Inflammation meets cancer, with NF-κB as the matchmaker

Nature Immunology

Volumn 12, Issue 8, 2011, Pages 715-723

  Ben Neriah, Yinon ^a   Karin, Michael ^b  

^a HEBREW UNIVERSITY   (Israel)

^b San Diego   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLSALICYLIC ACID; BORTEZOMIB; CYCLOOXYGENASE 2 INHIBITOR; I KAPPA B ALPHA; I KAPPA B KINASE INHIBITOR; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; NONSTEROID ANTIINFLAMMATORY AGENT; ROFECOXIB; VORINOSTAT;

CANCER CELL; CANCER PREVENTION; CANCER RISK; CARCINOGENESIS; CARCINOMA; CONFOUNDING VARIABLE; CYTOKINE PRODUCTION; GENE EXPRESSION; GENE OVEREXPRESSION; GENETIC LINKAGE; HUMAN; INFLAMMATION; LIVER CELL CARCINOMA; NONHUMAN; PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN FUNCTION; REVIEW; RISK REDUCTION; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT;

ANIMALS; HUMANS; IMMUNITY, INNATE; INFLAMMATION; NEOPLASMS; NF-KAPPA B;

EID: 80052014052     PISSN: 15292908     EISSN: 15292916     Source Type: Journal    
DOI: 10.1038/ni.2060     Document Type: Review

References (151)

1. Balkwill, F. & Mantovani, A. Cancer and inflammation: implications for pharmacology and therapeutics. Clin. Pharmacol. Ther. 87, 401-406 (2010).
2. Biswas, S.K. & Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 11, 889-896 (2010).
3. Grivennikov, S.I., Greten, F.R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883-899 (2010).
4. Erez, N. & Coussens, L.M. Leukocytes as paracrine regulators of metastasis and determinants of organ-specific colonization. Int. J. Cancer 128, 2536-2544 (2011).
5. Qian, B.Z. & Pollard, J.W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39-51 (2010).
6. Medzhitov, R. Inflammation 2010: new adventures of an old flame. Cell 140, 771-776 (2010).
7. Muller, W.E., Korzhev, M., Le Pennec, G., Muller, I.M. & Schroder, H.C. Origin of metazoan stem cell system in sponges: first approach to establish the model (Suberites domuncula). Biomol. Eng. 20, 369-379 (2003). (Pubitemid 36959689)
8. Barnes, P.J. & Karin, M. Nuclear factor-?B: a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 336, 1066-1071 (1997). (Pubitemid 27163860)
9. Tak, P.P. & Firestein, G.S. NF-kB: a key role in inflammatory diseases. J. Clin. Invest. 107, 7-11 (2001). (Pubitemid 32047405)
10. Foxwell, B.M., Bondeson, J., Brennan, F. & Feldmann, M. Adenoviral transgene delivery provides an approach to identifying important molecular processes in inflammation: evidence for heterogenecity in the requirement for NF?B in tumour necrosis factor production. Ann. Rheum. Dis. 59 (Suppl 1), i54-i59 (2000).
11. Lawrence, T., Gilroy, D.W., Colville-Nash, P.R. & Willoughby, D.A. Possible new role for NF-kB in the resolution of inflammation. Nat. Med. 7, 1291-1297 (2001). (Pubitemid 34007932)
12. Augustin, R., Fraune, S. & Bosch, T.C. How Hydra senses and destroys microbes. Semin. Immunol. 22, 54-58 (2010).
13. Hemmrich, G., Miller, D.J. & Bosch, T.C. The evolution of immunity: a low-life perspective. Trends Immunol. 28, 449-454 (2007). (Pubitemid 47444553)
14. Lange, C. 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. Srivastava, M. et al. The Amphimedon queenslandica genome and the evolution of animal complexity. Nature 466, 720-726 (2010).
16. Sarkar, D., Desalle, R. & Fisher, P.B. Evolution of MDA-5/RIG-I-dependent innate immunity: independent evolution by domain grafting. Proc. Natl. Acad. Sci. USA105, 17040-17045 (2008).
