309
Views
61
CrossRef citations to date
0
Altmetric
Review

Inflammation and lung carcinogenesis: applying findings in prevention and treatment

, , , , , , , , , , , , & show all
Pages 1405-1421 | Published online: 10 Jan 2014

References

  • Jemal A, Siegel R, Ward E et al. Cancer statistics, 2007. CA Cancer J. Clin.57(1), 43–66 (2007).
  • Coussens LM, Werb Z. Inflammation and cancer. Nature420(6917), 860–867 (2002).
  • de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer development. Nat. Rev. Cancer6(1), 24–37 (2006).
  • Smith CJ, Perfetti TA, King JA. Perspectives on pulmonary inflammation and lung cancer risk in cigarette smokers. Inhal. Toxicol.18(9), 667–677 (2006).
  • Brody JS, Spira A. State of the art. Chronic obstructive pulmonary disease, inflammation, and lung cancer. Proc. Am. Thorac. Soc.3(6), 535–537 (2006).
  • Schreinemachers DM, Everson RB. Aspirin use and lung, colon, and breast cancer incidence in a prospective study. Epidemiology5(2), 138–146 (1994).
  • Moysich KB, Menezes RJ, Ronsani A et al. Regular aspirin use and lung cancer risk. BMC Cancer2, 31 (2002).
  • Katori M, Majima M. Cyclooxygenase-2: its rich diversity of roles and possible application of its selective inhibitors. Inflamm. Res.49(8), 367–392 (2000).
  • Herschman HR. Prostaglandin synthase 2. Biochim. Biophys. Acta1299(1), 125–140 (1996).
  • Malkowski MG, Ginell SL, Smith WL, Garavito RM. The productive conformation of arachidonic acid bound to prostaglandin synthase. Science289(5486), 1933–1937 (2000).
  • FitzGerald GA. COX-2 and beyond: approaches to prostaglandin inhibition in human disease. Nat. Rev. Drug Discov.2(11), 879–890 (2003).
  • Jick SS. The risk of gastrointestinal bleed, myocardial infarction, and newly diagnosed hypertension in users of meloxicam, diclofenac, naproxen, and piroxicam. Pharmacotherapy20(7), 741–744 (2000).
  • Vane JR. Biomedicine. Back to an aspirin a day? Science296(5567), 474–475 (2002).
  • Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J. Clin. Invest.116(1), 4–15 (2006).
  • Huang M, Stolina M, Sharma S et al. Non-small cell lung cancer cyclooxygenase-2-dependent regulation of cytokine balance in lymphocytes and macrophages: up-regulation of interleukin 10 and down-regulation of interleukin 12 production. Cancer Res.58(6), 1208–1216 (1998).
  • Wolff H, Saukkonen K, Anttila S et al. Expression of cyclooxygenase-2 in human lung carcinoma. Cancer Res.58(22), 4997–5001 (1998).
  • Hida T, Yatabe Y, Achiwa H et al. Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res.58(17), 3761–3764 (1998).
  • Brabender J, Park J, Metzger R et al. Prognostic significance of cyclooxygenase 2 mRNA expression in non-small cell lung cancer. Ann. Surg.235(3), 440–443 (2002).
  • Achiwa H, Yatabe Y, Hida T et al. Prognostic significance of elevated cyclooxygenase 2 expression in primary, resected lung adenocarcinomas. Clin. Cancer Res.5(5), 1001–1005 (1999).
  • Hosomi Y, Yokose T, Hirose Y et al. Increased cyclooxygenase 2 (COX-2) expression occurs frequently in precursor lesions of human adenocarcinoma of the lung. Lung Cancer30(2), 73–81 (2000).
  • Kim HS, Youm HR, Lee JS et al. Correlation between cyclooxygenase-2 and tumor angiogenesis in non-small cell lung cancer. Lung Cancer42(2), 163–170 (2003).
  • Khuri FR, Wu H, Lee JJ et al. Cyclooxygenase-2 overexpression is a marker of poor prognosis in stage I non-small cell lung cancer. Clin. Cancer Res.7(4), 861–867 (2001).
  • Tsubochi H, Sato N, Hiyama M et al. Combined analysis of cyclooxygenase-2 expression with p53 and Ki-67 in nonsmall cell lung cancer. Ann. Thorac. Surg.82(4), 1198–1204 (2006).
  • Campa D, Zienolddiny S, Maggini V et al. Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer. Carcinogenesis25(2), 229–235 (2004).
  • Huang M, Sharma S, Mao JT, Dubinett SM. Non-small cell lung cancer-derived soluble mediators and prostaglandin E2 enhance peripheral blood lymphocyte IL-10 transcription and protein production. J. Immunol.157(12), 5512–5520 (1996).
  • Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell83(3), 493–501 (1995).
  • Krysan K, Merchant FH, Zhu L et al. COX-2-dependent stabilization of survivin in non-small cell lung cancer. FASEB J.18(1), 206–208 (2004).
  • Krysan K, Dalwadi H, Sharma S, Pold M, Dubinett S. Cyclooxygenase 2-dependent expression of survivin is critical for apoptosis resistance in non-small cell lung cancer. Cancer Res.64(18), 6359–6362 (2004).
  • Leahy KM, Koki AT, Masferrer JL. Role of cyclooxygenases in angiogenesis. Curr. Med. Chem.7(11), 1163–1170 (2000).
  • Gately S, Li WW. Multiple roles of COX-2 in tumor angiogenesis: a target for antiangiogenic therapy. Semin. Oncol.31(2 Suppl. 7), 2–11 (2004).
