Home LiteratureArticle Details
PMID: 22665059 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Oncogene ·Vol. 32 ·No. 14 ·2013-04-04 ·Pages 1752-60

López-Lago MA, Posner S, Thodima VJ, Molina AM, Motzer RJ, Chaganti RS

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.

MeSH Terms
Adult Animals Apoptosis Carcinoma, Renal Cell/metabolism,pathology,prevention & control Cell Line, Tumor Cell Proliferation Chemokines/antagonists & inhibitors,genetics,metabolism Disease Progression Fluorescent Antibody Technique Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Kidney Neoplasms/metabolism,pathology,prevention & control Lung Neoplasms/metabolism,prevention & control,secondary Male Mice Mice, Inbred BALB C Neutrophils/metabolism RNA, Messenger/genetics Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction
Chemicals
Chemokines RNA, Messenger
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
López-Lago M A
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Posner S
Thodima V J
Molina A M
Motzer R J
Chaganti R S K
References (50)
50 references, click to expand
  1. Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer.
    J Clin Invest. 1998 Aug 1;102(3):465-72 PMID: 9691082
  2. Tumor-host interactions: a far-reaching relationship.
    J Clin Oncol. 2010 Sep 10;28(26):4022-8 PMID: 20644094
  3. Molecular characterization of the tumor microenvironment in breast cancer.
    Cancer Cell. 2004 Jul;6(1):17-32 PMID: 15261139
  4. The genetic basis of cancer of the kidney.
    J Urol. 2003 Dec;170(6 Pt 1):2163-72 PMID: 14634372
  5. Disrupted expression of CXCL5 in colorectal cancer is associated with rapid tumor formation in rats and poor prognosis in patients.
    Clin Cancer Res. 2008 Apr 15;14(8):2276-84 PMID: 18413816
  6. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.
    N Engl J Med. 2007 Jan 11;356(2):115-24 PMID: 17215529
  7. The prognostic value of polymorphonuclear leukocyte elastase in patients with primary breast cancer.
    Cancer Res. 2003 Jan 15;63(2):337-41 PMID: 12543785
  8. Global gene expression analysis of reactive stroma in prostate cancer.
    Clin Cancer Res. 2009 Jun 15;15(12):3979-89 PMID: 19509179
  9. The role of myeloid cells in the promotion of tumour angiogenesis.
    Nat Rev Cancer. 2008 Aug;8(8):618-31 PMID: 18633355
  10. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds.
    PLoS Biol. 2004 Feb;2(2):E7 PMID: 14737219
  11. Establishment and characterization of human renal cancer and normal kidney cell lines.
    Cancer Res. 1990 Sep 1;50(17):5531-6 PMID: 2386958
  12. IL-8 produced by human malignant melanoma cells in vitro is an essential autocrine growth factor.
    J Immunol. 1993 Sep 1;151(5):2667-75 PMID: 8360485
  13. Renal-cell carcinoma.
    N Engl J Med. 2005 Dec 8;353(23):2477-90 PMID: 16339096
  14. 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 Feb 15;178(4):2278-86 PMID: 17277133
  15. In vivo selection of human renal cell carcinoma cells with high metastatic potential in nude mice.
    Clin Exp Metastasis. 1989 Jul-Aug;7(4):381-9 PMID: 2706827
  16. Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes.
    Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21248-55 PMID: 21081700
  17. Differential response of primary and metastatic melanomas to neutrophils attracted by IL-8.
    Int J Cancer. 2003 Jan 20;103(3):335-43 PMID: 12471616
  18. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited.
    Nat Rev Cancer. 2003 Jun;3(6):453-8 PMID: 12778135
  19. A murine renal cell carcinoma.
    J Natl Cancer Inst. 1973 Apr;50(4):1013-25 PMID: 4703766
  20. The CC chemokine MCP-1/CCL2 in pancreatic cancer progression: regulation of expression and potential mechanisms of antimalignant activity.
    Cancer Res. 2003 Nov 1;63(21):7451-61 PMID: 14612545
  21. A gene atlas of the mouse and human protein-encoding transcriptomes.
    Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6062-7 PMID: 15075390
  22. The distribution of secondary growths in cancer of the breast. 1889.
    Cancer Metastasis Rev. 1989 Aug;8(2):98-101 PMID: 2673568
  23. Identification of molecular markers and signaling pathway in endometrial cancer in Hong Kong Chinese women by genome-wide gene expression profiling.
    Oncogene. 2007 Mar 22;26(13):1971-82 PMID: 17043662
  24. Expression of interleukin 8 correlates with the metastatic potential of human melanoma cells in nude mice.
