Skip to main content
SpringerLink
Log in

Tumor Microenvironment

  • Chapter
  • First Online:
Lung Cancer

Part of the book series: Current Clinical Oncology ((CCO))

Abstract

While genetic changes are critical for the malignant transformation of epithelial cells, the microenvironment in which the cells reside also governs carcinogenesis. Most tumors arise within a cellular microenvironment characterized by suppressed host immunity, dysregulated inflammation, and increased production of cellular growth and survival factors that induce angiogenesis and inhibit apoptosis. The studies highlighted in this chapter indicate that the lung tumor and its microenvironment interact, together informing the process of carcinogenesis. Understanding the molecular mechanisms driving the contributions of the tumor microenvironment to lung carcinogenesis may afford us the opportunity to develop new drugs that target these reversible nonmutational events in the prevention and treatment of lung cancer. Findings from recent microenvironment-related clinical studies have implications for understanding the immunopathobiology of lung cancer, for targeting surgery and adjuvant therapy, and for designing future trials of adjuvant therapy. If the field is to progress and promising leads in the laboratory are to translate into anticancer therapeutics, future trials targeting the tumor microenvironment must incorporate improved patient risk assessment and selection, in addition to the continued evaluation of combination therapies using the optimal biological dose of each compound being tested. Appropriately targeting the tumor microenvironment in a highly selected patient population is a newly emerging strategy that holds unique potential for advancing the current state of lung cancer prevention and treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 279.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Bhattacharjee A, Richards WG, Staunton J et al (2001) Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci USA 98:13790-13795

    Article  PubMed  CAS  Google Scholar 

  2. Beer DG, Kardia SL, Huang CC et al (2002) Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nat Med 8:816-824

    PubMed  CAS  Google Scholar 

  3. Yanaihara N, Caplen N, Bowman E et al (2006) Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9:189-198

    Article  PubMed  CAS  Google Scholar 

  4. Potti A, Mukherjee S, Petersen R et al (2006) A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med 355:570-580

    Article  PubMed  CAS  Google Scholar 

  5. Seike M, Yanaihara N, Bowman ED et al (2007) Use of a cytokine gene expression signature in lung adenocarcinoma and the surrounding tissue as a prognostic classifier. J Natl Cancer Inst 99:1257-1269

    Article  PubMed  CAS  Google Scholar 

  6. Budhu A, Forgues M, Ye QH et al (2006) Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell 10:99-111

    Article  PubMed  CAS  Google Scholar 

  7. Farmer P, Bonnefoi H, Anderle P et al (2009) A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat Med 15:68-74

    Article  PubMed  CAS  Google Scholar 

  8. Zhong L, Roybal J, Chaerkady R et al (2008) Identification of secreted proteins that mediate cell-cell interactions in an in vitro model of the lung cancer microenvironment. Cancer Res 68:7237-7245

    Article  PubMed  CAS  Google Scholar 

  9. Allavena P, Sica A, Garlanda C, Mantovani A (2008) The Yin-Yang of tumor-associated macrophages in neoplastic progression and immune surveillance. Immunol Rev 222: 155-161

    Article  PubMed  CAS  Google Scholar 

  10. Bingle L, Brown NJ, Lewis CE (2002) The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 196:254-265

    Article  PubMed  CAS  Google Scholar 

  11. Dimitriadou V, Koutsilieris M (1997) Mast cell-tumor cell interactions: for or against tumour growth and metastasis? Anticancer Res 17:1541-1549

    PubMed  CAS  Google Scholar 

  12. Murdoch C, Muthana M, Coffelt SB, Lewis CE (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8:618-631

    Article  PubMed  CAS  Google Scholar 

  13. Chen JJ, Lin YC, Yao PL et al (2005) Tumor-associated macrophages: the double-edged sword in cancer progression. J Clin Oncol 23:953-964

    Article  PubMed  CAS  Google Scholar 

  14. Chen JJ, Yao PL, Yuan A et al (2003) Up-regulation of tumor interleukin-8 expression by infiltrating macrophages: its correlation with tumor angiogenesis and patient survival in non-small cell lung cancer. Clin Cancer Res 9:729-737

    PubMed  CAS  Google Scholar 

  15. Imada A, Shijubo N, Kojima H, Abe S (2000) Mast cells correlate with angiogenesis and poor outcome in stage I lung adenocarcinoma. Eur Respir J 15:1087-1093

    Article  PubMed  CAS  Google Scholar 

  16. Johnson SK, Kerr KM, Chapman AD et al (2000) Immune cell infiltrates and prognosis in primary carcinoma of the lung. Lung Cancer 27:27-35

    Article  PubMed  CAS  Google Scholar 

  17. Kerr KM, Johnson SK, King G, Kennedy MM, Weir J, Jeffrey R (1998) Partial regression in primary carcinoma of the lung: does it occur? Histopathology 33:55-63

    PubMed  CAS  Google Scholar 

  18. Koukourakis MI, Giatromanolaki A, Kakolyris S et al (1998) Different patterns of stromal and cancer cell thymidine phosphorylase reactivity in non-small-cell lung cancer: impact on tumour neoangiogenesis and survival. Br J Cancer 77:1696-1703

    Article  PubMed  CAS  Google Scholar 

  19. Nagata M, Shijubo N, Walls AF, Ichimiya S, Abe S, Sato N (2003) Chymase-positive mast cells in small sized adenocarcinoma of the lung. Virchows Arch 443:565-573

    Article  PubMed  Google Scholar 

  20. Takanami I, Takeuchi K, Kodaira S (1999) Tumor-associated macrophage infiltration in pulmonary adenocarcinoma: association with angiogenesis and poor prognosis. Oncology 57:138-142

    Article  PubMed  CAS  Google Scholar 

  21. Takanami I, Takeuchi K, Naruke M (2000) Mast cell density is associated with angiogenesis and poor prognosis in pulmonary adenocarcinoma. Cancer 88:2686-2692

    Article  PubMed  CAS  Google Scholar 

  22. Tomita M, Matsuzaki Y, Onitsuka T (1999) Correlation between mast cells and survival rates in patients with pulmonary adenocarcinoma. Lung Cancer 26:103-108

    Article  PubMed  CAS  Google Scholar 

  23. Toomey D, Smyth G, Condron C et al (2003) Infiltrating immune cells, but not tumour cells, express FasL in non-small cell lung cancer: no association with prognosis identified in 3-year follow-up. Int J Cancer 103:408-412

    Article  PubMed  CAS  Google Scholar 

  24. Ohno S, Inagawa H, Dhar DK et al (2003) The degree of macrophage infiltration into the cancer cell nest is a significant predictor of survival in gastric cancer patients. Anticancer Res 23:5015-5022

    PubMed  Google Scholar 

  25. Welsh TJ, Green RH, Richardson D, Waller DA, O’Byrne KJ, Bradding P (2005) Macrophage and mast-cell invasion of tumor cell islets confers a marked survival advantage in non-small-cell lung cancer. J Clin Oncol 23:8959-8967

