Background and Objective
Chronic localized pancreatic inflammation in the form of chronic pancreatitis is an established risk factor for human pancreatic ductal adenocarcinoma (PDAC) development. Constitutive activation of inflammation-related signal transducer and activator of transcription (Stat)3 signaling has been implicated in the development and progression a number of malignancies, including PDAC. Although, the Janus Kinase (Jak)/Stat pathway is a potential drug target, clinicopathological, molecular, and prognostic features of Stat3-activated PDAC remain uncertain. Our aim was to determine the clinicopathological impact of this inflammatory pathway in resectable PDAC.
Using a tissue microarray-based cohort of PDAC from 86 patients undergoing pancreaticoduodenectomy with curative intent and complete clinicopathological data available, we evaluated expression of the interleukin-6 receptor (IL-6R)/Jak/Stat pathway by immunohistochemistry. IL-6R, Jak, phospho (p)-Jak, Stat3, pStat3Tyr705, and pStat3Ser727 were assessed in PDAC and pancreatic intraepithelial neoplasia. A Cox regression multivariate analysis model was used to determine factors influencing survival. Activation of the IL-6R/Jak/Stat3 pathway was compared with the systemic inflammatory response as measured by serum C-reactive protein levels.
High pJak was associated with reduced overall survival in multivariate analysis when compared with those with moderate or low expression (p = 0.036; hazard ratio (HR) = 1.68) as was pStat3Tyr705 (p < 0.001; HR = 2.66) independent of lymph node status and tumor grade. Patients with a combination of pJakhigh/pStat3Tyr705 high expression had an especially poor prognosis (median survival of 8.8 months; 95 % CI, 4.4–13.2). While the IL-6R/Jak/Stat pathway did not correlate with serum C-reactive protein levels, high pStat3 expression was associated with a reduction in the density of the local tumoral immune response.
Activation of the Jak/Stat3 pathway via phosphorylation was associated with adverse outcome following resection of PDAC with curative intent supporting potential roles for pJak and pStat3 as prognostic biomarkers markers and therapeutic targets.
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Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin 2008; 58(2):71–96
Sener SF, Fremgen A, Menck HR, Winchester DP. Pancreatic cancer: a report of treatment and survival trends for 100,313 patients diagnosed from 1985–1995, using the National Cancer Database. J Am Coll Surg 1999; 189(1):1–7.
Jamieson NB, Denley SM, Logue J, Mackenzie DJ, Foulis AK, Dickson EJ, Imrie CW, Carter R, McKay CJ, McMillan DC. A prospective comparison of the prognostic value of tumor- and patient-related factors in patients undergoing potentially curative surgery for pancreatic ductal adenocarcinoma. Annals of Surgical Oncology 2011; 18(8):2318–28.
Glen P, Jamieson NB, McMillan DC, Carter R, Imrie CW, McKay CJ. Evaluation of an inflammation-based prognostic score in patients with inoperable pancreatic cancer. Pancreatology 2006; 6(5):450–3.
Martignoni ME, Kunze P, Hildebrandt W, Kunzli B, Berberat P, Giese T, Kloters O, Hammer J, Buchler MW, Giese NA, Friess H. Role of mononuclear cells and inflammatory cytokines in pancreatic cancer-related cachexia. Clin Cancer Res 2005; 11(16):5802–8.
Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankisch PG, Andersen JR, Dimagno EP, Andren-Sandberg A, Domellof L. Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med 1993; 328(20):1433–7.
Guerra C, Schuhmacher AJ, Canamero M, Grippo PJ, Verdaguer L, Perez-Gallego L, Dubus P, Sandgren EP, Barbacid M. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 2007; 11(3):291–302.
Coughlin SS, Calle EE, Patel AV, Thun MJ. Predictors of pancreatic cancer mortality among a large cohort of United States adults. Cancer Causes Control 2000; 11(10):915–23
Aggarwal BB, Kunnumakkara AB, Harikumar KB, Gupta SR, Tharakan ST, Koca C, Dey S, Sung B. Signal transducer and activator of transcription-3, inflammation, and cancer: how intimate is the relationship? Ann N Y Acad Sci 2009; 1171:59–76.
Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009; 9(11):798–809.
Yeh HH, Lai WW, Chen HH, Liu HS, Su WC. Autocrine IL-6-induced Stat3 activation contributes to the pathogenesis of lung adenocarcinoma and malignant pleural effusion. Oncogene 2006; 25(31):4300–9.
Morikawa T, Baba Y, Yamauchi M, Kuchiba A, Nosho K, Shima K, Tanaka N, Huttenhower C, Frank DA, Fuchs CS, Ogino S. STAT3 expression, molecular features, inflammation patterns, and prognosis in a database of 724 colorectal cancers. Clin Cancer Res 2011; 17(6):1452–62.
Bromberg J, Wang TC. Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell 2009; 15(2):79–80.
Ferrone C, Dranoff G. Dual roles for immunity in gastrointestinal cancers. J Clin Oncol 2010; 28(26):4045–51.
Scholz A, Heinze S, Detjen KM, Peters M, Welzel M, Hauff P, Schirner M, Wiedenmann B, Rosewicz S. Activated signal transducer and activator of transcription 3 (STAT3) supports the malignant phenotype of human pancreatic cancer. Gastroenterology 2003; 125(3):891–905.
Miyatsuka T, Kaneto H, Shiraiwa T, Matsuoka TA, Yamamoto K, Kato K, Nakamura Y, Akira S, Takeda K, Kajimoto Y, Yamasaki Y, Sandgren EP, Kawaguchi Y, Wright CV, Fujitani Y. Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation. Genes Dev 2006; 20(11):1435–40.
Fukuda A, Wang SC, Morris JPt, Folias AE, Liou A, Kim GE, Akira S, Boucher KM, Firpo MA, Mulvihill SJ, Hebrok M. Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell 2011; 19(4):441–55.
Aggarwal BB, Vijayalekshmi RV, Sung B. Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res 2009; 15(2):425–30.
Lin L, Hutzen B, Zuo M, Ball S, Deangelis S, Foust E, Pandit B, Ihnat MA, Shenoy SS, Kulp S, Li PK, Li C, Fuchs J, Lin J. Novel STAT3 phosphorylation inhibitors exhibit potent growth-suppressive activity in pancreatic and breast cancer cells. Cancer Res 2010; 70(6):2445–54.
Neoptolemos JP, Stocken DD, Dunn JA, Almond J, Beger HG, Pederzoli P, Bassi C, Dervenis C, Fernandez-Cruz L, Lacaine F, Buckels J, Deakin M, Adab FA, Sutton R, Imrie C, Ihse I, Tihanyi T, Olah A, Pedrazzoli S, Spooner D, Kerr DJ, Friess H, Buchler MW. Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial. Ann Surg 2001; 234(6):758–68.
Jamieson NB, Foulis AK, Oien KA, Going JJ, Glen P, Dickson EJ, Imrie CW, McKay CJ, Carter R. Positive mobilization margins alone do not influence survival following pancreatico-duodenectomy for pancreatic ductal adenocarcinoma. Ann Surg 2010; 251(6):1003–10.
The Royal College of Pathologists. Standards and Minimum Datasets for Reporting Cancers. Minimum Dataset for the Histopathological Reporting of Pancreatic, Ampulla of Vater and Bile Duct Carcinoma. London: The Royal College of Pathologists, 2002.
Jamieson NB, Mohamed M, Oien KA, Foulis AK, Dickson EJ, Imrie CW, Carter CR, McKay CJ, McMillan DC. The relationship between tumor inflammatory cell infiltrate and outcome in patients with pancreatic ductal adenocarcinoma. Ann Surg Oncol 2012; 19(11):3581–90.
Tam L, McGlynn LM, Traynor P, Mukherjee R, Bartlett JM, Edwards J. Expression levels of the JAK/STAT pathway in the transition from hormone-sensitive to hormone-refractory prostate cancer. Br J Cancer 2007; 97(3):378–83.
