Review Article | Published:

Inflammation meets cancer, with NF-κB as the matchmaker

Nature Immunology volume 12, pages 715723 (2011) | Download Citation

Abstract

Inflammation is a fundamental protective response that sometimes goes awry and becomes a major cofactor in the pathogenesis of many chronic human diseases, including cancer. Here we review the evolutionary relationship and opposing functions of the transcription factor NF-κB in inflammation and cancer. Although it seems to fulfill a distinctly tumor-promoting role in many types of cancer, NF-κB has a confounding role in certain tumors. Understanding the activity and function of NF-κB in the context of tumorigenesis is critical for its successful taming, an important challenge for modern cancer biology.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & Cancer and inflammation: implications for pharmacology and therapeutics. Clin. Pharmacol. Ther. 87, 401–406 (2010).

  2. 2.

    & Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 11, 889–896 (2010).

  3. 3.

    , & Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

  4. 4.

    & Leukocytes as paracrine regulators of metastasis and determinants of organ-specific colonization. Int. J. Cancer 128, 2536–2544 (2011).

  5. 5.

    & Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).

  6. 6.

    Inflammation 2010: new adventures of an old flame. Cell 140, 771–776 (2010).

  7. 7.

    , , , & Origin of metazoan stem cell system in sponges: first approach to establish the model (Suberites domuncula). Biomol. Eng. 20, 369–379 (2003).

  8. 8.

    & Nuclear factor-κB: a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 336, 1066–1071 (1997).

  9. 9.

    & NF-κB: a key role in inflammatory diseases. J. Clin. Invest. 107, 7–11 (2001).

  10. 10.

    , , & Adenoviral transgene delivery provides an approach to identifying important molecular processes in inflammation: evidence for heterogenecity in the requirement for NFκB in tumour necrosis factor production. Ann. Rheum. Dis. 59 (Suppl 1), i54–i59 (2000).

  11. 11.

    , , & Possible new role for NF-κB in the resolution of inflammation. Nat. Med. 7, 1291–1297 (2001).

  12. 12.

    , & How Hydra senses and destroys microbes. Semin. Immunol. 22, 54–58 (2010).

  13. 13.

    , & The evolution of immunity: a low-life perspective. Trends Immunol. 28, 449–454 (2007).

  14. 14.

    et al. Defining the origins of the NOD-like receptor system at the base of animal evolution. Mol. Biol. Evol. 28, 1687–1702 (2007).

  15. 15.

    et al. The Amphimedon queenslandica genome and the evolution of animal complexity. Nature 466, 720–726 (2010).

  16. 16.

    , & Evolution of MDA-5/RIG-I-dependent innate immunity: independent evolution by domain grafting. Proc. Natl. Acad. Sci. USA 105, 17040–17045 (2008).

  17. 17.

    & Phylostratigraphic tracking of cancer genes suggests a link to the emergence of multicellularity in metazoa. BMC Biol. 8, 66 (2010).

  18. 18.

    , , , & NF-κB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Mol. Cell. Biol. 19, 5785–5799 (1999).

  19. 19.

    , & Differential regulation of the c-myc oncogene promoter by the NF-κB rel family of transcription factors. Mol. Cell. Biol. 14, 1039–1044 (1994).

  20. 20.

    Apoptosis and NF-κB: the FADD connection. J. Clin. Invest. 109, 579–580 (2002).

  21. 21.

    , & Induction of endothelial cell surface adhesion molecules by tumor necrosis factor is blocked by protein tyrosine phosphatase inhibitors: role of the nuclear transcription factor NF-κB. Eur. J. Immunol. 27, 2172–2179 (1997).

  22. 22.

    et al. Transcriptional regulation of endothelial cell adhesion molecules: NF-κB and cytokine-inducible enhancers. FASEB J. 9, 899–909 (1995).

  23. 23.

    & NF-κB in mammary gland development and breast cancer. J. Mammary Gland Biol. Neoplasia 8, 215–223 (2003).

  24. 24.

    et al. B cells from p50/NF-κB knockout mice have selective defects in proliferation, differentiation, germ-line CH transcription, and Ig class switching. J. Immunol. 156, 183–191 (1996).

  25. 25.

    , , & Activation of the transcription factor NF-κB in Schwann cells is required for peripheral myelin formation. Nat. Neurosci. 6, 161–167 (2003).

  26. 26.

    et al. Oncogenic Ras diverts a host TNF tumor suppressor activity into tumor promoter. Dev. Cell 18, 999–1011 (2010).