    Article  PubMed  Google Scholar 

  26. Kim DW, Min HS, Lee KH et al (2008) High tumour islet macrophage infiltration correlates with improved patient survival but not with EGFR mutations, gene copy number or protein expression in resected non-small cell lung cancer. Br J Cancer 98:1118-1124

    Article  PubMed  CAS  Google Scholar 

  27. Kawai O, Ishii G, Kubota K et al (2008) Predominant infiltration of macrophages and CD8(+) T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer. Cancer 113:1387-1395

    Article  PubMed  CAS  Google Scholar 

  28. Rosenberg SA, Yang JC, Restifo NP (2004) Cancer immunotherapy: moving beyond current vaccines. Nat Med 10:909-915

    Article  PubMed  CAS  Google Scholar 

  29. Auberger J, Loeffler-Ragg J, Wurzer W, Hilbe W (2006) Targeted therapies in non-small cell lung cancer: proven concepts and unfulfilled promises. Curr Cancer Drug Targets 6:271-294

    Article  PubMed  CAS  Google Scholar 

  30. Baratelli F, Lin Y, Zhu L et al (2005) Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4+ T cells. J Immunol 175:1483-1490

    PubMed  CAS  Google Scholar 

  31. Batra RK, Lin Y, Sharma S et al (2003) Non-small cell lung cancer-derived soluble mediators enhance apoptosis in activated T lymphocytes through an I kappa B kinase-dependent mechanism. Cancer Res 63:642-646

    PubMed  CAS  Google Scholar 

  32. Huang M, Sharma S, Mao JT, Dubinett SM (1996) Non-small cell lung cancer-derived soluble mediators and prostaglandin E2 enhance peripheral blood lymphocyte IL-10 transcription and protein production. J Immunol 157:5512-5520

    PubMed  CAS  Google Scholar 

  33. Huang M, Stolina M, Sharma S et al (1998) 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 58:1208-1216

    PubMed  CAS  Google Scholar 

  34. Woo EY, Chu CS, Goletz TJ et al (2001) Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res 61:4766-4772

    PubMed  CAS  Google Scholar 

  35. Woo EY, Yeh H, Chu CS et al (2002) Cutting edge: regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol 168:4272-4276

    PubMed  CAS  Google Scholar 

  36. Yoshino I, Yano T, Murata M et al (1992) Tumor-reactive T-cells accumulate in lung cancer tissues but fail to respond due to tumor cell-derived factor. Cancer Res 52:775-781

    PubMed  CAS  Google Scholar 

  37. Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392:245-252

    Article  PubMed  CAS  Google Scholar 

  38. Steinman RM, Hemmi H (2006) Dendritic cells: translating innate to adaptive immunity. Curr Top Microbiol Immunol 311:17-58

    Article  PubMed  CAS  Google Scholar 

  39. Cerundolo V, Hermans IF, Salio M (2004) Dendritic cells: a journey from laboratory to clinic. Nat Immunol 5:7-10

    Article  PubMed  CAS  Google Scholar 

  40. Nestle FO, Farkas A, Conrad C (2005) Dendritic-cell-based therapeutic vaccination against cancer. Curr Opin Immunol 17:163-169

    Article  PubMed  CAS  Google Scholar 

  41. Svane IM, Soot ML, Buus S, Johnsen HE (2003) Clinical application of dendritic cells in cancer vaccination therapy. APMIS 111:818-834

    Article  PubMed  CAS  Google Scholar 

  42. Holtl L, Ramoner R, Zelle-Rieser C et al (2005) Allogeneic dendritic cell vaccination against metastatic renal cell carcinoma with or without cyclophosphamide. Cancer Immunol Immunother 54:663-670

    Article  PubMed  CAS  Google Scholar 

  43. Nestle FO, Alijagic S, Gilliet M et al (1998) Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 4:328-332

    Article  PubMed  CAS  Google Scholar 

  44. Redfern CH, Guthrie TH, Bessudo A et al (2006) Phase II trial of idiotype vaccination in previously treated patients with indolent non-Hodgkin’s lymphoma resulting in durable clinical responses. J Clin Oncol 24:3107-3112

    Article  PubMed  CAS  Google Scholar 

  45. Timmerman JM, Czerwinski DK, Davis TA et al (2002) Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients. Blood 99:1517-1526

    Article  PubMed  CAS  Google Scholar 

  46. Morse MA, Clay TM, Hobeika AC et al (2005) Phase I study of immunization with dendritic cells modified with fowlpox encoding carcinoembryonic antigen and costimulatory molecules. Clin Cancer Res 11:3017-3024

    Article  PubMed  CAS  Google Scholar 

  47. Kimura H, Iizasa T, Ishikawa A et al (2008) Prospective phase II study of post-surgical adjuvant chemo-immunotherapy using autologous dendritic cells and activated killer cells from tissue culture of tumor-draining lymph nodes in primary lung cancer patients. Anticancer Res 28:1229-1238

    PubMed  CAS  Google Scholar 

  48. Albert ML, Pearce SF, Francisco LM et al (1998) Immature dendritic cells phagocytose apoptotic cells via alphavbeta5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J Exp Med 188:1359-1368

    Article  PubMed  CAS  Google Scholar 

  49. Fields RC, Shimizu K, Mule JJ (1998) Murine dendritic cells pulsed with whole tumor lysates mediate potent antitumor immune responses in vitro and in vivo. Proc Natl Acad Sci USA 95:9482-9487

    Article  PubMed  CAS  Google Scholar 

  50. Hsu FJ, Benike C, Fagnoni F et al (1996) Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med 2:52-58

    Article  PubMed  CAS  Google Scholar 

  51. Boczkowski D, Nair SK, Nam JH, Lyerly HK, Gilboa E (2000) Induction of tumor immunity and cytotoxic T lymphocyte responses using dendritic cells transfected with messenger RNA amplified from tumor cells. Cancer Res 60:1028-1034

    PubMed  CAS  Google Scholar 

  52. Miller PW, Sharma S, Stolina M et al (2000) Intratumoral administration of adenoviral interleukin 7 gene-modified dendritic cells augments specific antitumor immunity and achieves tumor eradication. Hum Gene Ther 11:53-65

    Article  PubMed  CAS  Google Scholar 

  53. Wan Y, Bramson J, Carter R, Graham F, Gauldie J (1997) Dendritic cells transduced with an adenoviral vector encoding a model tumor-associated antigen for tumor vaccination. Hum Gene Ther 8:1355-1363

    Article  PubMed  CAS  Google Scholar 

  54. Lundqvist A, Choudhury A, Nagata T et al (2002) Recombinant adenovirus vector activates and protects human monocyte-derived dendritic cells from apoptosis. Hum Gene Ther 13:1541-1549

    Article  PubMed  CAS  Google Scholar 

  55. Song W, Tong Y, Carpenter H, Kong HL, Crystal RG (2000) Persistent, antigen-specific, therapeutic antitumor immunity by dendritic cells genetically modified with an adenoviral vector to express a model tumor antigen. Gene Ther 7:2080-2086

    Article  PubMed  CAS  Google Scholar 

  56. Basak SK, Kiertscher SM, Harui A, Roth MD (2004) Modifying adenoviral vectors for use as gene-based cancer vaccines. Viral Immunol 17:182-196

