A cytokine-mediated link between innate immunity, inflammation, and cancer.

It has been established that cancer can be promoted and/or exacerbated by inflammation and infections. Indeed, chronic inflammation orchestrates a tumor-supporting microenvironment that is an indispensable participant in the neoplastic process. The mechanisms that link infection, innate immunity, inflammation, and cancer are being unraveled at a fast pace. Important components in this linkage are the cytokines produced by activated innate immune cells that stimulate tumor growth and progression. In addition, soluble mediators produced by cancer cells recruit and activate inflammatory cells, which further stimulate tumor progression. However, inflammatory cells also produce cytokines that can limit tumor growth. Here we provide an overview of the current understanding of the role of inflammation-induced cytokines in tumor initiation, promotion, and progression.

[1]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.

[2]  K. Kinzler,et al.  Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer. , 1995, Cancer research.

[3]  J. Barber Medical genetics: advances in brief , 1995 .

[4]  T. Libermann,et al.  Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B. , 1996, Blood.

[5]  M. Leach,et al.  Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. , 1996, The Journal of clinical investigation.

[6]  A. Fulton,et al.  Interleukin-10 inhibits tumor metastasis, downregulates MHC class I, and enhances NK lysis. , 1997, Cellular immunology.

[7]  K. Shirabe,et al.  Circulating intercellular adhesion molecule-1 in patients with hepatocellular carcinoma before and after hepatic resection. , 1997, Hepato-gastroenterology.

[8]  D. Mullins,et al.  Tumor‐induced immune dysfunction: the macrophage connection , 1998, Journal of leukocyte biology.

[9]  M. Leach,et al.  IL-12, but not IFN-gamma, plays a major role in sustaining the chronic phase of colitis in IL-10-deficient mice. , 1998, Journal of immunology.

[10]  Resident Enteric Bacteria Are Necessary for Development of Spontaneous Colitis and Immune System Activation in Interleukin-10-Deficient Mice , 1998, Infection and Immunity.

[11]  G. Kollias,et al.  Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. , 1999, Nature medicine.

[12]  M. Mayo,et al.  Interleukin-10 signaling blocks inhibitor of kappaB kinase activity and nuclear factor kappaB DNA binding. , 1999, The Journal of biological chemistry.

[13]  Y. Chang,et al.  KSHV-encoded viral IL-6 activates multiple human IL-6 signaling pathways. , 1999, Human immunology.

[14]  A. Roberts,et al.  Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF‐β , 1999, The EMBO journal.

[15]  M. Mayo,et al.  Interleukin-10 Signaling Blocks Inhibitor of κB Kinase Activity and Nuclear Factor κB DNA Binding* , 1999, The Journal of Biological Chemistry.

[16]  H. Redmond,et al.  The role of endotoxin/lipopolysaccharide in surgically induced tumour growth in a murine model of metastatic disease , 1999, British Journal of Cancer.

[17]  J. Banchereau,et al.  Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. , 1999, Cancer research.

[18]  M. Bar‐eli,et al.  Regulation of tumor growth and metastasis by interleukin-10: the melanoma experience. , 1999, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[19]  N. Fausto,et al.  Impaired Preneoplastic Changes and Liver Tumor Formation in Tumor Necrosis Factor Receptor Type 1 Knockout Mice , 2000, The Journal of experimental medicine.

[20]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[21]  S. Markowitz,et al.  Molecular mechanisms of inactivation of TGF-β receptors during carcinogenesis , 2000 .

[22]  B. Bonavida,et al.  Inhibition of interleukin 10 by rituximab results in down-regulation of bcl-2 and sensitization of B-cell non-Hodgkin's lymphoma to apoptosis. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[23]  Ruslan Medzhitov,et al.  Toll-like receptors and innate immunity , 2001, Nature Reviews Immunology.

[24]  Mourad Sahbatou,et al.  Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease , 2001, Nature.

[25]  R. Coffman,et al.  Interleukin-10 and the interleukin-10 receptor. , 2001, Annual review of immunology.

[26]  A. Balmain,et al.  TGF-β signaling in tumor suppression and cancer progression , 2001, Nature Genetics.