    Cancer Res. 1994 Jun 15;54(12):3242-7 PMID: 8205546
  25. Evaluation of the clonal relationship between primary and metastatic renal cell carcinoma by comparative genomic hybridization.
    Am J Pathol. 1999 Jul;155(1):267-74 PMID: 10393858
  26. Construction of evolutionary tree models for renal cell carcinoma from comparative genomic hybridization data.
    Cancer Res. 2000 Nov 15;60(22):6503-9 PMID: 11103820
  27. Growth and metastasis of tumor cells isolated from a human renal cell carcinoma implanted into different organs of nude mice.
    Cancer Res. 1986 Aug;46(8):4109-15 PMID: 3731078
  28. Cancer and the chemokine network.
    Nat Rev Cancer. 2004 Jul;4(7):540-50 PMID: 15229479
  29. Microenvironmental regulation of metastasis.
    Nat Rev Cancer. 2009 Apr;9(4):239-52 PMID: 19279573
  30. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche.
    Nature. 2005 Dec 8;438(7069):820-7 PMID: 16341007
  31. Inhibition of interleukin-8 reduces tumorigenesis of human non-small cell lung cancer in SCID mice.
    J Clin Invest. 1996 Jun 15;97(12):2792-802 PMID: 8675690
  32. Down-regulation of CXCL5 inhibits squamous carcinogenesis.
    Cancer Res. 2006 Apr 15;66(8):4279-84 PMID: 16618752
  33. Neutrophil-dependent tumor rejection and priming of tumoricidal CD8+ T cell response induced by dendritic cells overexpressing CD95L.
    J Leukoc Biol. 2008 Sep;84(3):713-20 PMID: 18567840
  34. Presence of intratumoral neutrophils is an independent prognostic factor in localized renal cell carcinoma.
    J Clin Oncol. 2009 Oct 1;27(28):4709-17 PMID: 19720929
  35. Global analysis of metastasis-associated gene expression in primary cultures from clinical specimens of clear-cell renal-cell carcinoma.
    Int J Cancer. 2008 Sep 1;123(5):1080-8 PMID: 18546293
  36. Genomic deregulation during metastasis of renal cell carcinoma implements a myofibroblast-like program of gene expression.
    Cancer Res. 2010 Dec 1;70(23):9682-92 PMID: 20952505
  37. Genetic determinants of cancer metastasis.
    Nat Rev Genet. 2007 May;8(5):341-52 PMID: 17440531
  38. Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN.
    Cancer Cell. 2009 Sep 8;16(3):183-94 PMID: 19732719
  39. Gene expression signatures of morphologically normal breast tissue identify basal-like tumors.
    Breast Cancer Res. 2006;8(5):R58 PMID: 17054791
  40. Paradoxical roles of the immune system during cancer development.
    Nat Rev Cancer. 2006 Jan;6(1):24-37 PMID: 16397525
  41. The intriguing role of polymorphonuclear neutrophils in antitumor reactions.
    Blood. 2001 Jan 15;97(2):339-45 PMID: 11154206
  42. High expression of chemokine gene as a favorable prognostic factor in renal cell carcinoma.
    J Urol. 2004 Jun;171(6 Pt 1):2171-5 PMID: 15126779
  43. Significance analysis of microarrays applied to the ionizing radiation response.
    Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21 PMID: 11309499
  44. Immune surveillance: a balance between protumor and antitumor immunity.
    Curr Opin Genet Dev. 2008 Feb;18(1):11-8 PMID: 18308558
  45. Tumor entrained neutrophils inhibit seeding in the premetastatic lung.
    Cancer Cell. 2011 Sep 13;20(3):300-14 PMID: 21907922
  46. Inflammatory cell infiltration of tumors: Jekyll or Hyde.
    Cancer Metastasis Rev. 2007 Dec;26(3-4):373-400 PMID: 17717638
  47. Neutrophil alveolitis in bronchioloalveolar carcinoma: induction by tumor-derived interleukin-8 and relation to clinical outcome.
    Am J Pathol. 1998 Jan;152(1):83-92 PMID: 9422526
  48. Macrophages, innate immunity and cancer: balance, tolerance, and diversity.
    Curr Opin Immunol. 2010 Apr;22(2):231-7 PMID: 20144856
  49. IL-8 reduced tumorigenicity of human ovarian cancer in vivo due to neutrophil infiltration.
    J Immunol. 2000 Mar 1;164(5):2769-75 PMID: 10679119
  50. Interleukin-17 enhances bFGF-, HGF- and VEGF-induced growth of vascular endothelial cells.
    Immunol Lett. 2005 May 15;98(2):189-93 PMID: 15860217
Article Info
Journal
Oncogene
Abbr.
Oncogene
ISSN
1476-5594
DOI
10.1038/onc.2012.201
Published
2013-04-04
Epub
2012-00-04
Pages
1752-60
Language
English
Region
England
NLM ID
8711562
PMCID
PMC3435490
Subset
IM
Grants
NCI NIH HHS · R01 CA121327 · United States
NCI NIH HHS · CA-121327 · United States
External Links
PubMed source DOI: 10.1038/onc.2012.201 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2