    Article  PubMed  CAS  Google Scholar 

  57. Hromas R, Kim CH, Klemsz M et al (1997) Isolation and characterization of Exodus-2, a novel C-C chemokine with a unique 37-amino acid carboxyl-terminal extension. J Immunol 159:2554-2558

    PubMed  CAS  Google Scholar 

  58. Riedl K, Baratelli F, Batra RK et al (2003) Overexpression of CCL-21/secondary lymphoid tissue chemokine in human dendritic cells augments chemotactic activities for lymphocytes and antigen presenting cells. Mol Cancer 2:35

    Article  PubMed  Google Scholar 

  59. Yang SC, Batra RK, Hillinger S et al (2006) Intrapulmonary administration of CCL21 gene-modified dendritic cells reduces tumor burden in spontaneous murine bronchoalveolar cell carcinoma. Cancer Res 66:3205-3213

    Article  PubMed  CAS  Google Scholar 

  60. Yang SC, Hillinger S, Riedl K et al (2004) Intratumoral administration of dendritic cells overexpressing CCL21 generates systemic antitumor responses and confers tumor immunity. Clin Cancer Res 10:2891-2901

    Article  PubMed  CAS  Google Scholar 

  61. Arenberg DA, Zlotnick A, Strom SR, Burdick MD, Strieter RM (2001) The murine CC chemokine, 6C-kine, inhibits tumor growth and angiogenesis in a human lung cancer SCID mouse model. Cancer Immunol Immunother 49:587-592

    Article  PubMed  CAS  Google Scholar 

  62. Vicari AP, Ait-Yahia S, Chemin K, Mueller A, Zlotnik A, Caux C (2000) Antitumor effects of the mouse chemokine 6Ckine/SLC through angiostatic and immunological mechanisms. J Immunol 165:1992-2000

    PubMed  CAS  Google Scholar 

  63. Carragher DM, Rangel-Moreno J, Randall TD (2008) Ectopic lymphoid tissues and local immunity. Semin Immunol 20:26-42

    Article  PubMed  CAS  Google Scholar 

  64. Singh P, Coskun ZZ, Goode C, Dean A, Thompson-Snipes L, Darlington G (2008) Lymphoid neogenesis and immune infiltration in aged liver. Hepatology 47:1680-1690

    Article  PubMed  Google Scholar 

  65. Timmer TC, Baltus B, Vondenhoff M et al (2007) Inflammation and ectopic lymphoid structures in rheumatoid arthritis synovial tissues dissected by genomics technology: identification of the interleukin-7 signaling pathway in tissues with lymphoid neogenesis. Arthritis Rheum 56:2492-2502

    Article  PubMed  CAS  Google Scholar 

  66. Moyron-Quiroz JE, Rangel-Moreno J, Kusser K et al (2004) Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat Med 10:927-934

    Article  PubMed  CAS  Google Scholar 

  67. Schrama D, Voigt H, Eggert AO et al (2008) Immunological tumor destruction in a murine melanoma model by targeted LTalpha independent of secondary lymphoid tissue. Cancer Immunol Immunother 57:85-95

    Article  PubMed  Google Scholar 

  68. Kirk CJ, Hartigan-O’Connor D, Mule JJ (2001) The dynamics of the T-cell antitumor response: chemokine-secreting dendritic cells can prime tumor-reactive T cells extranodally. Cancer Res 61:8794-8802

    PubMed  CAS  Google Scholar 

  69. Coronella JA, Spier C, Welch M et al (2002) Antigen-driven oligoclonal expansion of tumor-infiltrating B cells in infiltrating ductal carcinoma of the breast. J Immunol 169:1829-1836

    PubMed  CAS  Google Scholar 

  70. Bell D, Chomarat P, Broyles D et al (1999) In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. J Exp Med 190:1417-1426

    Article  PubMed  CAS  Google Scholar 

  71. Eisenthal A, Polyvkin N, Bramante-Schreiber L, Misonznik F, Hassner A, Lifschitz-Mercer B (2001) Expression of dendritic cells in ovarian tumors correlates with clinical outcome in patients with ovarian cancer. Hum Pathol 32:803-807

    Article  PubMed  CAS  Google Scholar 

  72. Kurabayashi A, Furihata M, Matsumoto M, Hayashi H, Ohtsuki Y (2004) Distribution of tumor-infiltrating dendritic cells in human non-small cell lung carcinoma in relation to apoptosis. Pathol Int 54:302-310

    Article  PubMed  Google Scholar 

  73. Zeid NA, Muller HK (1993) S100 positive dendritic cells in human lung tumors associated with cell differentiation and enhanced survival. Pathology 25:338-343

    Article  PubMed  CAS  Google Scholar 

  74. Coppola D, Mule JJ (2008) Ectopic lymph nodes within human solid tumors. J Clin Oncol 26:4369-4370

    Article  PubMed  Google Scholar 

  75. Dieu-Nosjean MC, Antoine M, Danel C et al (2008) Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol 26:4410-4417

    Article  PubMed  CAS  Google Scholar 

  76. Kocks JR, Davalos-Misslitz AC, Hintzen G, Ohl L, Forster R (2007) Regulatory T cells interfere with the development of bronchus-associated lymphoid tissue. J Exp Med 204:723-734

    Article  PubMed  CAS  Google Scholar 

  77. Ishibashi Y, Tanaka S, Tajima K, Yoshida T, Kuwano H (2006) Expression of Foxp3 in non-small cell lung cancer patients is significantly higher in tumor tissues than in normal tissues, especially in tumors smaller than 30 mm. Oncol Rep 15:1315-1319

    PubMed  CAS  Google Scholar 

  78. Okita R, Saeki T, Takashima S, Yamaguchi Y, Toge T (2005) CD4+CD25+ regulatory T cells in the peripheral blood of patients with breast cancer and non-small cell lung cancer. Oncol Rep 14:1269-1273

    PubMed  CAS  Google Scholar 

  79. Zhang L, Dermawan K, Jin M et al (2008) Differential impairment of regulatory T cells rather than effector T cells by paclitaxel-based chemotherapy. Clin Immunol 129:219-229

    Article  PubMed  CAS  Google Scholar 

  80. Ichihara F, Kono K, Takahashi A, Kawaida H, Sugai H, Fujii H (2003) Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers. Clin Cancer Res 9:4404-4408

    PubMed  Google Scholar 

  81. Liyanage UK, Moore TT, Joo HG et al (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169:2756-2761

    PubMed  CAS  Google Scholar 

  82. Sasada T, Kimura M, Yoshida Y, Kanai M, Takabayashi A (2003) CD4+CD25+ regulatory T cells in patients with gastrointestinal malignancies: possible involvement of regulatory T cells in disease progression. Cancer 98:1089-1099

    Article  PubMed  Google Scholar 

  83. Wolf AM, Wolf D, Steurer M, Gastl G, Gunsilius E, Grubeck-Loebenstein B (2003) Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 9:606-612

