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Neutrophil chemokines secreted by tumor cells mount a lung antimetastatic response during renal cell carcinoma progression

Oncogene volume 32, pages 1752–1760 (2013)Cite this article

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Abstract

The mechanism by which renal cell carcinoma (RCC) colonizes the lung microenvironment during metastasis remains largely unknown. To investigate this process, we grafted human RCC cells with varying lung metastatic potential in mice. Gene expression profiling of the mouse lung stromal compartment revealed a signature enriched for neutrophil-specific functions that was induced preferentially by poorly metastatic cells. Analysis of the gene expression signatures of tumor cell lines showed an inverse correlation between metastatic activity and the levels of a number of chemokines, including CXCL5 and IL8. Enforced depletion of CXCL5 and IL8 in these cell lines enabled us to establish a functional link between lung neutrophil infiltration, secretion of chemokines by cancer cells and metastatic activity. We further show that human neutrophils display a higher cytotoxic activity against poorly metastatic cells compared with highly metastatic cells. Together, these results support a model in which neutrophils recruited to the lung by tumor-secreted chemokines build an antimetastatic barrier with loss of neutrophil chemokines in tumor cells acting as a critical rate-limiting step during lung metastatic seeding.

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References

  1. Cohen HT, McGovern FJ . Renal-cell carcinoma. N Engl J Med 2005; 353: 2477–2490.

    Article  CAS  Google Scholar 

  2. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356: 115–124.

    Article  CAS  Google Scholar 

  3. McAllister SS, Weinberg RA . Tumor-host interactions: a far-reaching relationship. J Clin Oncol 2010; 28: 4022–4028.

    Article  Google Scholar 

  4. Joyce JA, Pollard JW . Microenvironmental regulation of metastasis. Nat Rev Cancer 2009; 9: 239–252.

    Article  CAS  Google Scholar 

  5. Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 2004; 6: 17–32.

    Article  CAS  Google Scholar 

  6. Chang HY, Sneddon JB, Alizadeh AA, Sood R, West RB, Montgomery K et al. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol 2004; 2: E7.

    Article  Google Scholar 

  7. de Visser KE, Eichten A, Coussens LM . Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 2006; 6: 24–37.

    Article  CAS  Google Scholar 

  8. Mantovani A, Sica A . Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 2010; 22: 231–237.

    Article  CAS  Google Scholar 

  9. Talmadge JE, Donkor M, Scholar E . Inflammatory cell infiltration of tumors: Jekyll or Hyde. Cancer Metastasis Rev 2007; 26: 373–400.

    Article  Google Scholar 

  10. Ostrand-Rosenberg S . Immune surveillance: a balance between protumor and antitumor immunity. Curr Opin Genet Dev 2008; 18: 11–18.

    Article  CAS  Google Scholar 

  11. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 2009; 16: 183–194.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  13. Paget S . The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 1989; 8: 98–101.

    CAS  Google Scholar 

  14. Fidler IJ . The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 2003; 3: 453–458.

    Article  CAS  Google Scholar 

  15. Nguyen DX, Massague J . Genetic determinants of cancer metastasis. Nat Rev Genet 2007; 8: 341–352.

    Article  CAS  Google Scholar 

  16. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 2005; 438: 820–827.

    Article  CAS  Google Scholar 

  17. Lopez-Lago MA, Thodima VJ, Guttapalli A, Chan TA, Heguy A, Molina AM et al. Genomic Deregulation during Metastasis of Renal Cell Carcinoma Implements a Myofibroblast-Like Program of Gene Expression. Cancer Res 2010.

  18. Naito S, Walker SM, Fidler IJ . In vivo selection of human renal cell carcinoma cells with high metastatic potential in nude mice. Clin Exp Metastasis 1989; 7: 381–389.

    Article  CAS  Google Scholar 

  19. Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D et al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci USA 2004; 101: 6062–6067.

    Article  CAS  Google Scholar 

  20. Ebert T, Bander NH, Finstad CL, Ramsawak RD, Old LJ . Establishment and characterization of human renal cancer and normal kidney cell lines. Cancer Res 1990; 50: 5531–5536.

    CAS  PubMed  Google Scholar 

  21. Tan X, Zhai Y, Chang W, Hou J, He S, Lin L et al. Global analysis of metastasis-associated gene expression in primary cultures from clinical specimens of clear-cell renal-cell carcinoma. Int J Cancer 2008; 123: 1080–1088.

