Gastric cancer development in mice lacking the SHP2 binding site on the IL-6 family co-receptor gp130 (original) (raw)
Related papers
Expression of transforming growth factor 13(TGF43) receptor type II (RH) is required for the growth-inhebitory effects of TGF-fi on prolifer ating epithelial cells. TGF-j3 Ril mutations have been identified in a broad spectrum of human epithelial malignancies, including colon and gastric cancers, and are highly correlated with development of TGF4J resistance in cell lines derived from these tumors. In this study, the role of TGF-fi RU In regulating the tumorigenic potential of the SNU-638 human gastric cancer cell line was investigated by infecting these cells with retroviral construct (MFG) expressing TGF-fi RH. The SNU-638 cell line displays the DNA replication error phenotype and encodes a truncated, inactive TGF-fi RI! protein. Infection of these cells with retroviral constructs expressing wild-type TGF-fi 1111led to significant increases in TGF-fl RI! mRNA and protein expression. These cells responded to exogenous TGF4J with reduced proliferation compared to that of control cells infected with retroviral vector expressing chloramphenicol acetyltranferase. Addition of TGF-@-neutralizingantibodies led to increased proliferation of wild type TGF-fi RII.expressing SNU-638 cells but had no effect on control cells. The latter finding suggests that TGF-@acts in an autocrine fashion to inhibit cell proliferationin SNU-638cells. When transplantedinto athymic nude mice, wild-type TGF-@3 1111-expressing SNU-638 cells showed decreasedand delayed tumorigenicitycomparedwith control cells. This study suggests a strong association between the expression of wild-type TGF-1J RI! and the degree of malignancy in human gastric cancer cells.
Cancer research, 1989
Expression of mRNA-encoding transforming growth factors alpha and beta (TGF alpha and beta), epidermal growth factor receptor (EGFR), and platelet-derived growth factors (PDGF) A and B chains was examined in 63 human gastric biopsies. Despite considerable individual variation, transcript levels were generally higher in 16 paired gastric tumors compared with surrounding epithelium. Marked increases were observed for the TGFs and c-sis, whereas EGFR mRNA was poorly expressed; there was no correlation with pathological staging of the cancers. In the nonneoplastic tissues, 14 had normal histology and 27 displayed superficial (SG) or atrophic gastritis (AG). Transcript levels greater than or equal to + were similar between these categories for all the growth factors, but were about 50% higher for EGFR in the tissues with gastritis. Concurrent expression of TGF alpha and EGFR (greater than or equal to + level) was more frequent in the paired tumors (38%) than in adjacent nonmalignant tiss...
Gastroenterology, 2009
Gastric cancer is the second most common cause of cancer-related mortality worldwide, mainly as a result of late-stage detection. Interleukin (IL)-11 is a multifunctional cytokine reported to be up-regulated in human gastric cancer. Methods: We investigated the importance of IL-11 in gastric cancer progression by examining its role in a variety of mouse gastric tumor models, as well as in nonneoplastic and tumor tissues taken from gastric cancer patients. We then determined the transcriptional and translational outcomes of IL-11 overexpression in normal gastric mucosa and identified a novel gene signature important early in the progression toward gastric tumorigenesis. Results: IL-11 was up-regulated significantly in 4 diverse mouse models of gastric pathology as well as in human biopsy specimens adjacent to and within gastric cancer. Removal of IL-11 co-receptor ␣ significantly reduced HK-/-mouse fundic hyperplasia and ablated gp130 757F/F mouse tumorigenesis. Exogenous IL-11 but not IL-6 activated oncogenic signal transducer and activator of transcription-3, and altered expression of novel proliferative and cytoprotective genes RegIII-, RegIII-␥, gremlin-1, clusterin, and growth arrest specific-1 in wild-type gastric mucosa, a gene signature common in gp130 757F/F and HK-/-tumors as well as nonneoplastic mucosa of gastric cancer patients. One week of chronic IL-11 administration in wild-type mice sustained the gene signature, causing pretumorigenic changes in both antrum and fundus. Conclusions: Increased gastric IL-11 alters expression of proliferative and cytoprotective genes and promotes pretumorigenic cellular changes.
International Journal of Cancer, 1988
The expressions of epidermal growth factor (EGF) and its receptor were studied immunohistochemicafly in a total of 156 gastric carcinomas; 26 early and 130 advanced. No EGF immunoreactivity was found in early carcinomas, while EGFpositive tumor cells were detected in 38 (29.2%) of the 130 advanced carcinomas. EGF receptor immunoreactivity was detected in one (3.8%) of the 26 early carcinomas and in 44 (33.8%) of the 130 advanced carcinomas, the incidence being significantly different @<0.01). Out of the 130 advanced carcinomas, 17 (13. I %) had synchronous expression of EGF and its receptor and most of the tumors with strong expression of EGF were positive to EGF receptor. A significant correlation was observed between the depth of tumor invasion and EGF or its receptor immunoreactivity in tumor cells @< 0.05).