  • Liu VC, Wong LY, Jang T et al. Tumor evasion of the immune system by converting CD4+CD25- T cells into CD4+CD25+ T regulatory cells: role of tumor-derived TGF-β. J. Immunol.178(5), 2883–2892 (2007).
  • Baratelli F, Lin Y, Zhu L et al. Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4+ T cells. J. Immunol.175(3), 1483–1490 (2005).
  • Dohadwala M, Luo J, Zhu L et al. Non-small cell lung cancer cyclooxygenase-2-dependent invasion is mediated by CD44. J. Biol. Chem.276(24), 20809–20812 (2001).
  • Dohadwala M, Batra RK, Luo J et al. Autocrine/paracrine prostaglandin E2 production by non-small cell lung cancer cells regulates matrix metalloproteinase-2 and CD44 in cyclooxygenase-2-dependent invasion. J. Biol. Chem.277(52), 50828–50833 (2002).
  • Sheng H, Shao J, Washington MK, DuBois RN. Prostaglandin E2 increases growth and motility of colorectal carcinoma cells. J. Biol. Chem.276(21), 18075–18081 (2001).
  • Riedl K, Krysan K, Pold M et al. Multifaceted roles of cyclooxygenase-2 in lung cancer. Drug Resist. Updat.7(3), 169–184 (2004).
  • Krysan K, Reckamp KL, Dalwadi H et al. Prostaglandin E2 activates mitogen-activated protein kinase/Erk pathway signaling and cell proliferation in non-small cell lung cancer cells in an epidermal growth factor receptor-independent manner. Cancer Res.65(14), 6275–6281 (2005).
  • Pai R, Soreghan B, Szabo IL et al. Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat. Med.8(3), 289–293 (2002).
  • Krysan K, Reckamp KL, Sharma S, Dubinett SM. The potential and rationale for COX-2 inhibitors in lung cancer. Anticancer Agents Med. Chem.6(3), 209–220 (2006).
  • Ding Y, Tong M, Liu S, Moscow JA, Tai HH. NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) behaves as a tumor suppressor in lung cancer. Carcinogenesis26(1), 65–72 (2005).
  • Wolf I, O’Kelly J, Rubinek T et al. 15-hydroxyprostaglandin dehydrogenase is a tumor suppressor of human breast cancer. Cancer Res.66(15), 7818–7823 (2006).
  • Cho H, Tai HH. Inhibition of NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) by cyclooxygenase inhibitors and chemopreventive agents. Prostaglandins Leukot. Essent. Fatty Acids67(6), 461–465 (2002).
  • Hazra S, Batra RK, Tai HH et al. Pioglitazone and rosiglitazone decrease prostaglandin E2 in non-small-cell lung cancer cells by up-regulating 15-hydroxyprostaglandin dehydrogenase. Mol. Pharmacol.71(6), 1715–1720 (2007).
  • Han S, Inoue H, Flowers LC, Sidell N. Control of COX-2 gene expression through peroxisome proliferator-activated receptor γ in human cervical cancer cells. Clin. Cancer Res.9(12), 4627–4635 (2003).
  • Subbaramaiah K, Lin DT, Hart JC, Dannenberg AJ. Peroxisome proliferator-activated receptor γ ligands suppress the transcriptional activation of cyclooxygenase-2. Evidence for involvement of activator protein-1 and CREB-binding protein/p300. J. Biol. Chem.276(15), 12440–12448 (2001).
  • Li MY, Deng H, Zhao JM, Dai D, Tan XY. PPARγ pathway activation results in apoptosis and COX-2 inhibition in HepG2 cells. World J. Gastroenterol.9(6), 1220–1226 (2003).
  • Berger J, Moller DE. The mechanisms of action of PPARs. Annu. Rev. Med.53, 409–435 (2002).
  • Inoue H, Tanabe T, Umesono K. Feedback control of cyclooxygenase-2 expression through PPARγ. J. Biol. Chem.275(36), 28028–28032 (2000).
  • Rossi A, Kapahi P, Natoli G et al. Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase. Nature403(6765), 103–108 (2000).
  • Keshamouni VG, Arenberg DA, Reddy RC et al. PPAR-γ activation inhibits angiogenesis by blocking ELR+CXC chemokine production in non-small cell lung cancer. Neoplasia7(3), 294–301 (2005).
  • Bren-Mattison Y, Van Putten V, Chan D et al. Peroxisome proliferator-activated receptor-γ (PPARγ) inhibits tumorigenesis by reversing the undifferentiated phenotype of metastatic non-small-cell lung cancer cells (NSCLC). Oncogene24(8), 1412–1422 (2005).
  • Su CG, Wen X, Bailey ST et al. A novel therapy for colitis utilizing PPAR-γ ligands to inhibit the epithelial inflammatory response. J. Clin. Invest.104(4), 383–389 (1999).
  • Chang TH, Szabo E. Induction of differentiation and apoptosis by ligands of peroxisome proliferator-activated receptor γ in non-small cell lung cancer. Cancer Res.60(4), 1129–1138 (2000).
  • Han S, Roman J. Peroxisome proliferator-activated receptor γ: a novel target for cancer therapeutics? Anticancer Drugs18(3), 237–244 (2007).
  • Li M, Pascual G, Glass CK. Peroxisome proliferator-activated receptor γ-dependent repression of the inducible nitric oxide synthase gene. Mol. Cell. Biol.20(13), 4699–4707 (2000).
  • Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature391(6662), 79–82 (1998).
  • Weng JR, Chen CY, Pinzone JJ, Ringel MD, Chen CS. Beyond peroxisome proliferator-activated receptor γ signaling: the multi-facets of the antitumor effect of thiazolidinediones. Endocr. Relat. Cancer13(2), 401–413 (2006).
