Expression and processing of gastrin in hepatocellular carcinoma, fibrolamellar carcinoma and cholangiocarcinoma

Caplin, Martyn; Khan, K; Savage, Kay; Rode, J.; Varró, Andrea; Michaeli, D; Grimes, Stephen; Brett, Bernard; Pounder, R. E.; Dhillon, Amar P.

doi:10.1016/s0168-8278(99)80114-7

Cited by 49 publications

(44 citation statements)

References 27 publications

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“…In support of this hypothesis, recent studies have shown that CCK-B/gastrin receptors are also expressed by human cholangiocarcinoma. 45 Consistent with antiproliferative properties of gastrin on cholangiocytes, preliminary data from our laboratory have shown 46 that gastrin inhibits the growth of cholangiocarcinoma by interacting with CCK-B/gastrin receptors through a transduction pathway involving IP 3 , Ca 2ϩ , and PKC␣. Direct interaction of gastrin with cholangiocytes is further supported by the finding that serum levels of somatostatin or insulin, which have been shown to modulate cholangiocyte proliferation, 4,13-15 do not change after chronic infusion of gastrin to BDL rats.…”

Section: Discussionmentioning

confidence: 69%

Gastrin inhibits cholangiocyte growth in bile duct-ligated rats by interaction with cholecystokinin-B/gastrin receptors via d -myo-inositol 1,4,5-triphosphate-, Ca2+-, and protein kinase C α-dependent mechanisms

et al. 2000

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We studied the role of gastrin in regulating cholangiocyte proliferation induced by bile duct ligation (BDL). In purified cholangiocytes, we evaluated (1) In humans, cholangiocyte proliferation occurs in extrahepatic biliary obstruction, in the course of chronic cholestatic liver diseases and in many forms of liver injury (e.g., in response to alcohol, toxin, or drugs). 1,2 In animal models of ductal hyperplasia, cholangiocytes (mitotically dormant in normal conditions 1,3,4 ) proliferate in response to pathological maneuvers including bile duct ligation (BDL). 2-6 After BDL, cholangiocyte proliferation is associated with an increase in basal and secretin-stimulated adenosine 3Ј, 5Ј-monophosphate (cAMP) levels. [5][6][7] The cAMP system plays an important role in the regulation of growth of cholangiocytes 8,9 and other epithelia. 10,11 We have shown that inhibition of cholangiocyte growth by vagotomy in BDL rats is dependent on reduced cholangiocyte cAMP levels. 8 Furthermore, chronic treatment with forskolin (an activator of adenyl cyclase 12 ) prevents the decrease in cAMP levels and cholangiocyte proliferation induced by vagotomy in BDL rats. 8 Cholangiocyte growth is regulated by a number of factors including growth factors, gastrointestinal hormones, and nerves. 4,8,9,[13][14][15] Acetylcholine plays an important role in sustaining cholangiocyte proliferation induced by BDL. 8 Somatostatin inhibits cholangiocyte growth in response to BDL as well as the growth of cholangiocarcinoma cell lines. 14,15 No data exist regarding the role of gastrin in the modulation of cholangiocyte proliferation.Gastrin receptor belongs to the family of cholecystokinin (CCK-A and CCK-B) receptors. 16 Gastrin regulates epithelial cell functions through Ca 2ϩ -, D-myo-inositol 1,4,5-triphos-

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Section: Discussionmentioning

confidence: 69%

Gastrin inhibits cholangiocyte growth in bile duct-ligated rats by interaction with cholecystokinin-B/gastrin receptors via d -myo-inositol 1,4,5-triphosphate-, Ca2+-, and protein kinase C α-dependent mechanisms

et al. 2000

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“…Gastrin has been demonstrated as the most important trophic factor for gastrointestinal mucosa as well as a promoter for growth of human cancers including gastric cancer [9,10], colon cancer [11,12], pancreatic cancer [13][14][15], liver cancer [16], lung cancer [17] and renal cancer [18] etc. The promotion effect of gastrin on tumor cell growth can be reached by either an autocrine or paracrine manners [19].…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical Examination of Gastrin, Gastrin Precursors, and Gastrin/CCK-2 Receptor in Human Esophageal Squamous Cell Carcinomas

Yuan

Liu

et al. 2008

Pathol. Oncol. Res.