    PubMed  Google Scholar 

  84. Sutmuller RP, van Duivenvoorde LM, van Elsas A et al (2001) Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 194:823-832

    Article  PubMed  CAS  Google Scholar 

  85. Curiel TJ, Coukos G, Zou L et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942-949

    Article  PubMed  CAS  Google Scholar 

  86. Baratelli F, Takedatsu H, Hazra S et al (2008) Pre-clinical characterization of GMP grade CCL21-gene modified dendritic cells for application in a phase I trial in non-small cell lung cancer. J Transl Med 6:38

    Article  PubMed  CAS  Google Scholar 

  87. Sharma S, Yang SC, Zhu L et al (2005) Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer. Cancer Res 65:5211-5220

    Article  PubMed  CAS  Google Scholar 

  88. Dudley ME, Rosenberg SA (2003) Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat Rev Cancer 3:666-675

    Article  PubMed  CAS  Google Scholar 

  89. Klebanoff CA, Khong HT, Antony PA, Palmer DC, Restifo NP (2005) Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol 26:111-117

    Article  PubMed  CAS  Google Scholar 

  90. Rosenberg SA, Dudley ME (2004) Cancer regression in patients with metastatic melanoma after the transfer of autologous antitumor lymphocytes. Proc Natl Acad Sci USA 101(Suppl 2):14639-14645

    Article  PubMed  CAS  Google Scholar 

  91. Kreitman RJ, Pastan I (2003) Immunobiological treatments of hairy-cell leukaemia. Best Pract Res Clin Haematol 16:117-133

    Article  PubMed  CAS  Google Scholar 

  92. Dubinett SM, Sharma S, Huang M, Dohadwala M, Pold M, Mao JT (2003) Cyclooxygenase-2 in lung cancer. Prog Exp Tumor Res 37:138-162

    Article  PubMed  CAS  Google Scholar 

  93. Riedl K, Krysan K, Pold M et al (2004) Multifaceted roles of cyclooxygenase-2 in lung cancer. Drug Resist Updat 7:169-184

    Article  PubMed  CAS  Google Scholar 

  94. Sandler A, Gray R, Perry MC et al (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542-2550

    Article  PubMed  CAS  Google Scholar 

  95. Dannenberg AJ, Subbaramaiah K (2003) Targeting cyclooxygenase-2 in human neoplasia: rationale and promise. Cancer Cell 4:431-436

    Article  PubMed  CAS  Google Scholar 

  96. Coussens LM, Fingleton B, Matrisian LM (2002) Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295:2387-2392

    Article  PubMed  CAS  Google Scholar 

  97. Fingleton B (2008) MMPs as therapeutic targets - still a viable option? Semin Cell Dev Biol 19:61-68

    Article  PubMed  CAS  Google Scholar 

  98. Konstantinopoulos PA, Karamouzis MV, Papatsoris AG, Papavassiliou AG (2008) Matrix metalloproteinase inhibitors as anticancer agents. Int J Biochem Cell Biol 40:1156-1168

    Article  PubMed  CAS  Google Scholar 

  99. Murphy G (2008) The ADAMs: signalling scissors in the tumour microenvironment. Nat Rev Cancer 8:929-941

    Article  PubMed  CAS  Google Scholar 

  100. Noel A, Jost M, Maquoi E (2008) Matrix metalloproteinases at cancer tumor-host interface. Semin Cell Dev Biol 19:52-60

    Article  PubMed  CAS  Google Scholar 

  101. Overall CM, Kleifeld O (2006) Towards third generation matrix metalloproteinase inhibitors for cancer therapy. Br J Cancer 94:941-946

    Article  PubMed  CAS  Google Scholar 

  102. Overall CM, Kleifeld O (2006) Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer 6:227-239

    Article  PubMed  CAS  Google Scholar 

  103. Leinonen T, Pirinen R, Bohm J, Johansson R, Kosma VM (2008) Increased expression of matrix metalloproteinase-2 (MMP-2) predicts tumour recurrence and unfavourable outcome in non-small cell lung cancer. Histol Histopathol 23:693-700

    PubMed  Google Scholar 

  104. Sienel W, Polzer B, Elshawi K et al (2008) Cellular localization of EMMPRIN predicts prognosis of patients with operable lung adenocarcinoma independent from MMP-2 and MMP-9. Mod Pathol 21:1130-1138

    Article  PubMed  CAS  Google Scholar 

  105. Hakuma N, Betsuyaku T, Kinoshita I et al (2007) High incidence of extracellular matrix metalloproteinase inducer expression in non-small cell lung cancers. Association with clinicopathological parameters. Oncology 72:197-204

    Article  PubMed  CAS  Google Scholar 

  106. Kim SH, Choi HY, Lee J et al (2007) Elevated activities of MMP-2 in the non-tumorous lung tissues of curatively resected stage I NSCLC patients are associated with tumor recurrence and a poor survival. J Surg Oncol 95:337-346

    Article  PubMed  CAS  Google Scholar 

  107. Hsu CP, Shen GH, Ko JL (2006) Matrix metalloproteinase-13 expression is associated with bone marrow microinvolvement and prognosis in non-small cell lung cancer. Lung Cancer 52:349-357

    Article  PubMed  Google Scholar 

  108. Liu D, Nakano J, Ishikawa S et al (2007) Overexpression of matrix metalloproteinase-7 (MMP-7) correlates with tumor proliferation, and a poor prognosis in non-small cell lung cancer. Lung Cancer 58:384-391

    Article  PubMed  Google Scholar 

  109. Mino N, Takenaka K, Sonobe M et al (2007) Expression of tissue inhibitor of metalloproteinase-3 (TIMP-3) and its prognostic significance in resected non-small cell lung cancer. J Surg Oncol 95:250-257

    Article  PubMed  CAS  Google Scholar 

  110. Clark JC, Thomas DM, Choong PF, Dass CR (2007) RECK - a newly discovered inhibitor of metastasis with prognostic significance in multiple forms of cancer. Cancer Metastasis Rev 26:675-683

    Article  PubMed  CAS  Google Scholar 

  111. Takemoto N, Tada M, Hida Y et al (2007) Low expression of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) indicates a shorter survival after resection in patients with adenocarcinoma of the lung. Lung Cancer 58:376-383

    Article  PubMed  Google Scholar 

  112. Liu LT, Chang HC, Chiang LC, Hung WC (2003) Histone deacetylase inhibitor up-regulates RECK to inhibit MMP-2 activation and cancer cell invasion. Cancer Res 63:3069-3072

    PubMed  CAS  Google Scholar 

  113. Peebles KA, Lee JM, Mao JT et al (2007) Inflammation and lung carcinogenesis: applying findings in prevention and treatment. Expert Rev Anticancer Ther 7:1405-1421

    Article  PubMed  CAS  Google Scholar 

  114. Krysan K, Dalwadi H, Sharma S, Pold M, Dubinett S (2004) Cyclooxygenase 2-dependent expression of survivin is critical for apoptosis resistance in non-small cell lung cancer. Cancer Res 64:6359-6362