17. Domazet-Loso, T. & Tautz, D. Phylostratigraphic tracking of cancer genes suggests a link to the emergence of multicellularity in metazoa. BMC Biol. 8, 66 (2010).
18. Guttridge, D.C., Albanese, C., Reuther, J.Y., Pestell, R.G. & Baldwin, A.S. Jr. NF-kB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Mol. Cell. Biol. 19, 5785-5799 (1999). (Pubitemid 29339933)
19. La Rosa, F.A., Pierce, J.W. & Sonenshein, G.E. Differential regulation of the c-myc oncogene promoter by the NF-kB rel family of transcription factors. Mol. Cell. Biol. 14, 1039-1044 (1994). (Pubitemid 24036554)
20. Duckett, C.S. Apoptosis and NF-kB: the FADD connection. J. Clin. Invest. 109, 579-580 (2002).
21. Dhawan, S., Singh, S. & Aggarwal, B.B. 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-kB. Eur. J. Immunol. 27, 2172-2179 (1997). (Pubitemid 27404297)
22. Collins, T. et al. Transcriptional regulation of endothelial cell adhesion molecules: NF-kB and cytokine-inducible enhancers. FASEB J. 9, 899-909 (1995).
23. Cao, Y. & Karin, M. NF-kB in mammary gland development and breast cancer. J. Mammary Gland Biol. Neoplasia 8, 215-223 (2003). (Pubitemid 38129943)
24. Snapper, C.M. et al. B cells from p50/NF-kB knockout mice have selective defects in proliferation, differentiation, germ-line CH transcription, and Ig class switching. J. Immunol. 156, 183-191 (1996).
25. Nickols, J.C., Valentine, W., Kanwal, S. & Carter, B.D. Activation of the transcription factor NF-kB in Schwann cells is required for peripheral myelin formation. Nat. Neurosci. 6, 161-167 (2003). (Pubitemid 36182785)
26. Cordero, J.B. et al. Oncogenic Ras diverts a host TNF tumor suppressor activity into tumor promoter. Dev. Cell 18, 999-1011 (2010).
27. Feng, Y., Santoriello, C., Mione, M., Hurlstone, A. & Martin, P. Live imaging of innate immune cell sensing of transformed cells in zebrafish larvae: parallels between tumor initiation and wound inflammation. PLoSBiol. 8, e1000562 (2010).
28. Squires, D.F. Neoplasia in a coral? Science 148, 503-505 (1965).
29. Wiebecke, B., Brandts, A. & Eder, M. Epithelial proliferation and morphogenesis of hyperplastic adenomatous and villous polyps of the human colon. Virchows Arch. APathol. Anat. Histol. 364, 35-49 (1974).
30. Cole, J.W. & McKalen, A. Studies on the morphogenesis of adenomatous polyps in the human Colon. Cancer 16, 998-1002 (1963).
31. Dvorak, H.F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650-1659 (1986). (Pubitemid 17052899)
32. Eaves, C.J. Cancer stem cells: Here, there, everywhere? Nature 456, 581-582 (2008).
33. Shackleton, M., Quintana, E., Fearon, E.R. & Morrison, S.J. Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 138, 822-829 (2009).
34. Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608-611 (2009).
35. Sato, T. et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469, 415-418 (2010).
36. Apidianakis, Y., Pitsouli, C., Perrimon, N. & Rahme, L. Synergy between bacterial infection and genetic predisposition in intestinal dysplasia. Proc. Natl. Acad. Sci. USA106, 20883-20888 (2009).
37. Foster, S.L., Hargreaves, D.C. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972-978 (2007). (Pubitemid 46975746)
38. Bredel, M. et al. NFKBIA deletion in glioblastomas. N. Engl. J. Med. 364, 627-637 (2010).
39. Bivona, T.G. et al. FAS and NF-kB signalling modulate dependence of lung cancers on mutant EGFR. Nature 471, 523-526 (2011).