    Article  CAS  Google Scholar 

  22. Murphy GP, Hrushesky WJ . A murine renal cell carcinoma. J Natl Cancer Inst 1973; 50: 1013–1025.

    Article  CAS  Google Scholar 

  23. Finak G, Sadekova S, Pepin F, Hallett M, Meterissian S, Halwani F et al. Gene expression signatures of morphologically normal breast tissue identify basal-like tumors. Breast Cancer Res 2006; 8: R58.

    Article  Google Scholar 

  24. Dakhova O, Ozen M, Creighton CJ, Li R, Ayala G, Rowley D et al. Global gene expression analysis of reactive stroma in prostate cancer. Clin Cancer Res 2009; 15: 3979–3989.

    Article  CAS  Google Scholar 

  25. Jensen HK, Donskov F, Marcussen N, Nordsmark M, Lundbeck F, von der Maase H . Presence of intratumoral neutrophils is an independent prognostic factor in localized renal cell carcinoma. J Clin Oncol 2009; 27: 4709–4717.

    Article  Google Scholar 

  26. Bellocq A, Antoine M, Flahault A, Philippe C, Crestani B, Bernaudin JF et al. Neutrophil alveolitis in bronchioloalveolar carcinoma: induction by tumor-derived interleukin-8 and relation to clinical outcome. Am J Pathol 1998; 152: 83–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Foekens JA, Ries C, Look MP, Gippner-Steppert C, Klijn JG, Jochum M . The prognostic value of polymorphonuclear leukocyte elastase in patients with primary breast cancer. Cancer Res 2003; 63: 337–341.

    CAS  PubMed  Google Scholar 

  28. Di Carlo E, Forni G, Lollini P, Colombo MP, Modesti A, Musiani P . The intriguing role of polymorphonuclear neutrophils in antitumor reactions. Blood 2001; 97: 339–345.

    Article  CAS  Google Scholar 

  29. Buonocore S, Haddou NO, Moore F, Florquin S, Paulart F, Heirman C et al. Neutrophil-dependent tumor rejection and priming of tumoricidal CD8+ T cell response induced by dendritic cells overexpressing CD95L. J Leukoc Biol 2008; 84: 713–720.

    Article  CAS  Google Scholar 

  30. Schaider H, Oka M, Bogenrieder T, Nesbit M, Satyamoorthy K, Berking C et al. Differential response of primary and metastatic melanomas to neutrophils attracted by IL-8. Int J Cancer 2003; 103: 335–343.

    Article  CAS  Google Scholar 

  31. Kowanetz M, Wu X, Lee J, Tan M, Hagenbeek T, Qu X et al. Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes. Proc Natl Acad Sci USA. 2010; 107: 21248–21255.

    Article  CAS  Google Scholar 

  32. Granot Z, Henke E, Comen EA, King TA, Norton L, Benezra R . Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t] 2011; 20: 300–314.

    Article  CAS  Google Scholar 

  33. Balkwill F . Cancer and the chemokine network. Nat Rev Cancer 2004; 4: 540–550.

    Article  CAS  Google Scholar 

  34. Monti P, Leone BE, Marchesi F, Balzano G, Zerbi A, Scaltrini F et al. The CC chemokine MCP-1/CCL2 in pancreatic cancer progression: regulation of expression and potential mechanisms of antimalignant activity. Cancer Res 2003; 63: 7451–7461.

    CAS  Google Scholar 

  35. Gorbachev AV, Kobayashi H, Kudo D, Tannenbaum CS, Finke JH, Shu S et al. CXC chemokine ligand 9/monokine induced by IFN-gamma production by tumor cells is critical for T cell-mediated suppression of cutaneous tumors. J Immunol 2007; 178: 2278–2286.

    Article  CAS  Google Scholar 

  36. Kondo T, Ito F, Nakazawa H, Horita S, Osaka Y, Toma H . High expression of chemokine gene as a favorable prognostic factor in renal cell carcinoma. J Urol 2004; 171: 2171–2175.

    Article  CAS  Google Scholar 

  37. Schadendorf D, Moller A, Algermissen B, Worm M, Sticherling M, Czarnetzki BM . IL-8 produced by human malignant melanoma cells in vitro is an essential autocrine growth factor. J Immunol 1993; 151: 2667–2675.