  • Chawla A, Barak Y, Nagy L et al. PPAR-γ dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat. Med.7(1), 48–52 (2001).
  • Zou W, Liu X, Yue P, Khuri FR, Sun SY. PPARγ ligands enhance TRAIL-induced apoptosis through DR5 upregulation and c-FLIP downregulation in human lung cancer cells. Cancer Biol. Ther.6(1), 99–106 (2007).
  • Durbin RJ. Thiazolidinedione therapy in the prevention/delay of type 2 diabetes in patients with impaired glucose tolerance and insulin resistance. Diabetes Obes. Metab.6(4), 280–285 (2004).
  • Galli A, Mello T, Ceni E, Surrenti E, Surrenti C. The potential of antidiabetic thiazolidinediones for anticancer therapy. Expert Opin. Investig. Drugs15(9), 1039–1049 (2006).
  • Govindarajan R, Ratnasinghe L, Simmons DL et al. Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes. J. Clin. Oncol.25(12), 1476–1481 (2007).
  • Ramos-Nino ME, Maclean CD, Littenberg B. Association between cancer prevalence and use of thiazolidinediones (TZDs): results from the Vermont Diabetes Information System. BMC Med.5(1), 17 (2007).
  • Rosen CJ. The rosiglitazone story – lessons from an FDA advisory committee meeting. N. Engl. J. Med.357(9), 844–846 (2007).
  • No authors listed. Thiazolidinediones and cardiovascular disease. Med. Lett. Drugs Ther.49(1265), 57–58 (2007).
  • Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med.356(24), 2457–2471 (2007).
  • Stearman RS, Dwyer-Nield L, Zerbe L et al. Analysis of orthologous gene expression between human pulmonary adenocarcinoma and a carcinogen-induced murine model. Am. J. Pathol.167(6), 1763–1775 (2005).
  • Keith RL, Miller YE, Hudish TM et al. Pulmonary prostacyclin synthase overexpression chemoprevents tobacco smoke lung carcinogenesis in mice. Cancer Res.64(16), 5897–5904 (2004).
  • Keith RL, Miller YE, Hoshikawa Y et al. Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer. Cancer Res.62(3), 734–740 (2002).
  • Mao JT, Tsu IH, Dubinett SM et al. Modulation of pulmonary leukotriene B4 production by cyclooxygenase-2 inhibitors and lipopolysaccharide. Clin. Cancer Res.10(20), 6872–6878 (2004).
  • Dubois RN, Abramson SB, Crofford L et al. Cyclooxygenase in biology and disease. FASEB J.12(12), 1063–1073 (1998).
  • Breyer RM, Kennedy CR, Zhang Y, Breyer MD. Structure-function analyses of eicosanoid receptors. Physiologic and therapeutic implications. Ann. NY Acad. Sci.905, 221–231 (2000).
  • Yang L, Huang Y, Porta R et al. Host and direct antitumor effects and profound reduction in tumor metastasis with selective EP4 receptor antagonism. Cancer Res.66(19), 9665–9672 (2006).
  • Han S, Ritzenthaler JD, Wingerd B, Rivera HN, Roman J. Extracellular matrix fibronectin increases prostaglandin E2 receptor subtype EP4 in lung carcinoma cells through multiple signaling pathways: the role of AP-2. J. Biol. Chem.282(11), 7961–7972 (2007).
  • Sevenoaks MJ, Stockley RA. Chronic obstructive pulmonary disease, inflammation and co-morbidity – a common inflammatory phenotype? Respir. Res.7, 70 (2006).
  • Rennard SI. Chronic obstructive pulmonary disease: linking outcomes and pathobiology of disease modification. Proc. Am. Thorac. Soc.3(3), 276–280 (2006).
  • O’Donnell R, Breen D, Wilson S, Djukanovic R. Inflammatory cells in the airways in COPD. Thorax61(5), 448–454 (2006).
  • Reynolds PR, Cosio MG, Hoidal JR. Cigarette smoke-induced Egr-1 upregulates proinflammatory cytokines in pulmonary epithelial cells. Am. J. Respir. Cell Mol. Biol.35(3), 314–319 (2006).
  • Tan RJ, Fattman CL, Niehouse LM et al. Matrix metalloproteinases promote inflammation and fibrosis in asbestos-induced lung injury in mice. Am. J. Respir. Cell Mol. Biol.35(3), 289–297 (2006).
  • Soberman RJ, Christmas P. Revisiting prostacyclin: new directions in pulmonary fibrosis and inflammation. Am. J. Physiol. Lung Cell Mol. Physiol.291(2), L142–L143 (2006).
  • Charuworn B, Dohadwala M, Krysan K et al. Inflammation-mediated promotion of EMT in NSCLC: IL-1β mediates a MEK/Erk- and JNK/SAPK-dependent down-regulation of E-cadherin. In: Proceedings of the American Thoracic Society. Leff A (Ed.). The American Thoracic Society, NY , USA D96 (2006).
  • Leng Q, Bentwich Z, Borkow G. Increased TGF-β, Cbl-b and CTLA-4 levels and immunosuppression in association with chronic immune activation. Int. Immunol.18(5), 637–644 (2006).
  • Keshamouni VG, Michailidis G, Grasso CS et al. Differential protein expression profiling by iTRAQ-2DLC-MS/MS of lung cancer cells undergoing epithelial-mesenchymal transition reveals a migratory/invasive phenotype. J. Proteome Res.5(5), 1143–1154 (2006).
  • Dohadwala M, Yang SC, Luo J et al. Cyclooxygenase-2-dependent regulation of E-cadherin: prostaglandin E(2) induces transcriptional repressors ZEB1 and snail in non-small cell lung cancer. Cancer Res.66(10), 5338–5345 (2006).
  • Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr. Opin. Cell Biol.17(5), 548–558 (2005).
  • Dey SK, Chien SM, Cox CL, Crist RD. Prostaglandin synthesis in the rabbit blastocyst. Prostaglandins19(3), 449–453 (1980).
  • Davis DL, Pakrasi PL, Dey SK. Prostaglandins in swine blastocysts. Biol. Reprod.28(5), 1114–1118 (1983).
  • Cha YI, Kim SH, Sepich D et al. Cyclooxygenase-1-derived PGE2 promotes cell motility via the G-protein-coupled EP4 receptor during vertebrate gastrulation. Genes Dev.20(1), 77–86 (2006).
  • Thiery JP. Epithelial–mesenchymal transitions in development and pathologies. Curr. Opin. Cell Biol.15(6), 740–746 (2003).
  • Dasari V, Gallup M, Lemjabbar H, Maltseva I, McNamara N. Epithelial–mesenchymal transition in lung cancer: is tobacco the “smoking gun”? Am. J. Respir. Cell Mol. Biol.35(1), 3–9 (2006).
  • Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial–mesenchymal transition: new insights in signaling, development, and disease. J. Cell Biol.172(7), 973–981 (2006).
  • Lynch TJ, Adjei AA, Bunn PA Jr et al. Summary statement: novel agents in the treatment of lung cancer: advances in epidermal growth factor receptor-targeted agents. Clin. Cancer Res.12(14 Pt 2), S4365–S4371 (2006).
  • Lippman SM, Gibson N, Subbaramaiah K, Dannenberg AJ. Combined targeting of the epidermal growth factor receptor and cyclooxygenase-2 pathways. Clin. Cancer Res.11(17), 6097–6099 (2005).
  • Siegfried JM, Gubish CT, Rothstein ME, Queiroz De Oliveira PE, Stabile LP. Signaling pathways involved in cyclooxygenase-2 induction by hepatocyte growth factor in non-small cell lung cancer. Mol. Pharmacol.72(3), 769–779 (2007).
  • Subbaramaiah K, Norton L, Gerald W, Dannenberg AJ. Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: evidence for involvement of AP-1 and PEA3. J. Biol. Chem.277(21), 18649–18657 (2002).
  • Engelman JA, Zejnullahu K, Mitsudomi T et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science316(5827), 1039–1043 (2007).
  • Hsu AL, Ching TT, Wang DS et al. The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independently of Bcl-2. J. Biol. Chem.275(15), 11397–11403 (2000).
  • Liu XH, Yao S, Kirschenbaum A, Levine AC. NS398, a selective cyclooxygenase-2 inhibitor, induces apoptosis and down-regulates bcl-2 expression in LNCaP cells. Cancer Res.58(19), 4245–4249 (1998).
  • Sheng H, Shao J, Morrow J, Beauchamp R, DuBois R. Modulation of apoptosis and Bcl-2 expression by prostaglandin E2 in human colon cancer cells. Cancer Res.58, 362–366 (1998).
  • Tsujii M, Dubois R. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase-2. Cell83, 493–501 (1995).
  • Lin MT, Lee RC, Yang PC, Ho FM, Kuo ML. Cyclooxygenase-2 inducing Mcl-1-dependent survival mechanism in human lung adenocarcinoma CL1.0 cells. Involvement of phosphatidylinositol 3-kinase/Akt pathway. J. Biol. Chem.276(52), 48997–49002 (2001).
  • Chang YW, Jakobi R, McGinty A et al. Cyclooxygenase 2 promotes cell survival by stimulation of dynein light chain expression and inhibition of neuronal nitric oxide synthase activity. Mol. Cell. Biol.20(22), 8571–8579 (2000).
  • Erickson BA, Longo WE, Panesar N, Mazuski JE, Kaminski DL. The effect of selective cyclooxygenase inhibitors on intestinal epithelial cell mitogenesis. J. Surg. Res.81(1), 101–107 (1999).
  • Hara A, Yoshimi N, Niwa M, Ino N, Mori H. Apoptosis induced by NS-398, a selective cyclooxygenase-2 inhibitor, in human colorectal cancer cell lines. Jpn. J. Cancer Res.88(6), 600–604 (1997).
  • Sawaoka H, Kawano S, Tsuji S et al. Cyclooxygenase-2 inhibitors suppress the growth of gastric cancer xenografts via induction of apoptosis in nude mice. Am. J. Physiol.274(6 Pt 1), G1061–G1067 (1998).
  • Chang HC, Weng CF. Cyclooxygenase-2 level and culture conditions influence NS398-induced apoptosis and caspase activation in lung cancer cells. Oncol. Rep.8(6), 1321–1325 (2001).
  • Hida T, Kozaki K, Muramatsu H et al. Cyclooxygenase-2 inhibitor induces apoptosis and enhances cytotoxicity of various anticancer agents in non-small cell lung cancer cell lines. Clin. Cancer Res.6(5), 2006–2011 (2000).
  • Yao R, Rioux N, Castonguay A, You M. Inhibition of COX-2 and induction of apoptosis: two determinants of nonsteroidal anti-inflammatory drugs’ chemopreventive efficacies in mouse lung tumorigenesis. Exp. Lung Res.26(8), 731–742 (2000).
  • Gadgeel SM, Ruckdeschel JC, Heath EI et al. Phase II study of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), and celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, in patients with platinum refractory non-small cell lung cancer (NSCLC). J. Thorac. Oncol.2(4), 299–305 (2007).
  • O’Byrne KJ, Danson S, Dunlop D et al. Combination therapy with gefitinib and rofecoxib in patients with platinum-pretreated relapsed non small-cell lung cancer. J. Clin. Oncol.25(22), 3266–3273 (2007).