40. Smale, S. Hierarchies of NF-kB target-gene regulation. Nat. Immunol. 12, 689-694 (2011).
41. Bonizzi, G. & Karin, M. The two NF-kB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 25, 280-288 (2004). (Pubitemid 38610351)
42. Gewirtz, A.T. et al. Salmonella typhimurium induces epithelial IL-8 expression via Ca(2+)-mediated activation of the NF-kB pathway. J. Clin. Invest. 105, 79-92 (2000). (Pubitemid 30036390)
43. Lavon, I. et al. High susceptibility to bacterial infection, but no liver dysfunction, in mice compromised for hepatocyte NF-kB activation. Nat. Med. 6, 573-577 (2000). (Pubitemid 30305909)
44. Kaser, A., Zeissig, S. & Blumberg, R.S. Inflammatory bowel disease. Annu. Rev. Immunol. 28, 573-621 (2010).
45. Neurath, M.F., Pettersson, S., Meyer zum Buschenfelde, K.H. & Strober, W. Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-? B abrogates established experimental colitis in mice. Nat. Med. 2, 998-1004 (1996). (Pubitemid 26306838)
46. Tak, P.P. et al. Inhibitor of nuclear factor ?B kinase β is a key regulator of synovial inflammation. Arthritis Rheum. 44, 1897-1907 (2001). (Pubitemid 32758238)
47. Lizzul, P.F. et al. Differential expression of phosphorylated NF-kB/RelA in normal and psoriatic epidermis and downregulation of NF-kB in response to treatment with etanercept. J. Invest. Dermatol. 124, 1275-1283 (2005). (Pubitemid 40847416)
48. Williams, R.O., Paleolog, E. & Feldmann, M. Cytokine inhibitors in rheumatoid arthritis and other autoimmune diseases. Curr. Opin. Pharmacol. 7, 412-417 (2007). (Pubitemid 47289266)
49. MacMaster, J.F. et al. An inhibitor of I?B 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). (Pubitemid 38058225)
50. Gillooly, K.M. et al. Periodic, partial inhibition of I?B kinase β-mediated signaling yields therapeutic benefit in preclinical models of rheumatoid arthritis. J. Pharmacol. Exp. Ther. 331, 349-360 (2009).
51. Miagkov, A.V. et al. NF-kB activation provides the potential link between inflammation and hyperplasia in the arthritic joint. Proc. Natl. Acad. Sci. USA95, 13859-13864 (1998). (Pubitemid 28523063)
52. Schopf, L. et al. IKKβ inhibition protects against bone and cartilage destruction in a rat model of rheumatoid arthritis. Arthritis Rheum. 54, 3163-3173 (2006). (Pubitemid 44622087)
53. Pitts, W.J., Kempson, J. & John, E.M. (ed. Macor, J.E.) in Annual Reports in Medicinal Chemistry, Vol. 43, 155-170 (Academic, 2008).
54. Bohrer, H. et al. Role of NF?B in the mortality of sepsis. J. Clin. Invest. 100, 972-985 (1997).
55. Greten, F.R. et al. IKK β links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285-296 (2004). (Pubitemid 39061110)
56. Nenci, A. et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557-561 (2007). (Pubitemid 46514732)
57. Pasparakis, M. Regulation of tissue homeostasis by NF-kB signalling: implications for inflammatory diseases. Nat. Rev. Immunol. 9, 778-788 (2009).
58. Greten, F.R. et al. NF-kB is a negative regulator of IL-1β secretion as revealed by genetic and pharmacological inhibition of IKKβ. Cell 130, 918-931 (2007). (Pubitemid 47332565)
59. Bruey, J.M. et al. Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1. Cell 129, 45-56 (2007).
60. Hsu, L.C. et al. IL-1β-driven neutrophilia preserves antibacterial defense in the absence of the kinase IKKβ. Nat. Immunol. 12, 144-150 (2011).
61. Genovese, M.C. 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). (Pubitemid 38608062)
62. Apte, R.N. 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. Ruland, J. Return to homeostasis-downregulation of NF-κB responses. Nat. Immunol. 12, 709-714 (2011).
64. O'Dea, E. & Hoffmann, A. The regulatory logic of the NF-kB signaling system. Cold Spring Harb. Perspect. Biol. 2, a000216 (2010).