    Article  PubMed  CAS  Google Scholar 

  115. Krysan K, Merchant FH, Zhu L et al (2004) COX-2-dependent stabilization of survivin in non-small cell lung cancer. FASEB J 18:206-208

    PubMed  CAS  Google Scholar 

  116. Tsujii M, DuBois RN (1995) Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 83:493-501

    Article  PubMed  CAS  Google Scholar 

  117. Gately S, Li WW (2004) Multiple roles of COX-2 in tumor angiogenesis: a target for antiangiogenic therapy. Semin Oncol 31:2-11

    Article  PubMed  CAS  Google Scholar 

  118. Leahy KM, Koki AT, Masferrer JL (2000) Role of cyclooxygenases in angiogenesis. Curr Med Chem 7:1163-1170

    Article  PubMed  CAS  Google Scholar 

  119. Liu VC, Wong LY, Jang T et al (2007) Tumor evasion of the immune system by converting CD4+CD25- T cells into CD4+CD25+ T regulatory cells: role of tumor-derived TGF-beta. J Immunol 178:2883-2892

    PubMed  CAS  Google Scholar 

  120. Stolina M, Sharma S, Lin Y et al (2000) Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. J Immunol 164:361-370

    PubMed  CAS  Google Scholar 

  121. Dohadwala M, Batra RK, Luo J et al (2002) 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 277:50828-50833

    Article  PubMed  CAS  Google Scholar 

  122. Dohadwala M, Luo J, Zhu L et al (2001) Non-small cell lung cancer cyclooxygenase-2-dependent invasion is mediated by CD44. J Biol Chem 276:20809-20812

    Article  PubMed  CAS  Google Scholar 

  123. Lee JM, Yanagawa J, Peebles KA, Sharma S, Mao JT, Dubinett SM (2008) Inflammation in lung carcinogenesis: new targets for lung cancer chemoprevention and treatment. Crit Rev Oncol Hematol 66:208-217

    Article  PubMed  Google Scholar 

  124. Krysan K, Reckamp KL, Dalwadi H et al (2005) 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 65:6275-6281

    Article  PubMed  CAS  Google Scholar 

  125. Khuri FR, Wu H, Lee JJ et al (2001) Cyclooxygenase-2 overexpression is a marker of poor prognosis in stage I non-small cell lung cancer. Clin Cancer Res 7:861-867

    PubMed  CAS  Google Scholar 

  126. Tsubochi H, Sato N, Hiyama M et al (2006) Combined analysis of cyclooxygenase-2 expression with p53 and Ki-67 in nonsmall cell lung cancer. Ann Thorac Surg 82:1198-1204

    Article  PubMed  Google Scholar 

  127. Hosomi Y, Yokose T, Hirose Y et al (2000) Increased cyclooxygenase 2 (COX-2) expression occurs frequently in precursor lesions of human adenocarcinoma of the lung. Lung Cancer 30:73-81

    Article  PubMed  CAS  Google Scholar 

  128. Wolff H, Saukkonen K, Anttila S, Karjalainen A, Vainio H, Ristimaki A (1998) Expression of cyclooxygenase-2 in human lung carcinoma. Cancer Res 58:4997-5001

    PubMed  CAS  Google Scholar 

  129. Campa D, Zienolddiny S, Maggini V, Skaug V, Haugen A, Canzian F (2004) Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer. Carcinogenesis 25:229-235

    Article  PubMed  CAS  Google Scholar 

  130. Schreinemachers DM, Everson RB (1994) Aspirin use and lung, colon, and breast cancer incidence in a prospective study. Epidemiology 5:138-146

    Article  PubMed  CAS  Google Scholar 

  131. Mao JT, Fishbein MC, Adams B et al (2006) Celecoxib decreases Ki-67 proliferative index in active smokers. Clin Cancer Res 12:314-320

    Article  PubMed  CAS  Google Scholar 

  132. Lee JM, Mao JT, Krysan K, Dubinett SM (2007) Significance of cyclooxygenase-2 in prognosis, targeted therapy and chemoprevention of NSCLC. Future Oncol 3:149-153

    Article  PubMed  CAS  Google Scholar 

  133. Mao JT, Cui X, Reckamp K et al (2005) Chemoprevention strategies with cyclooxygenase-2 inhibitors for lung cancer. Clin Lung Cancer 7:30-39

    Article  PubMed  CAS  Google Scholar 

  134. Gadgeel SM, Ali S, Philip PA, Ahmed F, Wozniak A, Sarkar FH (2007) Response to dual blockade of epidermal growth factor receptor (EGFR) and cycloxygenase-2 in nonsmall cell lung cancer may be dependent on the EGFR mutational status of the tumor. Cancer 110:2775-2784

    Article  PubMed  CAS  Google Scholar 

  135. Gadgeel SM, Ruckdeschel JC, Heath EI, Heilbrun LK, Venkatramanamoorthy R, Wozniak A (2007) 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 2:299-305

    Article  PubMed  Google Scholar 

  136. Agarwala A, Fisher W, Bruetman D et al (2008) Gefitinib plus celecoxib in chemotherapy-naive patients with stage IIIB/IV non-small cell lung cancer: a phase II study from the Hoosier Oncology Group. J Thorac Oncol 3:374-379

    Article  PubMed  Google Scholar 

  137. O’Byrne KJ, Danson S, Dunlop D et al (2007) Combination therapy with gefitinib and rofecoxib in patients with platinum-pretreated relapsed non small-cell lung cancer. J Clin Oncol 25:3266-3273

    Article  PubMed  CAS  Google Scholar 

  138. Fidler MJ, Argiris A, Patel JD et al (2008) The potential predictive value of cyclooxygenase-2 expression and increased risk of gastrointestinal hemorrhage in advanced non-small cell lung cancer patients treated with erlotinib and celecoxib. Clin Cancer Res 14:2088-2094

    Article  PubMed  CAS  Google Scholar 

  139. Reckamp KL, Krysan K, Morrow JD et al (2006) 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 12:3381-3388

    Article  PubMed  CAS  Google Scholar 

  140. Gridelli C, Gallo C, Ceribelli A et al (2007) Factorial phase III randomised trial of rofecoxib and prolonged constant infusion of gemcitabine in advanced non-small-cell lung cancer: the GEmcitabine-COxib in NSCLC (GECO) study. Lancet Oncol 8:500-512

    Article  PubMed  CAS  Google Scholar 

  141. Gridelli C, Maione P, Rossi A, De Marinis F (2007) The role of bevacizumab in the treatment of non-small cell lung cancer: current indications and future developments. Oncologist 12:1183-1193

    Article  PubMed  CAS  Google Scholar 

  142. Juni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M (2004) Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 364:2021-2029

    Article  PubMed  CAS  Google Scholar 

  143. Solomon DH, Schneeweiss S, Levin R, Avorn J (2004) Relationship between COX-2 specific inhibitors and hypertension. Hypertension 44:140-145

    Article  PubMed  CAS  Google Scholar 

  144. Chan AT, Ogino S, Fuchs CS (2007) Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med 356:2131-2142

    Article  PubMed  CAS  Google Scholar 

  145. Edelman MJ, Watson D, Wang X et al (2008) Eicosanoid modulation in advanced lung cancer: cyclooxygenase-2 expression is a positive predictive factor for celecoxib + chemotherapy - Cancer and Leukemia Group B Trial 30203. J Clin Oncol 26:848-855