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A promoting effect of gastrin on stimulating Barrett's oesophagus proliferation has been demonstrated, but whether it plays a regulating role for esophageal squamous cell carcinoma (ESCC) to date has not been fully investigated. The aim of this study is to examine the expressions of gastrin, gastrin precursors and gastrin/CCK-2 receptor in ESCC. Tissue specimen sections from 38 patients with ESSC obtained from a high incidence area of north China were assessed using immunohistochemistry for amidated gastrin, gastrin precursors (progastrin and glycine-extended gastrin) and gastrin/CCK-2 receptors. Their clinical histopathological significance was also analyzed. Of 38 ESCC, the immunoreactivities of gastrin, glycine-extended gastrin and progastrin were observed in 13.2% (5/38), 7.9% (3/38) and 23.68% (9/38) cases. The expression of progastrin was obviously higher than other gastrins, though not significantly (P > 0.05). In positive cases for gastrin or glycine-extended gastrin, the scores of positive tumor cell numbers were at a lower density (<10/abundant-distributed field). However, the scores of progastrin positive tumor cell density in five of nine positive cases were over 10/abundant-distributed field. The immunoreactivity of gastrin/CCK-2 receptor was also observed in 15.8% (6/38) ESCC cases. There was not significant correlation regarding immunohistochemical results with known histomorphological parameters i.e. gender, tumor location and TNM stages. Based on our current results, ESCC tumor cells could be a possible cellular source of gastrin precursors, which has been postulated to play a role in regulating the growth in some human tumor cells.

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“…The mechanisms involved in the transcriptional regulation of mammalian antral gastrin gene expression have been challenging to study in vitro because of the absence of G cell lines and in vivo because of the lack of appropriate transgenic models. In addition, although numerous reports have suggested that gastrin is upregulated in colon, liver, pancreatic, lung, and ovarian cancer (1,4,5,8,18,39), studies of cell-specific expression of gastrin in the setting of neoplasia have been limited.…”

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confidence: 99%

In vivo analysis of mouse gastrin gene regulation in enhanced GFP-BAC transgenic mice

Takaishi

Shibata

Tomita

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Gastrin is secreted from a subset of neuroendocrine cells residing in the gastric antrum known as G cells, but low levels are also expressed in fetal pancreas and intestine and in many solid malignancies. Although past studies have suggested that antral gastrin is transcriptionally regulated by inflammation, gastric pH, somatostatin, and neoplastic transformation, the transcriptional regulation of gastrin has not previously been demonstrated in vivo. Here, we describe the creation of an enhanced green fluorescent protein reporter (mGAS-EGFP) mouse using a bacterial artificial chromosome that contains the entire mouse gastrin gene. Three founder lines expressed GFP signals in the gastric antrum and the transitional zone to the corpus. In addition, GFP(+) cells could be detected in the fetal pancreatic islets and small intestinal villi, but not in these organs of the adult mice. The administration of acid-suppressive reagents such as proton pump inhibitor omeprazole and gastrin/CCK-2 receptor antagonist YF476 significantly increased GFP signal intensity and GFP(+) cell numbers in the antrum, whereas these parameters were decreased by overnight fasting, octreotide (long-lasting somatostatin ortholog) infusion, and Helicobacter felis infection. GFP(+) cells were also detected in the anterior lobe of the pituitary gland and importantly in the colonic tumor cells induced by administration with azoxymethane and dextran sulfate sodium salt. This transgenic mouse provides a useful tool to study the regulation of mouse gastrin gene in vivo, thus contributing to our understanding of the mechanisms involved in transcriptional control of the gastrin gene.

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Expression and processing of gastrin in hepatocellular carcinoma, fibrolamellar carcinoma and cholangiocarcinoma

Cited by 49 publications

References 27 publications

Gastrin inhibits cholangiocyte growth in bile duct-ligated rats by interaction with cholecystokinin-B/gastrin receptors via d -myo-inositol 1,4,5-triphosphate-, Ca2+-, and protein kinase C α-dependent mechanisms

Gastrin inhibits cholangiocyte growth in bile duct-ligated rats by interaction with cholecystokinin-B/gastrin receptors via d -myo-inositol 1,4,5-triphosphate-, Ca2+-, and protein kinase C α-dependent mechanisms

Immunohistochemical Examination of Gastrin, Gastrin Precursors, and Gastrin/CCK-2 Receptor in Human Esophageal Squamous Cell Carcinomas

In vivo analysis of mouse gastrin gene regulation in enhanced GFP-BAC transgenic mice

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