  27. 27.

    , , , & Live imaging of innate immune cell sensing of transformed cells in zebrafish larvae: parallels between tumor initiation and wound inflammation. PLoS Biol. 8, e1000562 (2010).

  28. 28.

    Neoplasia in a coral? Science 148, 503–505 (1965).

  29. 29.

    , & Epithelial proliferation and morphogenesis of hyperplastic adenomatous and villous polyps of the human colon. Virchows Arch. A Pathol. Anat. Histol. 364, 35–49 (1974).

  30. 30.

    & Studies on the morphogenesis of adenomatous polyps in the human Colon. Cancer 16, 998–1002 (1963).

  31. 31.

    Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

  32. 32.

    Cancer stem cells: Here, there, everywhere? Nature 456, 581–582 (2008).

  33. 33.

    , , & Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 138, 822–829 (2009).

  34. 34.

    et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).

  35. 35.

    et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469, 415–418 (2010).

  36. 36.

    , , & Synergy between bacterial infection and genetic predisposition in intestinal dysplasia. Proc. Natl. Acad. Sci. USA 106, 20883–20888 (2009).

  37. 37.

    , & Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972–978 (2007).

  38. 38.

    et al. NFKBIA deletion in glioblastomas. N. Engl. J. Med. 364, 627–637 (2010).

  39. 39.

    et al. FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR. Nature 471, 523–526 (2011).

  40. 40.

    Hierarchies of NF-κB target-gene regulation. Nat. Immunol. 12, 689–694 (2011).

  41. 41.

    & The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 25, 280–288 (2004).

  42. 42.

    et al. Salmonella typhimurium induces epithelial IL-8 expression via Ca(2+)-mediated activation of the NF-κB pathway. J. Clin. Invest. 105, 79–92 (2000).

  43. 43.

    et al. High susceptibility to bacterial infection, but no liver dysfunction, in mice compromised for hepatocyte NF-κB activation. Nat. Med. 6, 573–577 (2000).

  44. 44.

    , & Inflammatory bowel disease. Annu. Rev. Immunol. 28, 573–621 (2010).

  45. 45.

    , , & Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-κ B abrogates established experimental colitis in mice. Nat. Med. 2, 998–1004 (1996).

  46. 46.

    et al. Inhibitor of nuclear factor κB kinase β is a key regulator of synovial inflammation. Arthritis Rheum. 44, 1897–1907 (2001).

  47. 47.

    et al. Differential expression of phosphorylated NF-κB/RelA in normal and psoriatic epidermis and downregulation of NF-κB in response to treatment with etanercept. J. Invest. Dermatol. 124, 1275–1283 (2005).

  48. 48.

    , & Cytokine inhibitors in rheumatoid arthritis and other autoimmune diseases. Curr. Opin. Pharmacol. 7, 412–417 (2007).

  49. 49.

    et al. An inhibitor of IκB kinase, BMS-345541, blocks endothelial cell adhesion molecule expression and reduces the severity of dextran sulfate sodium-induced colitis in mice. Inflamm. Res. 52, 508–511 (2003).

  50. 50.

    et al. Periodic, partial inhibition of IκB kinase β-mediated signaling yields therapeutic benefit in preclinical models of rheumatoid arthritis. J. Pharmacol. Exp. Ther. 331, 349–360 (2009).

  51. 51.

    et al. NF-κB activation provides the potential link between inflammation and hyperplasia in the arthritic joint. Proc. Natl. Acad. Sci. USA 95, 13859–13864 (1998).

  52. 52.

    et al. IKKβ inhibition protects against bone and cartilage destruction in a rat model of rheumatoid arthritis. Arthritis Rheum. 54, 3163–3173 (2006).

  53. 53.

    , & (ed. Macor, J.E.) in Annual Reports in Medicinal Chemistry, Vol. 43, 155–170 (Academic, 2008).

  54. 54.

    et al. Role of NFκB in the mortality of sepsis. J. Clin. Invest. 100, 972–985 (1997).

  55. 55.

    et al. IKK β links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296 (2004).

  56. 56.

    et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557–561 (2007).

  57. 57.

    Regulation of tissue homeostasis by NF-κB signalling: implications for inflammatory diseases. Nat. Rev. Immunol. 9, 778–788 (2009).

  58. 58.

    et al. NF-κB is a negative regulator of IL-1β secretion as revealed by genetic and pharmacological inhibition of IKKβ. Cell 130, 918–931 (2007).

