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Adding Fuel to the Fire: STAT3 Priming of Gastric Tumorigenesis

2006; Elsevier BV; Volume: 131; Issue: 4 Linguagem: Inglês

10.1053/j.gastro.2006.08.049

1528-0012

Lee A. Denson,

Mycobacterium research and diagnosis

See “STAT3 activation regulates growth, inflammation, and vascularization in a mouse model of gastric tumorigenesis” by Judd LM, Bredin K, Kalantzis A, Jenkins BJ, Ernst M, and Giraud AS, on page 1073. See “STAT3 activation regulates growth, inflammation, and vascularization in a mouse model of gastric tumorigenesis” by Judd LM, Bredin K, Kalantzis A, Jenkins BJ, Ernst M, and Giraud AS, on page 1073. The most significant factor in the pathogenesis of gastric cancer is chronic infection with Helicobacter pylori. However, the majority of infected individuals do not develop cancer, illustrating the importance of additional host, bacterial, and dietary factors.1Smith M.G. Hold G.L. Tahara E. El-Omar E.M. Cellular and molecular aspects of gastric cancer.World J Gastroenterol. 2006; 12: 2979-2990PubMed Google Scholar This includes the host inflammatory response, because risk is increased in individuals with proinflammatory cytokine/chemokine gene polymorphisms. Recent studies have suggested that activation of signal transducer and activator of transcription 3 (STAT3) should be included as an aspect of the host response, which can promote tumorigenesis.2Bromberg J. Stat proteins and oncogenesis.J Clin Invest. 2002; 109: 1139-1142Crossref PubMed Scopus (734) Google Scholar GP130 family cytokines signal by binding to their cognate receptors in combination with the gp130 signaling receptor to induce activation of intracellular targets, including STAT3.3Rose-John S. Scheller J. Elson G. Jones S.A. Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer.J Leukoc Biol. 2006; 80: 227-236Crossref PubMed Scopus (514) Google Scholar The Src homology domain 2 (SH2)-containing protein tyrosine phosphatase (SHP2) and suppressor of cytokine signaling 3 (SOCS3) then bind to the Y757 residue on gp130 in a cytokine-inducible fashion, activating SHP2–ERK signaling and terminating STAT3 activation.4Fischer P. Lehmann U. Sobota R.M. Schmitz J. Niemand C. Linnemann S. Haan S. Behrmann I. Yoshimura A. Johnston J.A. Muller-Newen G. Heinrich P.C. Schaper F. The role of the inhibitors of interleukin-6 signal transduction SHP2 and SOCS3 for desensitization of interleukin-6 signalling.Biochem J. 2004; 378: 449-460Crossref PubMed Scopus (62) Google Scholar This system is ideally suited for triggering rapid wound healing and leukocyte recruitment responses, which are then terminated when the acute insult has resolved.5Hurst S.M. Wilkinson T.S. McLoughlin R.M. Jones S. Horiuchi S. Yamamoto N. Rose-John S. Fuller G.M. Topley N. Jones S.A. Il-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation.Immunity. 2001; 14: 705-714Abstract Full Text Full Text PDF PubMed Scopus (644) Google Scholar However, constitutive STAT3 activation can lead to cellular transformation.2Bromberg J. Stat proteins and oncogenesis.J Clin Invest. 2002; 109: 1139-1142Crossref PubMed Scopus (734) Google Scholar In a recent series of articles, Tebbutt et al6Tebbutt N.C. Giraud A.S. Inglese M. Jenkins B. Waring P. Clay F.J. Malki S. Alderman B.M. Grail D. Hollande F. Heath J.K. Ernst M. Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice.Nat Med. 2002; 8: 1089-1097Crossref PubMed Scopus (406) Google Scholar reported observations from a novel murine model of gastric tumorigenesis owing to STAT3 hyperactivation.6Tebbutt N.C. Giraud A.S. Inglese M. Jenkins B. Waring P. Clay F.J. Malki S. Alderman B.M. Grail D. Hollande F. Heath J.K. Ernst M. Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice.Nat Med. 2002; 8: 1089-1097Crossref PubMed Scopus (406) Google Scholar They introduced an inactivating knock-in mutation in the SHP2/SOCS3 binding site on gp130 (gp130Y757F/Y757F; F/F). Loss of SHP2/SOCS3 binding has led to STAT1/3 hyperactivation, reduced SHP2-ERK–dependent trefoil factor 1 (Tff1) expression, and distal gastric adenomas, which resemble human intestinal-type gastric cancer. To test the contribution of STAT3 activation, the investigators introduced haploinsufficiency in STAT3 (F/F:+/−). The F/F:+/− mice exhibit reduced interleukin (IL)-6–dependent STAT3 activation; activation of gp130 and exaggerated STAT1 activation are preserved.7Jenkins B.J. Grail D. Nheu T. Najdovska M. Wang B. Waring P. Inglese M. McLoughlin R.M. Jones S.A. Topley N. Baumann H. Judd L.M. Giraud A.S. Boussioutas A. Zhu H.J. Ernst M. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling.Nat Med. 2005; 11: 845-852Crossref PubMed Scopus (249) Google Scholar The size, but not frequency, of gastric adenomas was significantly reduced in the initial report. Susceptibility to gastric adenoma resided within the epithelial compartment, as reconstitution of lethally irradiated gp130+/+ mice with F/F bone marrow transferred the splenic, but not gastric, abnormalities.7Jenkins B.J. Grail D. Nheu T. Najdovska M. Wang B. Waring P. Inglese M. McLoughlin R.M. Jones S.A. Topley N. Baumann H. Judd L.M. Giraud A.S. Boussioutas A. Zhu H.J. Ernst M. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling.Nat Med. 2005; 11: 845-852Crossref PubMed Scopus (249) Google Scholar These data demonstrated that STAT3 target genes regulating proliferation, survival, and angiogenesis were critical in promoting growth of gastric adenomas whose initiation was likely triggered by loss of the SHP2-ERK–dependent tumor-suppressor gene, Tff1. The group then asked whether the gp130 ligands IL-6 or IL-11 were required for adenoma growth in the F/F mice. Surprisingly, they found that IL-6 deficiency did not reduce gastric tumor growth or vascularization.8Howlett M. Judd L.M. Jenkins B. La Gruta N.L. Grail D. Ernst M. Giraud A.S. Differential regulation of gastric tumor growth by cytokines that signal exclusively through the coreceptor gp130.Gastroenterology. 2005; 129: 1005-1018Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar In fact, IL-6–deficient mice exhibited enhanced tumor invasion, in conjunction with up-regulation of IL-11 and Mmp9/13. This may have implications for patient care, as it suggests that inhibition of IL-6 trans-signaling might have an unexpected adverse effect in IL-11/STAT3–positive gastric cancers, by promoting IL-11/MMP expression and tumor invasion. In the current study,9Judd L.M. Bredin K. Kalantzis A. Jenkins B.J. Ernst M. Giraud A.S. STAT3 activation regulates growth, inflammation, and vascularization in a mouse model of gastric tumorigenesis.Gastroenterology. 2006; 131: 1073-1085Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar the investigators have further characterized the role of STAT3 in gastric adenoma growth and invasion. They have also defined the contribution of the microbial environment. Tumor growth was significantly reduced by STAT3 haploinsufficiency. However, in contrast to the previous report, the frequency of gastric adenomas was also reduced, with tumor initiation linked to the degree of STAT3 activation in the F/F:+/− mice. The basis for the reduced penetrance of tumor initiation in the F/F:+/− mice was not determined, but may be due to a change in the gastric flora in the colony over time. Future studies using association with specific Helicobacter spp will be useful in defining the interaction between the flora and the host genetic defect for both tumor initiation and growth. The observation that a threshold level of STAT3 activation regulates tumor initiation in the F/F mouse is novel; most studies have suggested that STAT3 contributes primarily to tumor growth.2Bromberg J. Stat proteins and oncogenesis.J Clin Invest. 2002; 109: 1139-1142Crossref PubMed Scopus (734) Google Scholar, 7Jenkins B.J. Grail D. Nheu T. Najdovska M. Wang B. Waring P. Inglese M. McLoughlin R.M. Jones S.A. Topley N. Baumann H. Judd L.M. Giraud A.S. Boussioutas A. Zhu H.J. Ernst M. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling.Nat Med. 2005; 11: 845-852Crossref PubMed Scopus (249) Google Scholar Chronic inflammation is a critical component in the development of human gastric cancer. The inflammatory infiltrate was reduced by STAT3 haploinsufficiency, consistent with prior reports showing that STAT3 activation is required for leukocyte recruitment to the gut.10McLoughlin R.M. Hurst S.M. Nowell M.A. Harris D.A. Horiuchi S. Morgan L.W. Wilkinson T.S. Yamamoto N. Topley N. Jones S.A. Differential regulation of neutrophil-activating chemokines by IL-6 and its soluble receptor isoforms.J Immunol. 2004; 172: 5676-5683Crossref PubMed Scopus (120) Google Scholar, 11McLoughlin R.M. Jenkins B.J. Grail D. Williams A.S. Fielding C.A. Parker C.R. Ernst M. Topley N. Jones S.A. IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation.Proc Natl Acad Sci U S A. 2005; 102: 9589-9594Crossref PubMed Scopus (228) Google Scholar, 12McLoughlin R.M. Witowski J. Robson R.L. Wilkinson T.S. Hurst S.M. Williams A.S. Williams J.D. Rose-John S. Jones S.A. Topley N. Interplay between IFN-gamma and IL-6 signaling governs neutrophil trafficking and apoptosis during acute inflammation.J Clin Invest. 