  • Reckamp KL, Krysan K, Morrow JD et al. A Phase I trial to determine the optimal biological dose of celecoxib when combined with erlotinib in advanced non-small cell lung cancer. Clin. Cancer Res.12(11 Pt 1), 3381–3388 (2006).
  • Witta SE, Gemmill RM, Hirsch FR et al. Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res.66(2), 944–950 (2006).
  • Garber K. HDAC inhibitors overcome first hurdle. Nat. Biotechnol.25(1), 17–19 (2007).
  • Hogan BL. Bone morphogenetic proteins in development. Curr. Opin. Genet. Dev.6(4), 432–438 (1996).
  • Okada H, Kalluri R. Recapitulation of kidney development paradigms by BMP-7 reverses chronic renal injury. Clin. Exp. Nephrol.9(2), 100–101 (2005).
  • Kopp JB. BMP-7 and the proximal tubule. Kidney Int.61(1), 351–352 (2002).
  • Shi W, Zhao J, Anderson KD, Warburton D. Gremlin negatively modulates BMP-4 induction of embryonic mouse lung branching morphogenesis. Am. J. Physiol. Lung Cell Mol. Physiol.280(5), L1030–L1039 (2001).
  • Bellusci S, Henderson R, Winnier G, Oikawa T, Hogan BL. Evidence from normal expression and targeted misexpression that bone morphogenetic protein (Bmp-4) plays a role in mouse embryonic lung morphogenesis. Development122(6), 1693–1702 (1996).
  • Zeisberg M, Hanai J, Sugimoto H et al. BMP-7 counteracts TGF-β1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat. Med.9(7), 964–968 (2003).
  • Zeisberg M, Yang C, Martino M et al. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J. Biol. Chem.282(32), 23337–23347(2007).
  • Langenfeld EM, Bojnowski J, Perone J, Langenfeld J. Expression of bone morphogenetic proteins in human lung carcinomas. Ann. Thorac. Surg.80(3), 1028–1032 (2005).
  • Dubinett S, Sharma S, Huang M, Mao JT, Batra R. Cancer and immune dysfunction. In: Immunotherapy at the Crossroads: How Tumors Evade Immunity and What Can be Done. Finke J, Bukowski R (Eds). Human Press Inc., NJ, USA 335 (2004).
  • Sogn JA. Tumor immunology: the glass is half full. Immunity9(6), 757–763 (1998).
  • Yoshino I, Yano T, Murata M et al. Tumor-reactive T-cells accumulate in lung cancer tissues but fail to respond due to tumor cell-derived factor. Cancer Res.52(4), 775–781 (1992).
  • Batra RK, Lin Y, Sharma S et al. Non-small cell lung cancer-derived soluble mediators enhance apoptosis in activated T lymphocytes through an I κ B kinase-dependent mechanism. Cancer Res.63(3), 642–646 (2003).
  • Redente EF, Orlicky DJ, Bouchard RJ, Malkinson AM. Tumor signaling to the bone marrow changes the phenotype of monocytes and pulmonary macrophages during urethane-induced primary lung tumorigenesis in A/J mice. Am. J. Pathol.170(2), 693–708 (2007).
  • Huang M, Wang J, Lee P et al. Human non-small cell lung cancer cells express a type 2 cytokine pattern. Cancer Res.55(17), 3847–3853 (1995).
  • Neuner A, Schindel M, Wildenberg U et al. Cytokine secretion: clinical relevance of immunosuppression in non-small cell lung cancer. Lung Cancer34(Suppl. 2), S79–S82 (2001).
  • Alleva DG, Burger CJ, Elgert KD. Tumor-induced regulation of suppressor macrophage nitric oxide and TNF-α production: role of tumor-derived IL-10, TGF-β and prostaglandin E2. J. Immunol.153(4), 1674–1686 (1994).
  • Stolina M, Sharma S, Lin Y et al. Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. J. Immunol.164(1), 361–370 (2000).
  • Wu C-Y, Demeure C, Kiniwa M, Gately M, Delespesse G. IL-12 induces the production of IFN-γ by neonatal human CD4 T cells. J. Immunol.151(4), 1938–1949 (1993).
  • D’Andrea A, Aste-Amezaga M, Valiante NM et al. Interleukin 10 (IL-10) inhibits human lymphocyte interferon γ-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J. Exp. Med.178(3), 1041–1048 (1993).
  • Hagenbaugh A, Sharma S, Dubinett S et al. Altered immune responses in IL-10 transgenic mice. J. Exp. Med.185(12), 2101–2110 (1997).
  • Halak BK, Maguire HC Jr, Lattime EC. Tumor-induced interleukin-10 inhibits type 1 immune responses directed at a tumor antigen as well as a non-tumor antigen present at the tumor site. Cancer Res.59(4), 911–917 (1999).
  • Kim J, Modlin RL, Moy RL et al. IL-10 production in cutaneous basal and squamous cell carcinomas: a mechanism for evading the local T cell immune response. J. Immunol.155(4), 2240–2247 (1995).
  • Sharma S, Stolina M, Lin Y et al. T cell-derived IL-10 promotes lung cancer growth by suppressing both T cell and APC function. J. Immunol.163(9), 5020–5028 (1999).
  • Hatanaka H, Abe Y, Naruke M et al. Significant correlation between interleukin 10 expression and vascularization through angiopoietin/TIE2 networks in non-small cell lung cancer. Clin. Cancer Res.7(5), 1287–1292 (2001).
  • Hatanaka H, Abe Y, Kamiya T et al. Clinical implications of interleukin (IL)-10 induced by non-small-cell lung cancer. Ann. Oncol.11(7), 815–819 (2000).