65. Chen, L.W. et al. The two faces of IKK and NF-kB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion. Nat. Med. 9, 575-581 (2003).
66. Eckmann, L. et al. Opposing functions of IKK β during acute and chronic intestinal inflammation. Proc. Natl. Acad. Sci. USA105, 15058-15063 (2008).
67. Gilmore, T.D. The Re1/NF-kB/I?B signal transduction pathway and cancer. Cancer Treat. Res. 115, 241-265 (2003).
68. Cabanes, A. 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). (Pubitemid 29131981)
69. Franzoso, G. et al. The candidate oncoprotein Bcl-3 is an antagonist of p50/NF-kB-mediated inhibition. Nature 359, 339-342 (1992).
70. Neri, A. et al. B cell lymphoma-associated chromosomal translocation involves candidate oncogene lyt-10, homologous to NF-? B p50. Cell 67, 1075-1087 (1991). (Pubitemid 121001521)
71. Karin, M., Cao, Y., Greten, F.R. & Li, Z.W. NF-kB in cancer: from innocent bystander to major culprit. Nat. Rev. Cancer 2, 301-310 (2002). (Pubitemid 37328783)
72. Willis, T.G. 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). (Pubitemid 29044151)
73. Uren, A.G. 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. Hacker, H. & Karin, M. Regulation and function of IKK and IKK-related kinases. Sci. STKE2006, re13 (2006).
75. Wertz, I.E. & Dixit, V.M. Signaling to NF-kB: regulation by ubiquitination. Cold Spring Harb. Perspect. Biol. 2, a003350 (2010).
76. Lenz, G. et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 319, 1676-1679 (2008). (Pubitemid 351432507)
77. Ngo, V.N. et al. A loss-of-function RNA interference screen for molecular targets in cancer. Nature 441, 106-110 (2006).
78. Staudt, L.M. Oncogenic activation of NF-kB. Cold Spring Harb. Perspect. Biol. 2, a000109 (2010).
79. Ngo, V.N. et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 470, 115-119 (2011).
80. Annunziata, C.M. et al. Frequent engagement of the classical and alternative NF-kB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 12, 115-130 (2007). (Pubitemid 47199123)
81. Keats, J.J. et al. Promiscuous mutations activate the noncanonical NF-kB pathway in multiple myeloma. Cancer Cell 12, 131-144 (2007). (Pubitemid 47208626)
82. Chapman, M.A. et al. Initial genome sequencing and analysis of multiple myeloma. Nature 471, 467-472 (2011).
83. Yaron, A. et al. Identification of the receptor component of the I?Bα-ubiquitin ligase. Nature 396, 590-594 (1998). (Pubitemid 28563722)
84. Liao, G., Zhang, M., Harhaj, E.W. & Sun, S.C. Regulation of the NF-kB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation. J. Biol. Chem. 279, 26243-26250 (2004). (Pubitemid 38798772)
85. Vallabhapurapu, S. & Karin, M. Regulation and function of NF-kB transcription factors in the immune system. Annu. Rev. Immunol. 27, 693-733 (2009).
86. Sasaki, Y. 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. USA105, 10883-10888 (2008).
87. Lam, L.T. et al. Compensatory IKKα activation of classical NF-kB signaling during IKKβ inhibition identified by an RNA interference sensitization screen. Proc. Natl. Acad. Sci. USA105, 20798-20803 (2008).
88. Pflueger, D. et al. Discovery of non-ETS gene fusions in human prostate cancer using next-generation RNA sequencing. Genome Res. (2010).
89. Stratton, M.R., Campbell, P.J. & Futreal, P.A. The cancer genome. Nature 458, 719-724 (2009).
90. Boehm, J.S. et al. Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell 129, 1065-1079 (2007). (Pubitemid 46891036)
91. Cao, Y., Luo, J.L. & Karin, M. I?B kinase α kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells. Proc. Natl. Acad. Sci. USA104, 15852-15857 (2007). (Pubitemid 350035388)
92. Gonzalez-Suarez, E. et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 468, 103-107 (2010).
93. Schramek, D. et al. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature 468, 98-102 (2010).
94. Tan, W. et al. Tumor-infiltrating T regulatory cells stimulate mammary cancer metastasis through RANKL-RANK signaling. Nature 470, 548-553 (2011).