  59. 59.

    et al. Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1. Cell 129, 45–56 (2007).

  60. 60.

    et al. IL-1β-driven neutrophilia preserves antibacterial defense in the absence of the kinase IKKβ. Nat. Immunol. 12, 144–150 (2011).

  61. 61.

    et al. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum. 50, 1412–1419 (2004).

  62. 62.

    et al. Effects of micro-environment- and malignant cell-derived interleukin-1 in carcinogenesis, tumour invasiveness and tumour-host interactions. Eur. J. Cancer 42, 751–759 (2006).

  63. 63.

    Return to homeostasis—downregulation of NF-κB responses. Nat. Immunol. 12, 709–714 (2011).

  64. 64.

    & The regulatory logic of the NF-κB signaling system. Cold Spring Harb. Perspect. Biol. 2, a000216 (2010).

  65. 65.

    et al. The two faces of IKK and NF-κB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion. Nat. Med. 9, 575–581 (2003).

  66. 66.

    et al. Opposing functions of IKK β during acute and chronic intestinal inflammation. Proc. Natl. Acad. Sci. USA 105, 15058–15063 (2008).

  67. 67.

    The Re1/NF-κB/IκB signal transduction pathway and cancer. Cancer Treat. Res. 115, 241–265 (2003).

  68. 68.

    et al. Enhancement of antitumor activity of polyethylene glycol-coated liposomal doxorubicin with soluble and liposomal interleukin 2. Clin. Cancer Res. 5, 687–693 (1999).

  69. 69.

    et al. The candidate oncoprotein Bcl-3 is an antagonist of p50/NF-κB-mediated inhibition. Nature 359, 339–342 (1992).

  70. 70.

    et al. B cell lymphoma-associated chromosomal translocation involves candidate oncogene lyt-10, homologous to NF-κ B p50. Cell 67, 1075–1087 (1991).

  71. 71.

    , , & NF-κB in cancer: from innocent bystander to major culprit. Nat. Rev. Cancer 2, 301–310 (2002).

  72. 72.

    et al. Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types. Cell 96, 35–45 (1999).

  73. 73.

    et al. Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma. Mol. Cell 6, 961–967 (2000).

  74. 74.

    & Regulation and function of IKK and IKK-related kinases. Sci. STKE 2006, re13 (2006).

  75. 75.

    & Signaling to NF-κB: regulation by ubiquitination. Cold Spring Harb. Perspect. Biol. 2, a003350 (2010).

  76. 76.

    et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 319, 1676–1679 (2008).

  77. 77.

    et al. A loss-of-function RNA interference screen for molecular targets in cancer. Nature 441, 106–110 (2006).

  78. 78.

    Oncogenic activation of NF-κB. Cold Spring Harb. Perspect. Biol. 2, a000109 (2010).

  79. 79.

    et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 470, 115–119 (2011).

  80. 80.

    et al. Frequent engagement of the classical and alternative NF-κB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 12, 115–130 (2007).

  81. 81.

    et al. Promiscuous mutations activate the noncanonical NF-κB pathway in multiple myeloma. Cancer Cell 12, 131–144 (2007).

  82. 82.

    et al. Initial genome sequencing and analysis of multiple myeloma. Nature 471, 467–472 (2011).

  83. 83.

    et al. Identification of the receptor component of the IκBα-ubiquitin ligase. Nature 396, 590–594 (1998).

  84. 84.

    , , & Regulation of the NF-κB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation. J. Biol. Chem. 279, 26243–26250 (2004).

  85. 85.

    & Regulation and function of NF-κB transcription factors in the immune system. Annu. Rev. Immunol. 27, 693–733 (2009).

  86. 86.

    et al. NIK overexpression amplifies, whereas ablation of its TRAF3-binding domain replaces BAFF:BAFF-R-mediated survival signals in B cells. Proc. Natl. Acad. Sci. USA 105, 10883–10888 (2008).

  87. 87.

    et al. Compensatory IKKα activation of classical NF-κB signaling during IKKβ inhibition identified by an RNA interference sensitization screen. Proc. Natl. Acad. Sci. USA 105, 20798–20803 (2008).

  88. 88.

    et al. Discovery of non-ETS gene fusions in human prostate cancer using next-generation RNA sequencing. Genome Res. (2010).

  89. 89.

    , & The cancer genome. Nature 458, 719–724 (2009).