  • De Vita F, Orditura M, Galizia G et al. Serum interleukin-10 levels as a prognostic factor in advanced non-small cell lung cancer patients. Chest117(2), 365–373 (2000).
  • Naruke M, Abe Y, Hatanaka H et al. Interleukin-10 expression is correlated with growth fraction in human non-small cell lung cancer xenografts. Int. J. Oncol.18(6), 1213–1217 (2001).
  • Colombo M, Vagliani M, Spreafico F et al. Amount of interleukin 12 available at the tumor site is critical for tumor regression. Cancer Res.56(11), 2531–2534 (1996).
  • Molina-Holgado E, Arevalo-Martin A, Ortiz S, Vela JM, Guaza C. Theiler’s virus infection induces the expression of cyclooxygenase-2 in murine astrocytes: inhibition by the anti-inflammatory cytokines interleukin-4 and interleukin-10. Neurosci. Lett.324(3), 237–241 (2002).
  • Bianchi R, Grohmann U, Belladonna M et al. IL-12 is both required and sufficient for initiating T cell reactivity to a class I-restricted tumor peptide (P815AB) following transfer of P815AB-pulsed dendritic cells. J. Immunol.157(4), 1589–1597 (1996).
  • Handel-Fernandez ME, Cheng X, Herbert LM, Lopez DM. Down-regulation of IL-12, not a shift from a T helper-1 to a T helper-2 phenotype, is responsible for impaired IFN-γ production in mammary tumor-bearing mice. J. Immunol.158(1), 280–286 (1997).
  • Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol.19, 683–765 (2001).
  • Pomini F, Caruso A, Challis JR. Interleukin-10 modifies the effects of interleukin-1β and tumor necrosis factor-α on the activity and expression of prostaglandin H synthase-2 and the NAD+-dependent 15-hydroxyprostaglandin dehydrogenase in cultured term human villous trophoblast and chorion trophoblast cells. J. Clin. Endocrinol. Metab.84(12), 4645–4651 (1999).
  • Heuze-Vourc’h N, Zhu L, Krysan K et al. Abnormal interleukin 10Rα expression contributes to the maintenance of elevated cyclooxygenase-2 in non-small cell lung cancer cells. Cancer Res.63(4), 766–770 (2003).
  • Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature392(6673), 245–252 (1998).
  • Trombetta ES, Mellman I. Cell biology of antigen processing in vitro and in vivo. Annu. Rev. Immunol.23, 975–1028 (2005).
  • Yang L, Yamagata N, Yadav R et al. Cancer-associated immunodeficiency and dendritic cell abnormalities mediated by the prostaglandin EP2 receptor. J. Clin. Invest.111(5), 727–735 (2003).
  • Sharma S, Stolina M, Yang SC et al. Tumor cyclooxygenase 2-dependent suppression of dendritic cell function. Clin. Cancer Res.9(3), 961–968 (2003).
  • Serafini P, De Santo C, Marigo I et al. Derangement of immune responses by myeloid suppressor cells. Cancer Immunol. Immunother.53(2), 64–72 (2004).
  • Serafini P, Borrello I, Bronte V. Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin. Cancer Biol.16(1), 53–65 (2006).
  • Rodriguez PC, Hernandez CP, Quiceno D et al. Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J. Exp. Med.202(7), 931–939 (2005).
  • Fontenot JD, Rudensky AY. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat. Immunol.6(4), 331–337 (2005).
  • Lee JM, Dubinett SM, Sharma S. Immunologic approaches to lung cancer therapy. In: Lung Cancer. Roth J (Ed.). Blackwell Publishers Inc., MA, USA (2005).
  • Sharma S, Yang SC, Zhu L et al. Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer. Cancer Res.65(12), 5211–5220 (2005).
  • Papiernik M, de Moraes ML, Pontoux C, Vasseur F, Penit C. Regulatory CD4 T cells: expression of IL-2R α chain, resistance to clonal deletion and IL-2 dependency. Int. Immunol.10(4), 371–378 (1998).
  • Nomura T, Sakaguchi S. Foxp3 and Aire in thymus-generated Treg cells: a link in self-tolerance. Nat. Immunol.8(4), 333–334 (2007).
  • Jordan MS, Boesteanu A, Reed AJ et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat. Immunol.2(4), 301–306 (2001).
  • Shevach EM. Regulatory T cells in autoimmmunity. Annu. Rev. Immunol.18, 423–449 (2000).
  • Sakaguchi S. The origin of FOXP3-expressing CD4+ regulatory T cells: thymus or periphery. J. Clin. Invest.112(9), 1310–1312 (2003).
  • Walker MR, Kasprowicz DJ, Gersuk VH et al. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25- T cells. J. Clin. Invest.112(9), 1437–1443 (2003).
  • Gavin MA, Rasmussen JP, Fontenot JD et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature445(7129), 771–775 (2007).
  • Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat. Rev. Immunol.7(1), 41–51 (2007).
  • Yu H, Jove R. The STATs of cancer – new molecular targets come of age. Nat. Rev. Cancer4(2), 97–105 (2004).
  • Murray PJ. The JAK-STAT signaling pathway: input and output integration. J. Immunol.178(5), 2623–2629 (2007).
  • Zhong Z, Wen Z, Darnell JE Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science264(5155), 95–98 (1994).
  • Yu CL, Meyer DJ, Campbell GS et al. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science269(5220), 81–83 (1995).
  • Odajima J, Matsumura I, Sonoyama J et al. Full oncogenic activities of v-Src are mediated by multiple signaling pathways. Ras as an essential mediator for cell survival. J. Biol. Chem.275(31), 24096–24105 (2000).
