,4 In the gastrointestinal tract, under physiological conditions, P-gp expression progressively decreases from ileum, where it shows the maximum level of expression, to the stomach where it is absent. 5 In contrast, P-gp is generally overexpressed in gastric cancer (GC), wh...

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Section: Discussionmentioning

confidence: 99%

MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells

Rocco

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Liguori

et al. 2012

Laboratory Investigation

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“…As they progressively acquire their specialized digestive functions, undifferentiated cells migrate from the junctional proliferative compartment (isthmus) towards the foveolus where they differentiate into surface mucous cells or towards the neck and base of glands where they give rise to neck mucous cells, acidogenic parietal cells and zymogenic chief cells. Such concepts were verified previously for the developing human stomach (Ménard and Arsenault 1990;Ménard et al 1993).…”

Section: Introductionmentioning

confidence: 93%

Expression of integrin subunits correlates with differentiation of epithelial cell lineages in developing human gastric mucosa

Chénard¹,

Basque²,

Chailler³

et al. 2000

Anatomy and Embryology

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Laminins may play important roles in gastric gland development due to the differential localization of their alpha chains in human fetal fundic (oxyntic) mucosa. To extend this hypothesis, the current investigation was undertaken to compare the anatomical and cellular distribution of epithelial integrin subunits with those of laminin alpha chains in the human stomach at different ages (8-22 weeks of gestation) using indirect immunofluorescence. In the body, fundus and antrum regions, the beta1 and alpha6 subunits were associated with the entire epithelium at all developmental stages in the same way as laminin chains (alpha1/alpha5) detected with 4C7 monoclonal antibody. By contrast, the alpha3 and beta4 subunits of alpha3beta1 and alpha6beta4 integrins together with the laminin alpha3-chain were concentrated in the surface and foveolus compartments composed of differentiating mucous cells. Most importantly, the alpha2 integrin subunit was expressed in a rather complex pattern: (1) it was located at the base and at cell-cell boundaries of surface/foveolar epithelium, (2) was specifically repressed in differentiating parietal cells, and (3) its expression increased in maturing glands, where it became concentrated at the basal pole of epithelial cells simultaneously exhibiting a strong reactivity for laminin-2 (alpha2-chain). Taken altogether, our observations provide new evidence for the implication of different laminins and their receptors in the development of all human gastric epithelial lineages, surface mucous cells or glandular cells. The coordinated expression of alpha2 and alpha3 integrin subunits as well as the cellular re-distribution of alpha2beta1 integrin likely represent key events for the differentiation of glandular secretory cell types, especially maturing chief cells responsible for the synthesis/secretion of gastric digestive enzymes in fundic-type glands.

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“…To determine the rate and site of DNA synthesis, 2 Ci [ 3 H]thymidine (80 Ci/mmol; Amersham Pharmacia Biotech Canada, Oakville, Ontario, Canada) were added per ml medium during the last 6 h of culture (2,27). The level of radiopercursor incorporated into trichloroacetic acidprecipitable material was expressed as disintegrations per min/mg tissue and reported as stimulation percentage vs. the control value.…”

Section: Tritiated Thymidine Incorporationmentioning

confidence: 99%

“…T HE HUMAN gastric mucosa develops very early during fetal life (starting ϳ9 weeks), and adult-type compartmentalization of fundic (oxyntic) glands involved in mucus, acid, and zymogen secretion becomes rapidly established (1)(2)(3). Mucous epithelial cells differentiate from mitotic progenitors during their migration from the isthmus toward the foveolus and the surface, whereas parietal, endocrine, and chief zymogenic cells appear in the forming glands, similar to those in normal renewing adult mucosa (2,4).…”

mentioning

confidence: 99%

Coordinated Control of Fetal Gastric Epithelial Functions by Insulin-Like Growth Factors and Their Binding Proteins¹

2001

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The influence of insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) on human gastric functions are unknown. This study was undertaken to evaluate the ability of fetal gastric mucosa to produce IGFBPs and to test the effects of IGF-I, IGF-II, and synthetic truncated IGFs that do not interact with IGFBPs on epithelial cell proliferation and glandular zymogenic function. Western blots, Far Western blots, and immunohistochemistry were performed to characterize the expression of IGFBP-1 to -6 and IGF-I receptor. The effects of growth factors on DNA synthesis and lipase and pepsin activities were determined in gastric explants maintained in serum-free organ culture. All gastric epithelial cells expressed the IGF-I receptor. IGFBP-2 to -6 were produced endogenously, and they were differentially localized along the foveolus-gland axis and modulated in culture. Exogenous IGF-I and IGF-II were able to reduce lipase activity without affecting pepsin, whereas they exerted different effects on cellular proliferation: IGF-I was stimulatory and IGF-II had no influence. Illustrating the complex regulatory effect that IGFBPs exert on IGF bioactivity, both truncated IGF-I and IGF-II stimulated DNA synthesis more than IGF-I. Moreover, the striking difference in mitogenic activity between truncated and native forms of IGF-II probably reflects the abundance of IGFBP-2 and IGFBP-6, two IGF-II carriers, in the foveolus/neck region, including the proliferative compartment. This study provides new evidence for the involvement of an intragastric IGF/IGFBP system in the fine regulation of epithelial cell division and also in the control of zymogen synthesis. Moreover, the specific influence of IGF-II as a mitogen appears to be tightly regulated by IGFBP isoforms preferentially associated with this growth factor and proliferative cells.

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Cell proliferation in developing human stomach

Cited by 32 publications

References 24 publications

MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells

MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells

Expression of integrin subunits correlates with differentiation of epithelial cell lineages in developing human gastric mucosa

Coordinated Control of Fetal Gastric Epithelial Functions by Insulin-Like Growth Factors and Their Binding Proteins¹

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Cell proliferation in developing human stomach

Cited by 32 publications

References 24 publications

MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells

MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells

Expression of integrin subunits correlates with differentiation of epithelial cell lineages in developing human gastric mucosa

Coordinated Control of Fetal Gastric Epithelial Functions by Insulin-Like Growth Factors and Their Binding Proteins1

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Coordinated Control of Fetal Gastric Epithelial Functions by Insulin-Like Growth Factors and Their Binding Proteins¹