    Article  PubMed  CAS  Google Scholar 

  146. Hazra S, Batra RK, Tai HH, Sharma S, Cui X, Dubinett SM (2007) Pioglitazone and rosiglitazone decrease prostaglandin E2 in non-small-cell lung cancer cells by up-regulating 15-hydroxyprostaglandin dehydrogenase. Mol Pharmacol 71:1715-1720

    Article  PubMed  CAS  Google Scholar 

  147. Hazra S, Peebles KA, Sharma S, Mao JT, Dubinett SM (2008) The role of PPARgamma in the cyclooxygenase pathway in lung cancer. PPAR Res 2008:790568

    Article  PubMed  CAS  Google Scholar 

  148. Ondrey F (2009) Peroxisome proliferator-activated receptor gamma pathway targeting in carcinogenesis: implications for chemoprevention. Clin Cancer Res 15:2-8

    Article  PubMed  CAS  Google Scholar 

  149. Nemenoff RA (2007) Peroxisome proliferator-activated receptor-gamma in lung cancer: defining specific versus “off-target” effectors. J Thorac Oncol 2:989-992

    Article  PubMed  Google Scholar 

  150. Lee SY, Hur GY, Jung KH et al (2006) PPAR-gamma agonist increase gefitinib’s antitumor activity through PTEN expression. Lung Cancer 51:297-301

    Article  PubMed  Google Scholar 

  151. Reddy RC, Srirangam A, Reddy K et al (2008) Chemotherapeutic drugs induce PPAR-gamma expression and show sequence-specific synergy with PPAR-gamma ligands in inhibition of non-small cell lung cancer. Neoplasia 10:597-603

    PubMed  CAS  Google Scholar 

  152. Girnun GD, Chen L, Silvaggi J et al (2008) Regression of drug-resistant lung cancer by the combination of rosiglitazone and carboplatin. Clin Cancer Res 14:6478-6486

    Article  PubMed  CAS  Google Scholar 

  153. Kim HJ, Hwang JY, Choi WS et al (2007) Expression of a peroxisome proliferator-activated receptor gamma 1 splice variant that was identified in human lung cancers suppresses cell death induced by cisplatin and oxidative stress. Clin Cancer Res 13:2577-2583

    Article  PubMed  CAS  Google Scholar 

  154. Govindarajan R, Ratnasinghe L, Simmons DL et al (2007) Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes. J Clin Oncol 25:1476-1481

    Article  PubMed  CAS  Google Scholar 

  155. Nemenoff RA, Weiser-Evans M, Winn RA (2008) Activation and molecular targets of peroxisome proliferator-activated receptor-gamma ligands in lung cancer. PPAR Res 2008:156875

    Article  PubMed  CAS  Google Scholar 

  156. (2007) Thiazolidinediones and cardiovascular disease. Med Lett Drugs Ther 49:57-58

    Google Scholar 

  157. Nissen SE, Wolski K (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356:2457-2471

    Article  PubMed  CAS  Google Scholar 

  158. Rosen CJ (2007) The rosiglitazone story - lessons from an FDA Advisory Committee meeting. N Engl J Med 357:844-846

    Article  PubMed  CAS  Google Scholar 

  159. Sasaki H, Tanahashi M, Yukiue H et al (2002) Decreased perioxisome proliferator-activated receptor gamma gene expression was correlated with poor prognosis in patients with lung cancer. Lung Cancer 36:71-76

    Article  PubMed  Google Scholar 

  160. Finckh A, Aronson MD (2005) Cardiovascular risks of cyclooxygenase-2 inhibitors: where we stand now. Ann Intern Med 142:212-214

    Article  PubMed  Google Scholar 

  161. Balkwill F, Charles KA, Mantovani A (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7:211-217

    Article  PubMed  CAS  Google Scholar 

  162. de Visser KE, Eichten A, Coussens LM (2006) Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6:24-37

    Article  PubMed  CAS  Google Scholar 

  163. DeNardo DG, Johansson M, Coussens LM (2008) Immune cells as mediators of solid tumor metastasis. Cancer Metastasis Rev 27:11-18

    Article  PubMed  CAS  Google Scholar 

  164. Walser T, Cui X, Yanagawa J et al (2008) Smoking and lung cancer: the role of inflammation. Proc Am Thorac Soc 5:811-815

    Article  PubMed  Google Scholar 

  165. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860-867

    Article  PubMed  CAS  Google Scholar 

  166. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436-444

    Article  PubMed  CAS  Google Scholar 

  167. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57-70

    Article  PubMed  CAS  Google Scholar 

  168. Mantovani A (2009) Cancer: inflaming metastasis. Nature 457:36-37

    Article  PubMed  CAS  Google Scholar 

  169. O’Donnell R, Breen D, Wilson S, Djukanovic R (2006) Inflammatory cells in the airways in COPD. Thorax 61:448-454

    Article  PubMed  Google Scholar 

  170. Sevenoaks MJ, Stockley RA (2006) Chronic obstructive pulmonary disease, inflammation and co-morbidity - a common inflammatory phenotype? Respir Res 7:70

    Article  PubMed  CAS  Google Scholar 

  171. Taraseviciene-Stewart L, Voelkel NF (2008) Molecular pathogenesis of emphysema. J Clin Invest 118:394-402

    Article  PubMed  CAS  Google Scholar 

  172. Dohadwala M, Yang SC, Luo J et al (2006) Cyclooxygenase-2-dependent regulation of E-cadherin: prostaglandin E(2) induces transcriptional repressors ZEB1 and snail in non-small cell lung cancer. Cancer Res 66:5338-5345

    Article  PubMed  CAS  Google Scholar 

  173. Keshamouni VG, Michailidis G, Grasso CS et al (2006) 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 5:1143-1154

    Article  PubMed  CAS  Google Scholar 

  174. Leng Q, Bentwich Z, Borkow G (2006) Increased TGF-beta, Cbl-b and CTLA-4 levels and immunosuppression in association with chronic immune activation. Int Immunol 18:637-644

    Article  PubMed  CAS  Google Scholar 

  175. Heinrich EL, Charuworn B, Dohadwala M, Dubinett SM. IL-1B dependent epithelial-mesenchymal transition in non-small cell lung cancer. Proceedings of the frontiers in cancer prevention research conference, Abstract vol A26, p 76

    Google Scholar 

  176. Skillrud DM (1986) COPD: causes, treatment, and risk for lung cancer. Compr Ther 12:13-16

    PubMed  CAS  Google Scholar 

  177. Skillrud DM, Offord KP, Miller RD (1986) Higher risk of lung cancer in chronic obstructive pulmonary disease. A prospective, matched, controlled study. Ann Intern Med 105:503-507

    Article  PubMed  CAS  Google Scholar 

  178. de Torres JP, Bastarrika G, Wisnivesky JP et al (2007) Assessing the relationship between lung cancer risk and emphysema detected on low-dose CT of the chest. Chest 132:1932-1938