  • Turkson J, Bowman T, Garcia R et al. Stat3 activation by Src induces specific gene regulation and is required for cell transformation. Mol. Cell. Biol.18(5), 2545–2552 (1998).
  • Song L, Turkson J, Karras JG, Jove R, Haura EB. Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. Oncogene22(27), 4150–4165 (2003).
  • Niu G, Wright KL, Huang M et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene21(13), 2000–2008 (2002).
  • Wei D, Le X, Zheng L et al. Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene22(3), 319–329 (2003).
  • Bromberg JF, Wrzeszczynska MH, Devgan G et al. Stat3 as an oncogene. Cell98(3), 295–303 (1999).
  • Kortylewski M, Kujawski M, Wang T et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat. Med.11(12), 1314–1321 (2005).
  • Niu G, Heller R, Catlett-Falcone R et al. Gene therapy with dominant-negative Stat3 suppresses growth of the murine melanoma B16 tumor in vivo. Cancer Res.59(20), 5059–5063 (1999).
  • Turkson J, Zhang S, Palmer J et al. Inhibition of constitutive signal transducer and activator of transcription 3 activation by novel platinum complexes with potent antitumor activity. Mol. Cancer Ther.3(12), 1533–1542 (2004).
  • Haura EB, Livingston S, Coppola D. Autocrine interleukin-6/interleukin-6 receptor stimulation in non-small-cell lung cancer. Clin. Lung Cancer7(4), 273–275 (2006).
  • Yanagawa H, Sone S, Takahashi Y et al. Serum levels of interleukin 6 in patients with lung cancer. Br. J. Cancer71(5), 1095–1098 (1995).
  • Dalwadi H, Krysan K, Heuze-Vourc’h N et al. Cyclooxygenase-2-dependent activation of signal transducer and activator of transcription 3 by interleukin-6 in non-small cell lung cancer. Clin. Cancer Res.11(21), 7674–7682 (2005).
  • Turkson J, Ryan D, Kim JS et al. Phosphotyrosyl peptides block Stat3-mediated DNA binding activity, gene regulation, and cell transformation. J. Biol. Chem.276(48), 45443–45455 (2001).
  • Torchilin VP, Lukyanov AN. Peptide and protein drug delivery to and into tumors: challenges and solutions. Drug Discov. Today8(6), 259–266 (2003).
  • Turkson J, Kim JS, Zhang S et al. Novel peptidomimetic inhibitors of signal transducer and activator of transcription 3 dimerization and biological activity. Mol. Cancer Ther.3(3), 261–269 (2004).
  • Siddiquee K, Zhang S, Guida WC et al. Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc. Natl Acad. Sci. USA104(18), 7391–7396 (2007).
  • Gunning PT, Katt WP, Glenn M et al. Isoform selective inhibition of STAT1 or STAT3 homo-dimerization via peptidomimetic probes: structural recognition of STAT SH2 domains. Bioorg. Med. Chem. Lett.17(7), 1875–1878 (2007).
  • Bromberg J, Darnell JE Jr. The role of STATs in transcriptional control and their impact on cellular function. Oncogene19(21), 2468–2473 (2000).
  • Turkson J, Zhang S, Mora LB et al. A novel platinum compound inhibits constitutive Stat3 signaling and induces cell cycle arrest and apoptosis of malignant cells. J. Biol. Chem.280(38), 32979–32988 (2005).
  • Sanchez-Ceja SG, Reyes-Maldonado E, Vazquez-Manriquez ME et al. Differential expression of STAT5 and Bcl-xL, and high expression of Neu and STAT3 in non-small-cell lung carcinoma. Lung Cancer54(2), 163–168 (2006).
  • Alvarez JV, Greulich H, Sellers WR, Meyerson M, Frank DA. Signal transducer and activator of transcription 3 is required for the oncogenic effects of non-small-cell lung cancer-associated mutations of the epidermal growth factor receptor. Cancer Res.66(6), 3162–3168 (2006).
  • Nunes M, Shi C, Greenberger LM. Phosphorylation of extracellular signal-regulated kinase 1 and 2, protein kinase B, and signal transducer and activator of transcription 3 are differently inhibited by an epidermal growth factor receptor inhibitor, EKB-569, in tumor cells and normal human keratinocytes. Mol. Cancer Ther.3(1), 21–27 (2004).
  • Cui X, Yang SC, Sharma S, Heuze-Vourc’h N, Dubinett SM. IL-4 regulates COX-2 and PGE2 production in human non-small cell lung cancer. Biochem. Biophys. Res. Commun.343(4), 995–1001 (2006).
  • Cui X, Zhang L, Luo J et al. Unphosphorylated STAT6 contributes to constitutive cyclooxygenase-2 expression in human non-small cell lung cancer. Oncogene26(29), 4253–4260 (2007).
  • Karin M. Nuclear factor-κB in cancer development and progression. Nature441(7092), 431–436 (2006).
  • Tang X, Liu D, Shishodia S et al. Nuclear factor-κB (NF-κB) is frequently expressed in lung cancer and preneoplastic lesions. Cancer107(11), 2637–2646 (2006).
  • Aggarwal BB. Nuclear factor-κB: the enemy within. Cancer Cell6(3), 203–208 (2004).
  • Luo JL, Kamata H, Karin M. IKK/NF-κB signaling: balancing life and death – a new approach to cancer therapy. J. Clin. Invest.115(10), 2625–2632 (2005).
  • Bharti AC, Aggarwal BB. Nuclear factor-κ B and cancer: its role in prevention and therapy. Biochem. Pharmacol.64(5–6), 883–888 (2002).