Morton JP, Timpson P, Karim SA, Ridgway RA, Athineos D, Doyle B, Jamieson NB, Oien KA, Lowy AM, Brunton VG, Frame MC, Evans TR, Sansom OJ. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc Natl Acad Sci U S A 2010; 107(1):246–51.
Kennedy AL, Morton JP, Manoharan I, Nelson DM, Jamieson NB, Pawlikowski JS, McBryan T, Doyle B, McKay C, Oien KA, Enders GH, Zhang R, Sansom OJ, Adams PD. Activation of the PIK3CA/AKT pathway suppresses senescence induced by an activated RAS oncogene to promote tumorigenesis. Mol Cell 2011; 42(1):36–49.
Kirkegaard T, Edwards J, Tovey S, McGlynn LM, Krishna SN, Mukherjee R, Tam L, Munro AF, Dunne B, Bartlett JM. Observer variation in immunohistochemical analysis of protein expression, time for a change? Histopathology 2006; 48(7):787–94.
McCarty KS, Jr., Szabo E, Flowers JL, Cox EB, Leight GS, Miller L, Konrath J, Soper JT, Budwit DA, Creasman WT, et al. Use of a monoclonal anti-estrogen receptor antibody in the immunohistochemical evaluation of human tumors. Cancer Res 1986; 46(8 Suppl):4244s–4248s.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144(5):646–74.
Maniati E, Bossard M, Cook N, Candido JB, Emami-Shahri N, Nedospasov SA, Balkwill FR, Tuveson DA, Hagemann T. Crosstalk between the canonical NF-kappaB and Notch signaling pathways inhibits Ppargamma expression and promotes pancreatic cancer progression in mice. J Clin Invest 2011; 121(12):4685–99.
Proctor MJ, Morrison DS, Talwar D, Balmer SM, Fletcher CD, O’Reilly DS, Foulis AK, Horgan PG, McMillan DC. A comparison of inflammation-based prognostic scores in patients with cancer. A Glasgow Inflammation Outcome Study. Eur J Cancer 2011; 47(17):2633–41.
Nesbitt JE, Fuller GM. Differential regulation of interleukin-6 receptor and gp130 gene expression in rat hepatocytes. Mol Biol Cell 1992; 3(1):103–12.
Corcoran RB, Contino G, Deshpande V, Tzatsos A, Conrad C, Benes CH, Levy DE, Settleman J, Engelman JA, Bardeesy N. STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res 2011; 71(14):5020–9.
Ebrahimi B, Tucker SL, Li D, Abbruzzese JL, Kurzrock R. Cytokines in pancreatic carcinoma: correlation with phenotypic characteristics and prognosis. Cancer 2004; 101(12):2727–36.
Talar-Wojnarowska R, Gasiorowska A, Smolarz B, Romanowicz-Makowska H, Kulig A, Malecka-Panas E. Clinical significance of interleukin-6 (IL-6) gene polymorphism and IL-6 serum level in pancreatic adenocarcinoma and chronic pancreatitis. Dig Dis Sci 2009; 54(3):683–9.
Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Kloppel G, Yoshimura A, Reindl W, Sipos B, Akira S, Schmid RM, Algul H. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 2011; 19(4):456–69.
Li N, Grivennikov SI, Karin M. The unholy trinity: inflammation, cytokines, and STAT3 shape the cancer microenvironment. Cancer Cell 2011; 19(4):429–31.
Schindler C, Darnell JE, Jr. Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. Annu Rev Biochem 1995; 64:621–51.
Zouein FA, Duhe RJ, Booz GW. JAKs go nuclear: emerging role of nuclear JAK1 and JAK2 in gene expression and cell growth. Growth Factors 2011; 29(6):245–52.
Nilsson J, Helou K, Kovacs A, Bendahl PO, Bjursell G, Ferno M, Carlsson P, Kannius-Janson M. Nuclear Janus-activated kinase 2/nuclear factor 1-C2 suppresses tumorigenesis and epithelial-to-mesenchymal transition by repressing Forkhead box F1. Cancer Res 2010; 70(5):2020–9.
Lin J, Jin X, Rothman K, Lin HJ, Tang H, Burke W. Modulation of signal transducer and activator of transcription 3 activities by p53 tumor suppressor in breast cancer cells. Cancer Res 2002; 62(2):376–80.