2003; 112: 598-607Crossref PubMed Scopus (229) Google Scholar, 13Romano M. Sironi M. Toniatti C. Polentarutti N. Fruscella P. Ghezzi P. Faggioni R. Luini W. van Hinsbergh V. Sozzani S. Bussolino F. Poli V. Ciliberto G. Mantovani A. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment.Immunity. 1997; 6: 315-325Abstract Full Text Full Text PDF PubMed Scopus (903) Google Scholar Expression of chemokines, which promote macrophage and neutrophil recruitment, including CCL1, CCL12, and CXCL2, was reduced. These chemokines may therefore be specifically involved in tumorigenesis, by driving recruitment of tumor-associated macrophages and neutrophils (TAM), which are a source for growth factors, cytokines, and MMPs, which promote tumor growth and invasion. To determine if an inflammatory response to the gastric flora was involved in setting a threshold level of STAT3 activation and thereby tumor growth, the flora in F/F mice were reduced with broad-spectrum antibiotics; this reduced tumor growth by approximately 70%. However, this occurred in the absence of a reduction in STAT3 activation, suggesting that activated STAT3 is necessary, but not sufficient, for maximal tumor growth. It will be important to identify the microbial targets distinct from STAT3, such as nuclear factor (NF)-κB, which contribute to tumorigenesis in the F/F mice. Surprisingly, the overall inflammatory infiltrate was not reduced by antibiotics, indicating that this was driven primarily by STAT3 hyperactivation. However, leukocytes, which likely drive tumorigenesis, including macrophages and activated neutrophils (eg, TAM) were reduced by approximately 50%. These data have shown that both environmental (stomach microbial flora) and host (STAT3 hyperactivation) factors contribute to leukocyte recruitment and activation and tumor growth in the F/F mouse. It would be interesting in future studies to determine whether oncogenic bacterial species (eg, H pylori in humans and H felis in mice) lead to differential NFκB and/or STAT3 activation in hosts who ultimately develop gastric cancer. The animal model of gastric cancer most similar to human disease involves infection of specific pathogen-free C57BL/6J mice with H felis. Over a period of 15 months, infected mice progress through each of the histologic stages observed in H pylori gastric tumorigenesis, culminating in antral carcinoma.14Cai X. Carlson J. Stoicov C. Li H. Wang T.C. Houghton J. Helicobacter felis eradication restores normal architecture and inhibits gastric cancer progression in C57BL/6 mice.Gastroenterology. 2005; 128: 1937-1952Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar As in the F/F mouse, glandular hyperplasia precedes dysplasia; this is completely reverted by early bacterial eradication. In humans, the H pylori CagA gene product has been strongly implicated in development of gastric adenocarcinoma, in part via activation of NFκB.1Smith M.G. Hold G.L. Tahara E. El-Omar E.M. Cellular and molecular aspects of gastric cancer.World J Gastroenterol. 2006; 12: 2979-2990PubMed Google Scholar Recently, tyrosine phosphorylated CagA has also been shown to interact with SHP2, leading to alterations in gastric epithelial cell morphology and motility that favor transformation.15Hatakeyama M. Higashi H. Helicobacter pylori CagA: a new paradigm for bacterial carcinogenesis.Cancer Sci. 2005; 96: 835-843Crossref PubMed Scopus (204) Google Scholar It would be interesting to know specifically what role activation of SHP2 or STAT3 plays in the H felis infection and eradication model, perhaps through a similar protocol using wild-type, F/F, STAT3+/−, and F/F:+/− mice. STAT1 is also constitutively activated in the F/F and F/F:+/− mice, and in contrast to STAT3, typically functions as a tumor suppressor. Therefore, gp130 activation up-regulates 2 distinct pathways involving SHP2 and STAT1, which may counterbalance the oncogenic effects of STAT3. In the antrum, loss of SHP2 alone is sufficient to permit tumorigenesis, perhaps pointing to the nonredundant importance of Tff1 as a tumor suppressor in this tissue. Importantly, tumors were not observed in other organs including colon, despite a widespread inflammatory infiltrate. Perhaps STAT1 activation is sufficient to inhibit tumorigenesis in other solid organs. This could be relevant in autoimmune diseases including inflammatory bowel disease, for example, in which STAT1/3 are typically both activated in the affected intestine. It would be useful in future studies to define genetically whether constitutive STAT1 activation in the F/F mouse actually limits tumor initiation and