[27]  A. Falus,et al.  Mouse plasmacytoma: an experimental model of human multiple myeloma. , 2001, Haematologica.

[28]  Alberto Mantovani,et al.  Inflammation and cancer: back to Virchow? , 2001, The Lancet.

[29]  S. Pawlowski,et al.  Elimination of colon cancer in germ-free transforming growth factor beta 1-deficient mice. , 2002, Cancer research.

[30]  M. Mai,et al.  Essential roles of tumor necrosis factor receptor p55 in liver metastasis of intrasplenic administration of colon 26 cells. , 2002, Cancer research.

[31]  D. Podolsky,et al.  Inflammatory bowel disease. , 2002, The New England journal of medicine.

[32]  E. Tartour,et al.  Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism. , 2002, Blood.

[33]  S. Weitzman,et al.  Chronic inflammation and cancer. , 2002, Oncology.

[34]  W. Lichtenegger,et al.  Polymorphism of IL-1 receptor antagonist gene: role in cancer. , 2002, Anticancer research.

[35]  C. Bucana,et al.  Lipopolysaccharide‐induced metastatic growth is associated with increased angiogenesis, vascular permeability and tumor cell invasion , 2002, International journal of cancer.

[36]  P. Gariglio,et al.  Interleukin‐10 promotes B16‐melanoma growth by inhibition of macrophage functions and induction of tumour and vascular cell proliferation , 2002, Immunology.

[37]  D. Glass,et al.  Cutting Edge: IL-10-Producing CD4+ T Cells Mediate Tumor Rejection1 , 2002, The Journal of Immunology.

[38]  P. Allavena,et al.  Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. , 2002, Trends in immunology.

[39]  Michael Karin,et al.  NF-κB in cancer: from innocent bystander to major culprit , 2002, Nature Reviews Cancer.

[40]  T. Hirano,et al.  IL-6 in autoimmune disease and chronic inflammatory proliferative disease. , 2002, Cytokine & growth factor reviews.

[41]  M. Smyth,et al.  Critical Role for Tumor Necrosis Factor–related Apoptosis-inducing Ligand in Immune Surveillance Against Tumor Development , 2002, The Journal of experimental medicine.

[42]  J. Crawford,et al.  T cells require TRAIL for optimal graft-versus-tumor activity , 2002, Nature Medicine.

[43]  Massimo Gadina,et al.  Cytokine Signaling in 2002 New Surprises in the Jak/Stat Pathway , 2002, Cell.

[44]  M. Lotze,et al.  Interleukin-17 promotes angiogenesis and tumor growth. , 2003, Blood.

[45]  E. El-Omar,et al.  The role of interleukin-1beta and other potential genetic markers as indicators of gastric cancer risk. , 2003, Canadian journal of gastroenterology = Journal canadien de gastroenterologie.

[46]  C. Harris,et al.  Radical causes of cancer , 2003, Nature Reviews Cancer.

[47]  J. Hadden Immunodeficiency and cancer: prospects for correction. , 2003, International immunopharmacology.

[48]  T. Mcclanahan,et al.  Divergent Pro- and Antiinflammatory Roles for IL-23 and IL-12 in Joint Autoimmune Inflammation , 2003, The Journal of experimental medicine.

[49]  G. Trinchieri,et al.  Interleukin-12 and the regulation of innate resistance and adaptive immunity , 2003, Nature Reviews Immunology.

[50]  Nigel J. Saunders,et al.  CD4+CD25+ TR Cells Suppress Innate Immune Pathology Through Cytokine-dependent Mechanisms , 2003, The Journal of experimental medicine.

[51]  K. Książek,et al.  Interleukin-17: a mediator of inflammatory responses , 2004, Cellular and Molecular Life Sciences CMLS.

[52]  A. Ashkenazi,et al.  Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy. , 2003, Cytokine & growth factor reviews.

[53]  Y. Saga,et al.  Interleukin-10-mediated inhibition of angiogenesis and tumor growth in mice bearing VEGF-producing ovarian cancer. , 2003, Cancer research.