    Article  PubMed  Google Scholar 

  179. Houghton AM, Mouded M, Shapiro SD (2008) Common origins of lung cancer and COPD. Nat Med 14:1023-1024

    Article  PubMed  CAS  Google Scholar 

  180. Adair-Kirk TL, Atkinson JJ, Senior RM (2008) Smoke particulates stress lung cells. Nat Med 14:1024-1025

    Article  PubMed  CAS  Google Scholar 

  181. Parimon T, Chien JW, Bryson CL, McDonell MB, Udris EM, Au DH (2007) Inhaled corticosteroids and risk of lung cancer among patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 175:712-719

    Article  PubMed  CAS  Google Scholar 

  182. Wilson R, McConnell EE, Ross M, Axten CW, Nolan RP (2008) Risk assessment due to environmental exposures to fibrous particulates associated with taconite ore. Regul Toxicol Pharmacol 52:S232-S245

    Article  PubMed  CAS  Google Scholar 

  183. Kim CF, Jackson EL, Woolfenden AE et al (2005) Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121:823-835

    Article  PubMed  CAS  Google Scholar 

  184. Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J (2008) Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320:674-677

    Article  PubMed  CAS  Google Scholar 

  185. Kelsen SG, Duan X, Ji R, Perez O, Liu C, Merali S (2008) Cigarette smoke induces an unfolded protein response in the human lung: a proteomic approach. Am J Respir Cell Mol Biol 38:541-550

    Article  PubMed  CAS  Google Scholar 

  186. Sin DD, Man SF, Marciniuk DD et al (2008) The effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 177:1207-1214

    Article  PubMed  CAS  Google Scholar 

  187. Krysan K, Lee JM, Dohadwala M et al (2008) Inflammation, epithelial to mesenchymal transition, and epidermal growth factor receptor tyrosine kinase inhibitor resistance. J Thorac Oncol 3:107-110

    Article  PubMed  Google Scholar 

  188. Walser TC, Yanagawa J, Luo J et al (2008) Snail-induced and EMT-mediated early lung cancer development: promotion of invasion and expansion of stem cell populations. Proceedings of the frontiers in cancer prevention research conference, Abstract vol PR-11, p 67

    Google Scholar 

  189. Yanagawa J, Walser TC, Zhu LX, et al (2008) The zinc-finger E-box-binding transcriptional repressor Snail promotes tumor progression and angiogenesis in non-small cell lung cancer. Proceedings of the frontiers in cancer prevention research conference, Abstract vol A1, p 69

    Google Scholar 

  190. Lee JM, Dedhar S, Kalluri R, Thompson EW (2006) The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol 172:973-981

    Article  PubMed  CAS  Google Scholar 

  191. Buck E, Eyzaguirre A, Barr S et al (2007) Loss of homotypic cell adhesion by epithelial-mesenchymal transition or mutation limits sensitivity to epidermal growth factor receptor inhibition. Mol Cancer Ther 6:532-541

    Article  PubMed  CAS  Google Scholar 

  192. Witta SE, Gemmill RM, Hirsch FR et al (2006) Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res 66:944-950

    Article  PubMed  CAS  Google Scholar 

  193. Yauch RL, Januario T, Eberhard DA et al (2005) Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. Clin Cancer Res 11:8686-8698

    Article  PubMed  CAS  Google Scholar 

  194. Reckamp KL, Gardner BK, Figlin RA et al (2008) Tumor response to combination celecoxib and erlotinib therapy in non-small cell lung cancer is associated with a low baseline matrix metalloproteinase-9 and a decline in serum-soluble E-cadherin. J Thorac Oncol 3:117-124

    Article  PubMed  Google Scholar 

  195. Mani SA, Guo W, Liao MJ et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704-715

    Article  PubMed  CAS  Google Scholar 

  196. Sanchez-Garcia I (2009) The crossroads of oncogenesis and metastasis. N Engl J Med 360:297-299

    Article  PubMed  CAS  Google Scholar 

  197. Wang XW, Tan NS, Ho B, Ding JL (2006) Evidence for the ancient origin of the NF-kappaB/IkappaB cascade: its archaic role in pathogen infection and immunity. Proc Natl Acad Sci USA 103:4204-4209

    Article  PubMed  CAS  Google Scholar 

  198. Xiao W (2004) Advances in NF-kappaB signaling transduction and transcription. Cell Mol Immunol 1:425-435

    PubMed  CAS  Google Scholar 

  199. Dey A, Tergaonkar V, Lane DP (2008) Double-edged swords as cancer therapeutics: simultaneously targeting p53 and NF-kappaB pathways. Nat Rev Drug Discov 7:1031-1040

    Article  PubMed  CAS  Google Scholar 

  200. Lee DF, Hung MC (2008) Advances in targeting IKK and IKK-related kinases for cancer therapy. Clin Cancer Res 14:5656-5662

    Article  PubMed  CAS  Google Scholar 

  201. Mitchell BS (2003) The proteasome - an emerging therapeutic target in cancer. N Engl J Med 348:2597-2598

    Article  PubMed  Google Scholar 

  202. Richardson PG, Barlogie B, Berenson J et al (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609-2617

    Article  PubMed  CAS  Google Scholar 

  203. Fisher RI, Bernstein SH, Kahl BS et al (2006) Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 24:4867-4874

    Article  PubMed  Google Scholar 

  204. Davies AM, Ruel C, Lara PN et al (2008) The proteasome inhibitor bortezomib in combination with gemcitabine and carboplatin in advanced non-small cell lung cancer: a California Cancer Consortium Phase I study. J Thorac Oncol 3:68-74

    Article  PubMed  Google Scholar 

  205. Voortman J, Smit EF, Honeywell R et al (2007) A parallel dose-escalation study of weekly and twice-weekly bortezomib in combination with gemcitabine and cisplatin in the first-line treatment of patients with advanced solid tumors. Clin Cancer Res 13:3642-3651

    Article  PubMed  CAS  Google Scholar 

  206. Davies AM, Chansky K, Lara PN Jr et al (2009) Bortezomib plus gemcitabine/carboplatin as first-line treatment of advanced non-small cell lung cancer: a phase II Southwest Oncology Group Study (S0339). J Thorac Oncol 4:87-92

    Article  PubMed  Google Scholar 

  207. Fossella FV, DeVore R, Kerr RN et al (2000) Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 18:2354-2362

    PubMed  CAS  Google Scholar 

  208. Shepherd FA, Dancey J, Ramlau R et al (2000) Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18:2095-2103

    PubMed  CAS  Google Scholar 

  209. Hanna N, Shepherd FA, Fossella FV et al (2004) Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22:1589-1597

    Article  PubMed  CAS  Google Scholar 

  210. Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123-132

    Article  PubMed  CAS  Google Scholar 

  211. Fanucchi MP, Fossella FV, Belt R et al (2006) Randomized phase II study of bortezomib alone and bortezomib in combination with docetaxel in previously treated advanced non-small-cell lung cancer. J Clin Oncol 24:5025-5033