growth. Mechanisms characterized in the F/F mice are likely to be quite relevant to human disease; activated STAT3 has been demonstrated in up to 30% of human gastric cancer specimens, and inhibition of STAT3 activation in vitro has induced apoptosis of several human gastric cancer cell lines. The STAT3 target gene survivin has been implicated; STAT3 inhibition reduces survivin expression, and survivin overexpression promotes gastric cancer cell survival.16Kanda N. Seno H. Konda Y. Marusawa H. Kanai M. Nakajima T. Kawashima T. Nanakin A. Sawabu T. Uenoyama Y. Sekikawa A. Kawada M. Suzuki K. Kayahara T. Fukui H. Sawada M. Chiba T. STAT3 is constitutively activated and supports cell survival in association with survivin expression in gastric cancer cells.Oncogene. 2004; 23: 4921-4929Crossref PubMed Scopus (275) Google Scholar Importantly, STAT3 activation has also been related to vascular endothelial growth factor expression, increased microvessel density, and poor survival.17Gong W. Wang L. Yao J.C. Ajani J.A. Wei D. Aldape K.D. Xie K. Sawaya R. Huang S. Expression of activated signal transducer and activator of transcription 3 predicts expression of vascular endothelial growth factor in and angiogenic phenotype of human gastric cancer.Clin Cancer Res. 2005; 11: 1386-1393Crossref PubMed Scopus (137) Google Scholar, 18Yu L.F. Cheng Y. Qiao M.M. Zhang Y.P. Wu Y.L. Activation of STAT3 signaling in human stomach adenocarcinoma drug-resistant cell line and its relationship with expression of vascular endothelial growth factor.World J Gastroenterol. 2005; 11: 875-879PubMed Google Scholar In terms of mechanisms, inactivating hypermethylation of SOCS-1 has recently been linked to constitutive IL-6–dependent STAT3 activation in gastric cancer cell lines, and SOCS-1 methylation was detected in 30% of primary gastric tumors tested.19To K.F. Chan M.W. Leung W.K. Ng E.K. Yu J. Bai A.H. Lo A.W. Chu S.H. Tong J.H. Lo K.W. Sung J.J. Chan F.K. Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line.Br J Cancer. 2004; 91: 1335-1341Crossref PubMed Scopus (87) Google Scholar It will be of interest to determine whether reduced SHP2 and/or STAT1 activation is also present in a subset of human gastric cancers containing activated STAT3. Thus, constitutive STAT3 activation in gastric cancer can be added to the increasing list of human solid tumors, leukemias, and lymphomas in which this event may be required for cellular transformation.2Bromberg J. Stat proteins and oncogenesis.J Clin Invest. 2002; 109: 1139-1142Crossref PubMed Scopus (734) Google Scholar, 20Bromberg J.F. Horvath C.M. Besser D. Lathem W.W. Darnell Jr, J.E. Stat3 activation is required for cellular transformation by v-src.Mol Cell Biol. 1998; 18: 2553-2558Crossref PubMed Scopus (566) Google Scholar The primary clinical implication of this study is that therapy targeting the gp130 signaling axis may be useful in human gastric cancers expressing activated STAT3. This could be used in addition to antibiotic eradication of H pylori as a chemopreventive strategy, or to reduce growth and invasion of established tumors. Several strategies for inhibiting STAT signaling are in practice and/or development. Importantly, preclinical studies have shown that blocking constitutive STAT3 activation typically induces apoptosis of tumor cells without damaging normal cells, indicating that this approach may be well tolerated in terms of toxicity.21Buettner R. Mora L.B. Jove R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention.Clin Cancer Res. 2002; 8: 945-954PubMed Google Scholar The most common approach so far has involved blockade of specific cytokine/growth factor receptors or tyrosine kinases which are upstream of STAT activation; however, toxicity with this approach may be increased, because multiple downstream targets are affected. A more specific approach could involve administration of STAT3 antisense oligonucleotides, or a naturally occurring STAT3β dominant negative variant via gene therapy.21Buettner R. Mora L.B. Jove R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention.Clin Cancer Res. 2002; 8: 945-954PubMed Google Scholar Small molecule inhibitors of STAT3 dimerization and binding are also in development. Each of these approaches, when combined with diagnostic assays for the degree of STAT3 activation in a given tumor, holds promise. However, an understanding of the specific molecular mechanisms operative in an individual patient will be required to optimally use this strategy, without inducing adverse effects on STAT3-dependent epithelial wound healing or acute phase responses to infection.