[54]  J. Fox,et al.  CD4+ CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice. , 2003, The American journal of pathology.

[55]  Hiroshi Yamamoto,et al.  Transduction of the IL-21 and IL-23 genes in human pancreatic carcinoma cells produces natural killer cell-dependent and -independent antitumor effects , 2003, Cancer Gene Therapy.

[56]  Cheng-Wen Wu,et al.  Antitumor and Antimetastatic Activity of IL-231 , 2003, The Journal of Immunology.

[57]  J. Fox,et al.  CD4(+)CD25(+) regulatory lymphocytes require interleukin 10 to interrupt colon carcinogenesis in mice. , 2003, Cancer research.

[58]  T. Moseley,et al.  Interleukin-17 family and IL-17 receptors. , 2003, Cytokine & growth factor reviews.

[59]  S. Wahl,et al.  TGF-β: the missing link in CD4+CD25+ regulatory T cell-mediated immunosuppression , 2003 .

[60]  A. Ashkenazi,et al.  Apo2L/TRAIL and its death and decoy receptors , 2003, Cell Death and Differentiation.

[61]  R. Derynck,et al.  Smad-dependent and Smad-independent pathways in TGF-beta family signalling. , 2003, Nature.

[62]  Sarah L. Gaffen,et al.  Functional Cooperation between Interleukin-17 and Tumor Necrosis Factor-α Is Mediated by CCAAT/Enhancer-binding Protein Family Members* , 2004, Journal of Biological Chemistry.

[63]  N. Tsuyama,et al.  Receptor synergy of interleukin-6 (IL-6) and insulin-like growth factor-I in myeloma cells that highly express IL-6 receptor alpha [corrected]. , 2003, Blood.

[64]  G. Marti,et al.  Studies in NZB IL-10 knockout mice of the requirement of IL-10 for progression of B-cell lymphoma , 2004, Leukemia.

[65]  B. Nathwani,et al.  IL-6 levels and genotype are associated with risk of young adult Hodgkin lymphoma. , 2004, Blood.

[66]  Stefan Wirtz,et al.  TGF-β Suppresses Tumor Progression in Colon Cancer by Inhibition of IL-6 trans-Signaling , 2004 .

[67]  Michael Karin,et al.  IKKβ Links Inflammation and Tumorigenesis in a Mouse Model of Colitis-Associated Cancer , 2004, Cell.

[68]  M. Smyth,et al.  Cytokines in cancer immunity and immunotherapy , 2004, Immunological reviews.

[69]  D. Longo,et al.  Ammonium Trichloro(dioxoethylene-o,o′)tellurate (AS101) Sensitizes Tumors to Chemotherapy by Inhibiting the Tumor Interleukin 10 Autocrine Loop , 2004, Cancer Research.

[70]  Y. Ben-Neriah,et al.  NF-κB functions as a tumour promoter in inflammation-associated cancer , 2004, Nature.

[71]  F. Balkwill,et al.  Expression of both TNF-α receptor subtypes is essential for optimal skin tumour development , 2004, Oncogene.

[72]  C. D. Krause,et al.  Interleukin-10 and related cytokines and receptors. , 2004, Annual review of immunology.

[73]  F. Berger The interleukin-6 gene: a susceptibility factor that may contribute to racial and ethnic disparities in breast cancer mortality , 2004, Breast Cancer Research and Treatment.

[74]  M. Karin,et al.  Inhibition of NF-κB in cancer cells converts inflammation- induced tumor growth mediated by TNFα to TRAIL-mediated tumor regression , 2004 .

[75]  Yuka Kanno,et al.  Signaling by IL‐12 and IL‐23 and the immunoregulatory roles of STAT4 , 2004, Immunological reviews.

[76]  G. Trinchieri,et al.  Interleukin‐10 in viral diseases and cancer: exiting the labyrinth? , 2004, Immunological reviews.

[77]  Jiahuai Han,et al.  Limiting inflammatory responses during activation of innate immunity , 2005, Nature Immunology.