Doucas H, Mann CD, Sutton CD, Garcea G, Neal CP, Berry DP, Manson MM. Expression of nuclear Notch3 in pancreatic adenocarcinomas is associated with adverse clinical features, and correlates with the expression of STAT3 and phosphorylated Akt. J Surg Oncol 2008; 97(1):63–8.
Farrow B, Sugiyama Y, Chen A, Uffort E, Nealon W, Mark Evers B. Inflammatory mechanisms contributing to pancreatic cancer development. Ann Surg 2004; 239(6):763–9.
Bracci PM. Obesity and pancreatic cancer: overview of epidemiologic evidence and biologic mechanisms. Mol Carcinog 2012; 51(1):53–63.
Hursting SD, Berger NA. Energy balance, host-related factors, and cancer progression. J Clin Oncol 2010; 28(26):4058–65.
Kowalska I, Straczkowski M, Nikolajuk A, Adamska A, Karczewska-Kupczewska M, Otziomek E, Kinalska I, Gorska M. Insulin resistance, serum adiponectin, and proinflammatory markers in young subjects with the metabolic syndrome. Metabolism 2008; 57(11):1539–44.
Halappanavar S, Stampfli MR, Berndt-Weis L, Williams A, Douglas GR, Yauk CL. Toxicogenomic analysis of mainstream tobacco smoke-exposed mice reveals repression of plasminogen activator inhibitor-1 gene in heart. Inhal Toxicol 2009; 21(1):78–85.
Hedvat M, Huszar D, Herrmann A, Gozgit JM, Schroeder A, Sheehy A, Buettner R, Proia D, Kowolik CM, Xin H, Armstrong B, Bebernitz G, Weng S, Wang L, Ye M, McEachern K, Chen H, Morosini D, Bell K, Alimzhanov M, Ioannidis S, McCoon P, Cao ZA, Yu H, Jove R, Zinda M. The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell 2009; 16(6):487–97.
Li H, Huang C, Huang K, Wu W, Jiang T, Cao J, Feng Z, Qiu Z. STAT3 knockdown reduces pancreatic cancer cell invasiveness and matrix metalloproteinase-7 expression in nude mice. PLoS One 2011; 6(10):e25941.
Nagaraj NS, Washington MK, Merchant NB. Combined blockade of Src kinase and epidermal growth factor receptor with gemcitabine overcomes STAT3-mediated resistance of inhibition of pancreatic tumor growth. Clin Cancer Res 2011; 17(3):483–93.
Verbeke CS, Leitch D, Menon KV, McMahon MJ, Guillou PJ, Anthoney A. Redefining the R1 resection in pancreatic cancer. Br J Surg 2006; 93(10):1232–7.
Poon E, Harris AL, Ashcroft M. Targeting the hypoxia-inducible factor (HIF) pathway in cancer. Expert Rev Mol Med 2009; 11:e26.
Lang SA, Moser C, Gaumann A, Klein D, Glockzin G, Popp FC, Dahlke MH, Piso P, Schlitt HJ, Geissler EK, Stoeltzing O. Targeting heat shock protein 90 in pancreatic cancer impairs insulin-like growth factor-I receptor signaling, disrupts an interleukin-6/signal-transducer and activator of transcription 3/hypoxia-inducible factor-1alpha autocrine loop, and reduces orthotopic tumor growth. Clin Cancer Res 2007; 13(21):6459–68.
Majewski IJ, Bernards R. Taming the dragon: genomic biomarkers to individualize the treatment of cancer. Nat Med 2011; 17(3):304–12.
Presentation: This work has been presented in part at the 46th Annual Pancreas Club Meeting, San Diego, Friday 18th May 2012.
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Denley, S.M., Jamieson, N.B., McCall, P. et al. Activation of the IL-6R/Jak/Stat Pathway is Associated with a Poor Outcome in Resected Pancreatic Ductal Adenocarcinoma. J Gastrointest Surg 17, 887–898 (2013). https://doi.org/10.1007/s11605-013-2168-7