  90. 90.

    et al. Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell 129, 1065–1079 (2007).

  91. 91.

    , & IκB kinase α kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells. Proc. Natl. Acad. Sci. USA 104, 15852–15857 (2007).

  92. 92.

    et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 468, 103–107 (2010).

  93. 93.

    et al. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature 468, 98–102 (2010).

  94. 94.

    et al. Tumor-infiltrating T regulatory cells stimulate mammary cancer metastasis through RANKL-RANK signaling. Nature 470, 548–553 (2011).

  95. 95.

    , & An epigenetic switch involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 139, 693–706 (2009).

  96. 96.

    , , , & B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature 464, 302–305 (2010).

  97. 97.

    et al. Nuclear cytokine-activated IKKα controls prostate cancer metastasis by repressing Maspin. Nature 446, 690–694 (2007).

  98. 98.

    et al. NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461–466 (2004).

  99. 99.

    et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15, 103–113 (2009).

  100. 100.

    et al. Blocking TNF-α in mice reduces colorectal carcinogenesis associated with chronic colitis. J. Clin. Invest. 118, 560–570 (2008).

  101. 101.

    , , & Inflammation and colon cancer. Gastroenterology 138, 2101–2114 (2010).

  102. 102.

    Nuclear factor-κB in cancer development and progression. Nature 441, 431–436 (2006).

  103. 103.

    , & Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat. Rev. Immunol. 7, 41–51 (2007).

  104. 104.

    , , , & Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30, 1073–1081 (2009).

  105. 105.

    et al. gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 15, 91–102 (2009).

  106. 106.

    , , , & IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121, 977–990 (2005).

  107. 107.

    et al. Hepatocyte IKKβ /NF-κB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 17, 286–297 (2010).

  108. 108.

    et al. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFκB. Genes Dev. 21, 1396–1408 (2007).

  109. 109.

    & Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr. Opin. Immunol. 22, 231–237 (2010).

  110. 110.

    et al. 'Re-educating' tumor-associated macrophages by targeting NF-κB. J. Exp. Med. 205, 1261–1268 (2008).

  111. 111.

    et al. Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor κB. Proc. Natl. Acad. Sci. USA 106, 14978–14983 (2009).

  112. 112.

    , , , & Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-κB-dependent manner. Cancer Cell 17, 135–147 (2010).

  113. 113.

    , & STATs in cancer inflammation and immunity: a leading role for STAT3. Nat. Rev. Cancer 9, 798–809 (2009).

  114. 114.

    et al. Bone marrow stromal cells from multiple myeloma patients uniquely induce bortezomib resistant NF-κB activity in myeloma cells. Mol. Cancer 9, 176 (2010).

  115. 115.

    et al. NF-κB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421, 639–643 (2003).

  116. 116.

    et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008).

  117. 117.

    et al. p38α suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway. Nat. Genet. 39, 741–749 (2007).

  118. 118.

    et al. Hepatocyte necrosis induced by oxidative stress and IL-1α release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 14, 156–165 (2008).

  119. 119.

    et al. Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 11, 119–132 (2007).

  120. 120.

    et al. Disruption of TAK1 in hepatocytes causes hepatic injury, inflammation, fibrosis, and carcinogenesis. Proc. Natl. Acad. Sci. USA 107, 844–849 (2010).

  121. 121.

    et al. TAK1 suppresses a NEMO-dependent but NF-κB-independent pathway to liver cancer. Cancer Cell 17, 481–496 (2010).

  122. 122.

    et al. Overexpression of interleukin-1β induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell 14, 408–419 (2008).

  123. 123.

    et al. A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell 16, 295–308 (2009).

  124. 124.

    et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 121–124 (2007).

  125. 125.

    et al. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood 113, 6069–6076 (2009).

  126. 126.

    et al. NF-κ B activation in human breast cancer specimens and its role in cell proliferation and apoptosis. Proc. Natl. Acad. Sci. USA 101, 10137–10142 (2004).

  127. 127.

    et al. Mutations of multiple genes cause deregulation of NF-κB in diffuse large B-cell lymphoma. Nature 459, 717–721 (2009).

  128. 128.

    et al. NF-κB inhibition through proteasome inhibition or IKKβ blockade increases the susceptibility of melanoma cells to cytostatic treatment through distinct pathways. J. Invest. Dermatol. 130, 1073–1086 (2010).