[78]  John N Weinstein,et al.  The p53 tumor suppressor network is a key responder to microenvironmental components of chronic inflammatory stress. , 2005, Cancer research.

[79]  R. Weissleder,et al.  Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-β signals in vivo , 2005 .

[80]  A. Mantovani,et al.  Smoldering and polarized inflammation in the initiation and promotion of malignant disease. , 2005, Cancer cell.

[81]  M. Dobrovolskaia,et al.  Inflammation and cancer: when NF-kappaB amalgamates the perilous partnership. , 2005, Current cancer drug targets.

[82]  R. Alon,et al.  Immune cell migration in inflammation: present and future therapeutic targets , 2005, Nature Immunology.

[83]  Michael Karin,et al.  IKK/NF-κB signaling: balancing life and death – a new approach to cancer therapy , 2005 .

[84]  Michael Karin,et al.  IKK/NF-kappaB signaling: balancing life and death--a new approach to cancer therapy. , 2005, The Journal of clinical investigation.

[85]  M. Karin,et al.  NOD2 and Crohn's disease: loss or gain of function? , 2005, Immunity.

[86]  F. Marincola,et al.  Interleukin‐10 and the immune response against cancer: a counterpoint , 2005, Journal of leukocyte biology.

[87]  T. Blankenstein The role of tumor stroma in the interaction between tumor and immune system. , 2005, Current opinion in immunology.

[88]  Eric B Haura,et al.  Mechanisms of Disease: insights into the emerging role of signal transducers and activators of transcription in cancer , 2005, Nature Clinical Practice Oncology.

[89]  T. Mcclanahan,et al.  IL-23 drives a pathogenic T cell population that induces autoimmune inflammation , 2005, The Journal of experimental medicine.

[90]  Ying Wang,et al.  A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17 , 2005, Nature Immunology.

[91]  M. Lotze,et al.  IL-17 Enhances the Net Angiogenic Activity and In Vivo Growth of Human Non-Small Cell Lung Cancer in SCID Mice through Promoting CXCR-2-Dependent Angiogenesis1 , 2005, The Journal of Immunology.

[92]  T. Nheu,et al.  Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-β signaling , 2005, Nature Medicine.

[93]  B. Chauffert,et al.  Tumor cells convert immature myeloid dendritic cells into TGF-β–secreting cells inducing CD4+CD25+ regulatory T cell proliferation , 2005, The Journal of experimental medicine.

[94]  C. Gregory,et al.  Enhanced Apoptotic Cell Clearance Capacity and B Cell Survival Factor Production by IL-10-Activated Macrophages: Implications for Burkitt’s Lymphoma1 , 2005, The Journal of Immunology.

[95]  E. Hurt,et al.  The role of IL-6 and STAT3 in inflammation and cancer. , 2005, European journal of cancer.

[96]  Carlo Riccardo Rossi,et al.  Tumor necrosis factor, cancer and anticancer therapy. , 2005, Cytokine & growth factor reviews.

[97]  C. Jobin,et al.  STAT3 regulates NF-κB recruitment to the IL-12p40 promoter in dendritic cells , 2005 .

[98]  Michael Karin,et al.  NF-κB: linking inflammation and immunity to cancer development and progression , 2005, Nature Reviews Immunology.

[99]  W. Yeh,et al.  IMPLICATION OF TOLL-LIKE RECEPTOR AND TUMOR NECROSIS FACTOR α SIGNALING IN SEPTIC SHOCK , 2005 .

[100]  Jane J. Sohn,et al.  CD4+CD25+ regulatory lymphocytes induce regression of intestinal tumors in ApcMin/+ mice. , 2005, Cancer research.

[101]  S. Leibundgut-Landmann,et al.  Myeloid C-type lectins in innate immunity , 2006, Nature Immunology.

[102]  Xinchun Chen,et al.  Tumor-derived CD4+CD25+ regulatory T cell suppression of dendritic cell function involves TGF-β and IL-10 , 2006, Cancer Immunology, Immunotherapy.

[103]  L. Coussens,et al.  Paradoxical roles of the immune system during cancer development , 2006, Nature Reviews Cancer.