95. Iliopoulos, D., Hirsch, H.A. & Struhl, K. An epigenetic switch involving NF-kB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 139, 693-706 (2009).
96. Ammirante, M., Luo, J.L., Grivennikov, S., Nedospasov, S. & Karin, M. B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature 464, 302-305 (2010).
97. Luo, J.L. et al. Nuclear cytokine-activated IKKα controls prostate cancer metastasis by repressing Maspin. Nature 446, 690-694 (2007).
98. Pikarsky, E. et al. NF-kB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461-466 (2004). (Pubitemid 39329586)
99. Grivennikov, S. 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. Popivanova, B.K. et al. Blocking TNF-α in mice reduces colorectal carcinogenesis associated with chronic colitis. J. Clin. Invest. 118, 560-570 (2008). (Pubitemid 351206546)
101. Terzic, J., Grivennikov, S., Karin, E. & Karin, M. Inflammation and colon cancer. Gastroenterology 138, 2101-2114 (2010).
102. Karin, M. Nuclear factor-?B in cancer development and progression. Nature 441, 431-436 (2006). (Pubitemid 44050137)
103. Yu, H., Kortylewski, M. & Pardoll, D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat. Rev. Immunol. 7, 41-51 (2007). (Pubitemid 46020826)
104. Colotta, F., Allavena, P., Sica, A., Garlanda, C. & Mantovani, A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30, 1073-1081 (2009).
105. Bollrath, J. 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. Maeda, S., Kamata, H., Luo, J.L., Leffert, H. & Karin, M. IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121, 977-990 (2005). (Pubitemid 40884391)
107. He, G. et al. Hepatocyte IKKβ /NF-kB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 17, 286-297 (2010).
108. Yang, J. et al. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NF?B. Genes Dev. 21, 1396-1408 (2007). (Pubitemid 46871042)
109. Mantovani, A. & Sica, A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr. Opin. Immunol. 22, 231-237 (2010).
110. Hagemann, T. et al. 'Re-educating' tumor-associated macrophages by targeting NF-kB. J. Exp. Med. 205, 1261-1268 (2008). (Pubitemid 351831483)
111. Porta, C. et al. Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor ?B. Proc. Natl. Acad. Sci. USA106, 14978-14983 (2009).
112. Erez, N., Truitt, M., Olson, P., Arron, S.T. & Hanahan, D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kB-dependent manner. Cancer Cell 17, 135-147 (2010).
113. Yu, H., Pardoll, D. & Jove, R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat. Rev. Cancer 9, 798-809 (2009).
114. Markovina, S. et al. Bone marrow stromal cells from multiple myeloma patients uniquely induce bortezomib resistant NF-kB activity in myeloma cells. Mol. Cancer 9, 176 (2010).
115. Dajee, M. et al. NF-kB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421, 639-643 (2003). (Pubitemid 36227672)
116. Acosta, J.C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006-1018 (2008). (Pubitemid 351795610)
117. Hui, L. et al. p38α suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway. Nat. Genet. 39, 741-749 (2007). (Pubitemid 46848584)
118. Sakurai, T. 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. Luedde, T. et al. Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 11, 119-132 (2007). (Pubitemid 46209851)
120. Inokuchi, S. et al. Disruption of TAK1 in hepatocytes causes hepatic injury, inflammation, fibrosis, and carcinogenesis. Proc. Natl. Acad. Sci. USA107, 844-849 (2010).
121. Bettermann, K. et al. TAK1 suppresses a NEMO-dependent but NF-kB-independent pathway to liver cancer. Cancer Cell 17, 481-496 (2010).
122. Tu, S. 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. Haybaeck, J. et al. A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell 16, 295-308 (2009).