  • Ballaz S, Mulshine JL. The potential contributions of chronic inflammation to lung carcinogenesis. Clin. Lung Cancer5(1), 46–62 (2003).
  • Karin M, Yamamoto Y, Wang QM. The IKK NF-κ B system: a treasure trove for drug development. Nat. Rev. Drug Discov.3(1), 17–26 (2004).
  • Moncada S, Vane JR. Prostacyclin: its biosynthesis, actions and clinical potential. Philos. Trans. R. Soc. Lond. B Biol. Sci.294(1072), 305–329 (1981).
  • Honn KV, Cicone B, Skoff A. Prostacyclin: a potent antimetastatic agent. Science212(4500), 1270–1272 (1981).
  • Lim HJ, Moon I, Han K. Transcriptional cofactors exhibit differential preference toward peroxisome proliferator-activated receptors α and δ in uterine cells. Endocrinology145(6), 2886–2895 (2004).
  • Fukumoto K, Yano Y, Virgona N et al. Peroxisome proliferator-activated receptor δ as a molecular target to regulate lung cancer cell growth. FEBS Lett.579(17), 3829–3836 (2005).
  • Malkinson AM. Role of inflammation in mouse lung tumorigenesis: a review. Exp. Lung Res.31(1), 57–82 (2005).
  • Dwyer-Nield LD, Srebernak MC, Barrett BS et al. Cytokines differentially regulate the synthesis of prostanoid and nitric oxide mediators in tumorigenic versus non-tumorigenic mouse lung epithelial cell lines. Carcinogenesis26(7), 1196–1206 (2005).
  • Malkinson AM, Beer DS. Major effect on susceptibility to urethan-induced pulmonary adenoma by a single gene in BALB/cBy mice. J. Natl Cancer Inst.70(5), 931–936 (1983).
  • Malkinson AM, Koski KM, Evans WA, Festing MF. Butylated hydroxytoluene exposure is necessary to induce lung tumors in BALB mice treated with 3-methylcholanthrene. Cancer Res.57(14), 2832–2834 (1997).
  • Duperron C, Castonguay A. Chemopreventive efficacies of aspirin and sulindac against lung tumorigenesis in A/J mice. Carcinogenesis18(5), 1001–1006 (1997).
  • Rioux N, Castonguay A. Prevention of NNK-induced lung tumorigenesis in A/J mice by acetylsalicylic acid and NS-398. Cancer Res.58(23), 5354–5360 (1998).
  • Ermert L, Dierkes C, Ermert M. Immunohistochemical expression of cyclooxygenase isoenzymes and downstream enzymes in human lung tumors. Clin. Cancer Res.9(5), 1604–1610 (2003).
  • Stearman RS, Grady MC, Nana-Sinkam P, Varella-Garcia M, Geraci MW. Genetic and epigenetic regulation of the human prostacyclin synthase promoter in lung cancer cell lines. Mol. Cancer Res.5(3), 295–308 (2007).
  • Vane JR, Botting RM. Pharmacodynamic profile of prostacyclin. Am. J. Cardiol.75(3), 3A–10A (1995).
  • Komarova EA, Krivokrysenko V, Wang K et al. p53 is a suppressor of inflammatory response in mice. FASEB J.19(8), 1030–1032 (2005).
  • Rayet B, Gelinas C. Aberrant rel/nfkb genes and activity in human cancer. Oncogene18(49), 6938–6947 (1999).
  • Sparmann A, Bar-Sagi D. Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell6(5), 447–458 (2004).
  • Pold M, Zhu LX, Sharma S et al. Cyclooxygenase-2-dependent expression of angiogenic CXC chemokines ENA-78/CXC Ligand (CXCL) 5 and interleukin-8/CXCL8 in human non-small cell lung cancer. Cancer Res.64(5), 1853–1860 (2004).
  • Hanahan D, Weinberg RA. The hallmarks of cancer. Cell100(1), 57–70 (2000).
  • Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J. Clin. Invest.117(5), 1175–1183 (2007).
  • Clevers H. At the crossroads of inflammation and cancer. Cell118(6), 671–674 (2004).
  • Spira A, Beane JE, Shah V et al. Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer. Nat. Med.13(3), 361–366 (2007).
  • Seike M, Yanaihara N, Bowman ED et al. Use of a cytokine gene expression signature in lung adenocarcinoma and the surrounding tissue as a prognostic classifier. J. Natl Cancer Inst.99(16), 1257–1269 (2007).
  • Lilenbaum R, Socinski MA, Altorki NK et al. Randomized Phase II trial of docetaxel/irinotecan and gemcitabine/irinotecan with or without celecoxib in the second-line treatment of non-small-cell lung cancer. J. Clin. Oncol.24(30), 4825–4832 (2006).
  • Kummar S, Kinders R, Rubinstein L et al. Compressing drug development timelines in oncology using Phase ‘0’ trials. Nat. Rev. Cancer7(2), 131–139 (2007).
  • Mao JT, Fishbein MC, Adams B et al. Celecoxib decreases Ki-67 proliferative index in active smokers. Clin. Cancer Res.12(1), 314–320 (2006).
  • Mao JT, Cui X, Reckamp K et al. Chemoprevention strategies with cyclooxygenase-2 inhibitors for lung cancer. Clin. Lung Cancer7(1), 30–39 (2005).
  • Lee JM, Mao JT, Krysan K, Dubinett SM. Significance of cyclooxygenase-2 in prognosis, targeted therapy and chemoprevention of NSCLC. Future Oncol.3(2), 149–153 (2007).
  • Dannenberg AJ, Subbaramaiah K. Targeting cyclooxygenase-2 in human neoplasia: rationale and promise. Cancer Cell4(6), 431–436 (2003).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.