[104]  A. Ben-Baruch Inflammation-associated immune suppression in cancer: the roles played by cytokines, chemokines and additional mediators. , 2006, Seminars in cancer biology.

[105]  S. Akira,et al.  Pathogen Recognition and Innate Immunity , 2006, Cell.

[106]  87 TNF-α inhibits asbestos induced cytotoxicity via a NF-kB dependent pathway: A possible mechanism for asbestos-induced oncogenesis , 2006 .

[107]  B. Shan,et al.  Immune enhancement and anti-tumour activity of IL-23 , 2006, Cancer Immunology, Immunotherapy.

[108]  J. Scheller,et al.  Interleukin‐6 biology is coordinated by membrane‐bound and soluble receptors: role in inflammation and cancer , 2006, Journal of leukocyte biology.

[109]  Y. Carmi,et al.  The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor-host interactions , 2006, Cancer and Metastasis Reviews.

[110]  R. D. Hatton,et al.  Transforming growth factor-beta induces development of the T(H)17 lineage. , 2006, Nature.

[111]  M. Karin Nuclear factor-κB in cancer development and progression , 2006, Nature.

[112]  H. Pass,et al.  TNF-α inhibits asbestos-induced cytotoxicity via a NF-κB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis , 2006, Proceedings of the National Academy of Sciences.

[113]  R. Houot,et al.  Elevated IL-10 plasma levels correlate with poor prognosis in diffuse large B-cell lymphoma. , 2006, European cytokine network.

[114]  H. Alexander,et al.  Journal of Translational Medicine Interleukin-1 and Cancer Progression: the Emerging Role of Interleukin-1 Receptor Antagonist as a Novel Therapeutic Agent in Cancer Treatment , 2022 .

[115]  P. Treuting,et al.  Helicobacter infection is required for inflammation and colon cancer in SMAD3-deficient mice. , 2006, Cancer research.

[116]  K. Arihiro,et al.  Tumor-driven evolution of immunosuppressive networks during malignant progression. , 2006, Cancer research.

[117]  R. Bargou,et al.  Signalling and survival pathways in multiple myeloma. , 2006, European journal of cancer.

[118]  R. Bataille,et al.  Pathogen-associated molecular patterns are growth and survival factors for human myeloma cells through Toll-like receptors , 2006, Leukemia.

[119]  H. Grönberg,et al.  Interactions of Sequence Variants in Interleukin-1 Receptor–Associated Kinase4 and the Toll-Like Receptor 6-1-10 Gene Cluster Increase Prostate Cancer Risk , 2006, Cancer Epidemiology Biomarkers & Prevention.

[120]  T. Mcclanahan,et al.  IL-23 promotes tumour incidence and growth , 2006, Nature.

[121]  Jian Sun,et al.  The rational designed antagonist derived from the complex structure of interleukin-6 and its receptor affectively blocking interleukin-6 might be a promising treatment in multiple myeloma. , 2006, Biochimie.

[122]  M. Colonna,et al.  The TREM receptor family and signal integration , 2006, Nature Immunology.

[123]  M. Karin Nuclear factor-kappaB in cancer development and progression. , 2006, Nature.

[124]  D. Philpott,et al.  Nod-like proteins in immunity, inflammation and disease , 2006, Nature Immunology.

[125]  Y. Sung,et al.  STAT3 and NF-κB Signal Pathway Is Required for IL-23-Mediated IL-17 Production in Spontaneous Arthritis Animal Model IL-1 Receptor Antagonist-Deficient Mice1 , 2006, The Journal of Immunology.

[126]  M. Neurath,et al.  TGF-beta as a T cell regulator in colitis and colon cancer. , 2006, Cytokine & growth factor reviews.

[127]  T. Espevik,et al.  Toll-like receptors mediate proliferation and survival of multiple myeloma cells , 2006, Leukemia.

[128]  M. Karin NF‐κB and cancer: Mechanisms and targets , 2006 .

[129]  T. Wang,et al.  Inflammation, atrophy, and gastric cancer. , 2007, The Journal of clinical investigation.