  129. 129.

    et al. Small molecule inhibitors of IκB kinase are selectively toxic for subgroups of diffuse large B-cell lymphoma defined by gene expression profiling. Clin. Cancer Res. 11, 28–40 (2005).

  130. 130.

    & Advances in targeting IKK and IKK-related kinases for cancer therapy. Clin. Cancer Res. 14, 5656–5662 (2008).

  131. 131.

    et al. KINK-1, a novel small-molecule inhibitor of IKKβ, and the susceptibility of melanoma cells to antitumoral treatment. J. Natl. Cancer Inst. 100, 862–875 (2008).

  132. 132.

    & Nuclear factor-κB inhibitors as sensitizers to anticancer drugs. Nat. Rev. Cancer 5, 297–309 (2005).

  133. 133.

    et al. Inhibition of constitutively activated nuclear factor-κB induces reactive oxygen species- and iron-dependent cell death in cutaneous T-cell lymphoma. Cancer Res. 69, 2365–2374 (2009).

  134. 134.

    et al. Three-kinase inhibitor combination recreates multipathway effects of a geldanamycin analogue on hepatocellular carcinoma cell death. Mol. Cancer Ther. 8, 2183–2192 (2009).

  135. 135.

    & Development of the proteasome inhibitor Velcade (bortezomib). Cancer Invest. 22, 304–311 (2004).

  136. 136.

    et al. Targeting transcription factor NFκB: comparative analysis of proteasome and IKK inhibitors. Cell Cycle 8, 1559–1566 (2009).

  137. 137.

    et al. 17-DMAG targets the nuclear factor-κB family of proteins to induce apoptosis in chronic lymphocytic leukemia: clinical implications of HSP90 inhibition. Blood 116, 45–53 (2010).

  138. 138.

    Combination therapy of bortezomib with novel targeted agents: an emerging treatment strategy. Clin. Cancer Res. 16, 4094–4104 (2010).

  139. 139.

    et al. MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-κB-dependent lymphoma. Blood 116, 1515–1523 (2010).

  140. 140.

    , , & Ubiquitination and degradation of the inhibitors of NF-κB. Cold Spring Harb. Perspect. Biol. 2, a000166 (2010).

  141. 141.

    et al. Spermatogenesis rescue in a mouse deficient for the ubiquitin ligase SCFβ-TrCP by single substrate depletion. Genes Dev. 24, 470–477 (2010).

  142. 142.

    et al. Nuclear factor-κB protects the liver against genotoxic stress and functions independently of p53. Cancer Res. 63, 25–30 (2003).

  143. 143.

    et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 377, 31–41 (2011).

  144. 144.

    et al. Phase III randomized trial assessing rofecoxib in the adjuvant setting of colorectal cancer: final results of the VICTOR trial. J. Clin. Oncol. 28, 4575–4580 (2010).

  145. 145.

    & Inflammation and cancer. Nature 420, 860–867 (2002).

  146. 146.

    & NF-κB: linking inflammation and immunity to cancer development and progression. Nat. Rev. Immunol. 5, 749–759 (2005).

  147. 147.

    & Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

  148. 148.

    Challenging problems in cocarcinogenesis. Cancer Res. 45, 1917–1921 (1985).

  149. 149.

    , & Involvement of activation-induced cytidine deaminase in the development of colitis-associated colorectal cancers. J. Gastroenterol. 46 (Suppl 1), 6–10 (2011).

  150. 150.

    et al. CKIα ablation highlights a critical role for p53 in invasiveness control. Nature 470, 409–413 (2011).

  151. 151.

    et al. p53 point mutations in dysplastic and cancerous ulcerative colitis lesions. Gastroenterology 104, 1633–1639 (1993).

Download references

Acknowledgements

We thank E. Pikarsky, I. Alkalay-Snir and A. Pribluda for comments and discussions. Supported by the Israel Science Foundation, Israel Cancer Research Fund, the Crohn's & Colitis Foundation of America, the German-Israeli Foundation, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the US National Institutes of Health and the American Cancer Society.

Author information

Affiliations

  1. Lautenberg Center for Immunology, Institute for Medical Research-Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.

    • Yinon Ben-Neriah
  2. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Cancer Center, School of Medicine, University of California, San Diego, La Jolla, California, USA.

    • Michael Karin

Authors

  1. Search for Yinon Ben-Neriah in:

  2. Search for Michael Karin in:

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Yinon Ben-Neriah or Michael Karin.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/ni.2060