124. Naugler, W.E. et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 121-124 (2007). (Pubitemid 47056470)
125. Dunleavy, K. et al. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood 113, 6069-6076 (2009).
126. Biswas, D.K. et al. NF-? B activation in human breast cancer specimens and its role in cell proliferation and apoptosis. Proc. Natl. Acad. Sci. USA101, 10137-10142 (2004). (Pubitemid 38891208)
127. Compagno, M. et al. Mutations of multiple genes cause deregulation of NF-kB in diffuse large B-cell lymphoma. Nature 459, 717-721 (2009).
128. Amschler, K. et al. NF-kB 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. Lam, L.T. et al. Small molecule inhibitors of I?B kinase are selectively toxic for subgroups of diffuse large B-cell lymphoma defined by gene expression profiling. Clin. Cancer Res. 11, 28-40 (2005). (Pubitemid 40075775)
130. Lee, D.F. & Hung, M.C. Advances in targeting IKK and IKK-related kinases for cancer therapy. Clin. Cancer Res. 14, 5656-5662 (2008).
131. Schon, M. 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). (Pubitemid 351881954)
132. Nakanishi, C. & Toi, M. Nuclear factor-?B inhibitors as sensitizers to anticancer drugs. Nat. Rev. Cancer 5, 297-309 (2005). (Pubitemid 40488635)
133. Kiessling, M.K. et al. Inhibition of constitutively activated nuclear factor-?B induces reactive oxygen species- and iron-dependent cell death in cutaneous T-cell lymphoma. Cancer Res. 69, 2365-2374 (2009).
134. Pritchard, J.R. 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. Adams, J. & Kauffman, M. Development of the proteasome inhibitor Velcade (bortezomib). Cancer Invest. 22, 304-311 (2004). (Pubitemid 38725184)
136. Gasparian, A.V. et al. Targeting transcription factor NF?B: comparative analysis of proteasome and IKK inhibitors. Cell Cycle 8, 1559-1566 (2009).
137. Hertlein, E. et al. 17-DMAG targets the nuclear factor-?B family of proteins to induce apoptosis in chronic lymphocytic leukemia: clinical implications of HSP90 inhibition. Blood 116, 45-53 (2010).
138. Wright, J.J. Combination therapy of bortezomib with novel targeted agents: an emerging treatment strategy. Clin. Cancer Res. 16, 4094-4104 (2010).
139. Milhollen, M.A. et al. MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-kB-dependent lymphoma. Blood 116, 1515-1523 (2010).
140. Kanarek, N., London, N., Schueler-Furman, O. & Ben-Neriah, Y. Ubiquitination and degradation of the inhibitors of NF-kB. Cold Spring Harb. Perspect. Biol. 2, a000166 (2010).
141. Kanarek, N. 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. Lavon, I. et al. Nuclear factor-?B protects the liver against genotoxic stress and functions independently of p53. Cancer Res. 63, 25-30 (2003). (Pubitemid 36070414)
143. Rothwell, P.M. 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. Midgley, R.S. 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. Coussens, L.M. & Werb, Z. Inflammation and cancer. Nature 420, 860-867 (2002). (Pubitemid 36019639)
146. Karin, M. & Greten, F.R. NF-kB: linking inflammation and immunity to cancer development and progression. Nat. Rev. Immunol. 5, 749-759 (2005). (Pubitemid 41400849)
147. Hanahan, D. & Weinberg, R.A. Hallmarks of cancer: the next generation. Cell 144, 646-674 (2011).
148. Berenblum, I. Challenging problems in cocarcinogenesis. Cancer Res. 45, 1917-1921 (1985). (Pubitemid 15024359)
149. Endo, Y., Marusawa, H. & Chiba, T. Involvement of activation-induced cytidine deaminase in the development of colitis-associated colorectal cancers. J. Gastroenterol. 46 (Suppl 1), 6-10 (2011).
150. Elyada, E. et al. CKIα ablation highlights a critical role for p53 in invasiveness control. Nature 470, 409-413 (2011).
151. Yin, J. et al. p53 point mutations in dysplastic and cancerous ulcerative colitis lesions. Gastroenterology 104, 1633-1639 (1993). (Pubitemid 23235452)