Augmented gp130-mediated cytokine signalling accompanies human gastric cancer progression
Journal of Pathology, 2007
H. pylori infection accounts for most cases of gastric cancer, but the initiating events remain unclear. The principal H. pylori pathogenicity-associated CagA protein disrupts intracellular SHP-2 signalling pathways including those used by the IL-6 family cytokines, IL-6 and IL-11. Imbalanced IL-6 family cytokine signalling in the gp130757FF mouse model of gastric cancer arising from hyperactivation of oncogenic STAT3 after altered SHP-2 : ERK1/2 signalling produces dysplastic antral tumours preceded by gastritis and metaplasia. In a cohort of patient gastric biopsies with known H. pylori and CagA status, we investigated whether (i) STAT3 and ERK1/2 activation is altered in H. pylori-dependent gastritis; (ii) these profiles are more pronounced in CagA+ H. pylori infection; and (iii) the expression of pro-inflammatory cytokines that activate STAT3 and ERK 1/2 pathways is associated with progression to gastric cancer. IL-6, IL-11, and activated STAT3 and ERK1/2 were quantified in antral biopsies from gastritic stomach, metaplastic tissue, and resected gastric cancer tissues. We observed significantly increased STAT3 and ERK1/2 activation (p = 0.001) in H. pylori-dependent gastritis, which was further enhanced in the presence of CagA+ H. pylori strains. Of known gastric ligands that drive STAT3 activation, IL-6 expression was increased after H. pylori infection and both IL-6 and IL-11 were strongly up-regulated in the gastric cancer biopsies. This suggests a mechanism by which IL-11 drives STAT3 activation and proliferation during gastric cancer progression. We addressed this using an in vitro approach, demonstrating that recombinant human IL-11 activates STAT3 and concomitantly increases proliferation of MKN28 gastric epithelial cells. In summary, we show increased STAT3 and ERK1/2 activation in H. pylori-dependent gastritis that is likely driven in an IL-6-dependent fashion. IL-11 expression is associated with adenocarcinoma development, but not gastritic lesions, and we identify a novel mechanism for IL-11 as a potent inducer of proliferation in the human gastric cancer setting. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Expression of epidermal growth factor receptor in human gastric and colonic carcinomas
1988
The expression of epidermal growth factor (EGF) receptor was ex amined immunohistochemically in a total of 122 gastric and 61 colonie carcinomas, out of which 16 gastric and 8 colonie carcinomas were also examined by I2sl-labeled EGF binding analysis and Western blotting. The values of EGF binding were 12.68 ±1.98 (SE; n = 16) fmol/mg protein in gastric carcinomas and 5.72 ±2.15 (n = 8) fmol/mg protein in nonneoplastic gastric mucosa, the difference being significant (/' < 0.01). In the colonie tissue, the binding capacities in carcinomas and nonneo plastic mucosa were 13.29 ± 4.17 (n = 8) and 10.68 ± 0.41 (n = 3) fmol/ mg protein, respectively. Scatchard analysis of I25l-labeled EGF binding indicated a single class of receptors in gastric and colonie carcinomas with an apparent A"dvalue of from 111 to 277 (n = 4) and from 87.4 to 341 IM (n = 5), respectively, except for one gastric carcinoma having two classes of receptors (A',,= 15.9 and 896 CM).In Western blotting using monoclonal anti-EGF receptor antibody, various levels of EGF receptor expression were detected in 12 (85.7%) of the 14 gastric carcinomas and ¡n 7 (87.5%) of the 8 colonie carcinomas. Immunohistochemically, EGF receptor immunoreactivity was detected in one (3.8%) of the 26 early gastric carcinomas, while it was observed in 33 (34.4%) of the 96 advanced gastric carcinomas, the incidence between the two being signif icantly different (/' < 0.01). In the colonie carcinomas, 47 (77.1%) of the 61 cases showed positive immunoreactivity to EGF receptor, which did not differ by histológica!type.
Cytokine signalling via gp130 in gastric cancer
Biochimica Et Biophysica Acta: Molecular Cell Research, 2009
Cytokine signalling pathways that depend on gp130 are dysregulated in several epithelial cancers including gastric cancer. It has been established that blockade of SHP2 activation of MAPK signalling results in hyperactivation of STAT3 resulting in increased cell proliferation, angiogenesis, inflammation and inhibition of both immunocyte and epithelial cell apoptosis. Additionally, key genes regulated downstream of gp130 via MAPK activation such as the stomach-specific tumor suppressor gene tff1 are suppressed, contributing to the oncogenic outcome. The main cytokine driver of gp130 signalling in the stomach is IL-11, with IL-6 having little activity in the antral stomach in which most pathology initiates. IL-11 is up-regulated in both mouse and human gastric cancer and in pre-neoplastic mucosa. A characteristic gene signature specifically associated with IL-11 drive has been observed, although the prognostic value of the signature has not yet been assessed. Infection of human or mouse stomach with Helicobacter pylori, especially that expressing the CagA cytotoxin, produces constitutive MAPK activation, but also activated STAT3 and increases IL-11 expression. The possibility of designing and utilising small molecule inhibitors of either IL-11 or STAT3 activation may be worthwhile in developing new cancer therapeutics.
Digestive diseases and …, 2003
Aging and gastrointestinal malignancies, including that of the stomach are associated with increased activation of EGF-receptor (EGFR). Although the intracellular events that regulate this process are poorly understood, we hypothesize that loss of ERRP (EGFR-related protein; GenBank accession number AF187818), a recently identified negative regulator of EGFR, that possesses a substantial homology to the ligand binding extracellular domain of EGFR, may contribute to this event. In support of our hypothesis, we have observed that in Fischer-344 rats, whereas aging is associated with increased activation of EGFR in the gastric mucosa, expression of ERRP decreases in this tissue during this period. The latter is accompanied by a concomitant reduction in the amount of TGF-α bound to ERRP. In contrast, the amount of TGF-α bound to EGFR is found to be higher in the gastric mucosa of aged than in young rats. This is accompanied by a concomitant rise in EGFR levels. In the gastric mucosa, EGFR and ERRP are found to be colocalized. Gastric adenocarcinoma in humans, which has been shown to be associated with increased activation of EGFR, shows a substantial reduction in ERRP expression, when compared with benign tissues. We conclude that increased activation of EGFR in the gastric mucosa during aging and carcinogenesis may partly be due to the loss of ERRP.