    CAS  PubMed  Google Scholar 

  38. Singh RK, Gutman M, Radinsky R, Bucana CD, Fidler IJ . Expression of interleukin 8 correlates with the metastatic potential of human melanoma cells in nude mice. Cancer Res 1994; 54: 3242–3247.

    CAS  PubMed  Google Scholar 

  39. Arenberg DA, Kunkel SL, Polverini PJ, Glass M, Burdick MD, Strieter RM . Inhibition of interleukin-8 reduces tumorigenesis of human non-small cell lung cancer in SCID mice. J Clin Invest 1996; 97: 2792–2802.

    Article  CAS  Google Scholar 

  40. Lee LF, Hellendall RP, Wang Y, Haskill JS, Mukaida N, Matsushima K et al. IL-8 reduced tumorigenicity of human ovarian cancer in vivo due to neutrophil infiltration. J Immunol 2000; 164: 2769–2775.

    Article  CAS  Google Scholar 

  41. Takahashi H, Numasaki M, Lotze MT, Sasaki H . Interleukin-17 enhances bFGF-, HGF- and VEGF-induced growth of vascular endothelial cells. Immunol Lett 2005; 98: 189–193.

    Article  CAS  Google Scholar 

  42. Arenberg DA, Keane MP, DiGiovine B, Kunkel SL, Morris SB, Xue YY et al. Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer. J Clin Invest 1998; 102: 465–472.

    Article  CAS  Google Scholar 

  43. Wong YF, Cheung TH, Lo KW, Yim SF, Siu NS, Chan SC et al. Identification of molecular markers and signaling pathway in endometrial cancer in Hong Kong Chinese women by genome-wide gene expression profiling. Oncogene 2007; 26: 1971–1982.

    Article  CAS  Google Scholar 

  44. Miyazaki H, Patel V, Wang H, Edmunds RK, Gutkind JS, Yeudall WA . Down-regulation of CXCL5 inhibits squamous carcinogenesis. Cancer Res 2006; 66: 4279–4284.

    Article  CAS  Google Scholar 

  45. Speetjens FM, Kuppen PJ, Sandel MH, Menon AG, Burg D, van de Velde CJ et al. Disrupted expression of CXCL5 in colorectal cancer is associated with rapid tumor formation in rats and poor prognosis in patients. Clin Cancer Res 2008; 14: 2276–2284.

    Article  CAS  Google Scholar 

  46. Linehan WM, Walther MM, Zbar B . The genetic basis of cancer of the kidney. J Urol 2003; 170: 2163–2172.

    Article  CAS  Google Scholar 

  47. Jiang F, Desper R, Papadimitriou CH, Schaffer AA, Kallioniemi OP, Richter J et al. Construction of evolutionary tree models for renal cell carcinoma from comparative genomic hybridization data. Cancer Res 2000; 60: 6503–6509.

    CAS  Google Scholar 

  48. Bissig H, Richter J, Desper R, Meier V, Schraml P, Schaffer AA et al. Evaluation of the clonal relationship between primary and metastatic renal cell carcinoma by comparative genomic hybridization. Am J Pathol 1999; 155: 267–274.

    Article  CAS  Google Scholar 

  49. Naito S, von Eschenbach AC, Giavazzi R, Fidler IJ . Growth and metastasis of tumor cells isolated from a human renal cell carcinoma implanted into different organs of nude mice. Cancer Res 1986; 46: 4109–4115.

    CAS  PubMed  Google Scholar 

  50. Tusher VG, Tibshirani R, Chu G . Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.] 2001; 98: 5116–5121.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by research grants from the National Cancer Institute (CA-121327), the V-Foundation and a Syms kidney cancer award. We thank Marco Seandel and Eric Pamer for critical reading of the manuscript. The MSKCC Genomics Core Facility provided expert assistance in performing the gene expression profiling assays. R Chaganti is a Board member and a paid consultant of Cancer Genetics Inc., Rutherford, NJ, USA.

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Authors and Affiliations

  1. Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    M A López-Lago, S Posner, V J Thodima & R S K Chaganti

  2. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    A M Molina, R J Motzer & R S K Chaganti

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  1. M A López-Lago
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Correspondence to R S K Chaganti.

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López-Lago, M., Posner, S., Thodima, V. et al. Neutrophil chemokines secreted by tumor cells mount a lung antimetastatic response during renal cell carcinoma progression. Oncogene 32, 1752–1760 (2013). https://doi.org/10.1038/onc.2012.201

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