    Article  PubMed  CAS  Google Scholar 

  212. Lara PN Jr, Koczywas M, Quinn DI et al (2006) Bortezomib plus docetaxel in advanced non-small cell lung cancer and other solid tumors: a phase I California Cancer Consortium trial. J Thorac Oncol 1:126-134

    Article  PubMed  Google Scholar 

  213. Davies AM, Ho C, Metzger AS et al (2007) Phase I study of two different schedules of bortezomib and pemetrexed in advanced solid tumors with emphasis on non-small cell lung cancer. J Thorac Oncol 2:1112-1116

    Article  PubMed  Google Scholar 

  214. Lynch TJ, Fenton DW, Hirsh V, et al Randomized phase II study of erlotinib alone and in combination with bortezomib in previously treated advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2007; ASCO annual meeting proceedings, part I, vol 25, no 18S (June 20 Supplement), p 7680

    Google Scholar 

  215. Lara PN Jr, Chansky K, Davies AM et al (2006) Bortezomib (PS-341) in relapsed or refractory extensive stage small cell lung cancer: a Southwest Oncology Group phase II trial (S0327). J Thorac Oncol 1:996-1001

    Article  PubMed  Google Scholar 

  216. Cooper CS, Park M, Blair DG et al (1984) Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature 311:29-33

    Article  PubMed  CAS  Google Scholar 

  217. Sattler M, Salgia R (2007) c-Met and hepatocyte growth factor: potential as novel targets in cancer therapy. Curr Oncol Rep 9:102-108

    Article  PubMed  CAS  Google Scholar 

  218. Ma PC, Tretiakova MS, Nallasura V, Jagadeeswaran R, Husain AN, Salgia R (2007) Downstream signalling and specific inhibition of c-MET/HGF pathway in small cell lung cancer: implications for tumour invasion. Br J Cancer 97:368-377

    Article  PubMed  CAS  Google Scholar 

  219. Nakamura Y, Niki T, Goto A et al (2007) c-Met activation in lung adenocarcinoma tissues: an immunohistochemical analysis. Cancer Sci 98:1006-1013

    Article  PubMed  CAS  Google Scholar 

  220. Toschi L, Janne PA (2008) Single-agent and combination therapeutic strategies to inhibit hepatocyte growth factor/MET signaling in cancer. Clin Cancer Res 14:5941-5946

    Article  PubMed  CAS  Google Scholar 

  221. Engelman JA, Zejnullahu K, Mitsudomi T et al (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039-1043

    Article  PubMed  CAS  Google Scholar 

  222. Gordon MS, Mendelson DS, Sweeney C et al (2007) Interim results from a first-in-human study with AMG102, a fully human monoclonal antibody that neutralizes hepatocyte growth factor (HGF), the ligand to cMET receptor, in patients (pts) with advanced solid tumors. J Clin Oncol; ASCO annual meeting proceedings, part 1, vol 25, no 18S (June 20 Supplement), p 3551

    Google Scholar 

  223. Rosen PJ, Sweeney CJ, Park DJ et al (2008) AMG 102, an HGF/SF antagonist, in combination with anti-angiogenesis targeted therapies in adult patients with advanced solid tumors. J Clin Oncol; ASCO annual meeting proceedings, part I, vol 26 (May 20 Supplement), p 3570

    Google Scholar 

  224. Zou HY, Li Q, Lee JH et al (2007) An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res 67:4408-4417

    Article  PubMed  CAS  Google Scholar 

  225. Garcia A, Rosen L, Cunningham CC et al (2007) Phase 1 study of ARQ 197, a selective inhibitor of the c-Met RTK in patients with metastatic solid tumors reaches recommended phase 2 dose. J Clin Oncol; ASCO annual meeting proceedings, part 1, vol 25, no 18S (June 20 Supplement), p 3525

    Article  Google Scholar 

  226. Eder JP, Heath E, Appleman L et al (2007) Phase I experience with c-MET inhibitor XL880 administered orally to patients (pts) with solid tumors. J Clin Oncol; ASCO annual meeting proceedings, part 1, vol 25, no 18S (June 20 Supplement), p 3526

    Google Scholar 

  227. Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3:401-410

    Article  PubMed  CAS  Google Scholar 

  228. Ma J, Waxman DJ (2008) Combination of antiangiogenesis with chemotherapy for more effective cancer treatment. Mol Cancer Ther 7:3670-3684

    Article  PubMed  CAS  Google Scholar 

  229. Gettinger S (2008) Targeted therapy in advanced non-small-cell lung cancer. Semin Respir Crit Care Med 29:291-301

    Article  PubMed  Google Scholar 

  230. Ramalingam SS, Dahlberg SE, Langer CJ et al (2008) Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol 26:60-65

    Article  PubMed  CAS  Google Scholar 

  231. Manegold C, von Powel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Reck M (2008) BO17704 (AVAiL): a phase III randomised study of first-line bevacizumab combined with cisplatin/gemcitabine (CG) in patients (pts) with advanced or recurrent non-squamous, non-small cell lung cancer (NSCLC). In: European society for medical oncology; Ann Oncol 19 (Suppl 8):viii1-viii4

    Google Scholar 

  232. Shaked Y, Henke E, Roodhart JM et al (2008) Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell 14:263-273

    Article  PubMed  CAS  Google Scholar 

  233. Keane MP, Belperio JA, Xue YY, Burdick MD, Strieter RM (2004) Depletion of CXCR2 inhibits tumor growth and angiogenesis in a murine model of lung cancer. J Immunol 172:2853-2860

    PubMed  CAS  Google Scholar 

  234. Wislez M, Fujimoto N, Izzo JG et al (2006) High expression of ligands for chemokine receptor CXCR2 in alveolar epithelial neoplasia induced by oncogenic kras. Cancer Res 66:4198-4207

    Article  PubMed  CAS  Google Scholar 

  235. Mizukami Y, Jo WS, Duerr EM et al (2005) Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cells. Nat Med 11:992-997

    PubMed  CAS  Google Scholar 

  236. Keedy VL, Sandler AB (2007) Inhibition of angiogenesis in the treatment of non-small cell lung cancer. Cancer Sci 98:1825-1830

    Article  PubMed  CAS  Google Scholar 

  237. Stinchcombe TE, Socinski MA (2007) Bevacizumab in the treatment of non-small-cell lung cancer. Oncogene 26:3691-3698

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Pulmonary & Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA

    Steven M. Dubinett

Authors
  1. Tonya C. Walser
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jane Yanagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Edward Garon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jay M. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Steven M. Dubinett
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Steven M. Dubinett .

Editor information

Editors and Affiliations

  1. M. D. Anderson Cancer Center, University of Texas, Holcombe Blvd. 1515, Houston, 77030, U.S.A.

    David J. Stewart

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Humana Press, a part of Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Walser, T.C., Yanagawa, J., Garon, E., Lee, J.M., Dubinett, S.M. (2010). Tumor Microenvironment. In: Stewart, D. (eds) Lung Cancer. Current Clinical Oncology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-524-8_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-524-8_2

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-60761-523-1

  • Online ISBN: 978-1-60761-524-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation