Dynamic aberrant NF-κB spurs tumorigenesis: A new model encompassing the microenvironment

Cytokine and Growth Factor Reviews

Volumn 26, Issue 4, 2015, Pages 389-403

  Vlahopoulos, Spiros A ^a   Cen, Osman ^b   Hengen, Nina ^c   Agan, James ^b   Moschovi, Maria ^a   Critselis, Elena ^a   Adamaki, Maria ^a   Bacopoulou, Flora ^a   Copland, John A ^d   Boldogh, Istvan ^e   Karin, Michael ^f   Chrousos, George P ^a  

^a UNIVERSITY OF ATHENS   (Greece)

^b NORTHWESTERN UNIVERSITY   (United States)

^c SHENANDOAH UNIVERSITY   (United States)

^d MAYO CLINIC   (United States)

^e University of Texas Medical Branch School of Medicine   (United States)

^f San Diego   (United States)

Author keywords

Cancer; Homeostasis; Immunity; Inflammation; Nuclear Factor kappa B

Indexed keywords

CYCLOOXYGENASE 2; GLUCOCORTICOID; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 1BETA; INTERLEUKIN 23; INTERLEUKIN 6; PROTEOME; REACTIVE OXYGEN METABOLITE; STAT3 PROTEIN; TRANSCRIPTION FACTOR NANOG; TRANSCRIPTION FACTOR RELA;

ADAPTIVE IMMUNITY; BINDING SITE; CANCER INHIBITION; CARCINOGENESIS; CELL CYCLE REGULATION; CELL DIFFERENTIATION; CELL FUNCTION; CELL SHAPE; CELLS BY BODY ANATOMY; DNA BINDING; DNA REPAIR; ENZYME ACTIVITY; GENE EXPRESSION; GENE PRODUCT; GENOME; HOMEOSTASIS; HUMAN; HYPERCHOLESTEROLEMIA; IMMUNE RESPONSE; INFLAMMATION; LYMPHATIC SYSTEM TUMOR; MITOCHONDRION; MOLECULAR DYNAMICS; NONHUMAN; ONCOGENE; ONCOGENE MYC; ONCOGENE STAT3; OXIDATIVE STRESS; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN METABOLISM; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; REVIEW; SIGNAL TRANSDUCTION; STEM CELL NICHE; TRANSCRIPTION INITIATION; TUMOR MICROENVIRONMENT; ANIMAL; GENETICS; METABOLISM; PHYSIOLOGY;

ANIMALS; CARCINOGENESIS; HUMANS; NF-KAPPA B; TUMOR MICROENVIRONMENT;

EID: 84938286749     PISSN: 13596101     EISSN: 18790305     Source Type: Journal    
DOI: 10.1016/j.cytogfr.2015.06.001     Document Type: Review

References (146)

1. Staudt L.M. Oncogenic activation of NF-kappaB. Cold Spring Harb. Perspect. Biol. 2010, 2:a000109.
2. Parker M., Mohankumar K.M., Punchihewa C., Weinlich R., et al. C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma. Nature 2014, 506:451-455.
3. Lin D.-C., Zhang Y., Pan Q.-J., Yang H., et al. PLK1 is transcriptionally activated by NF-κB during cell detachment and enhances anoikis resistance through inhibiting β-catenin degradation in esophageal squamous cell carcinoma. Clin. Cancer Res. 2011, 17:4285-4295.
4. Daniluk J., Liu Y., Deng D., Chu J., et al. An NF-κB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice. J. Clin. Invest. 2012, 122:1519-1528.
5. Cao Y., Luo J.-L., Karin M. IkappaB kinase alpha kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells. Proc. Natl. Acad. Sci. U. S. A. 2007, 104:15852-15857.
6. Razani B., Reichardt A.D., Cheng G. Non-canonical NF-κB signaling activation and regulation: principles and perspectives. Immunol. Rev. 2011, 244:44-54.
7. Han Y., Weinman S., Boldogh I., Walker R.K., et al. Tumor necrosis factor-alpha-inducible IkappaBalpha proteolysis mediated by cytosolic m-calpain. A mechanism parallel to the ubiquitin-proteasome pathway for nuclear factor-kappab activation. J. Biol. Chem. 1999, 274:787-794.
8. Jia L., Gopinathan G., Sukumar J.T., Gribben J.G. Blocking autophagy prevents bortezomib-induced NF-κB activation by reducing I-κBα degradation in lymphoma cells. PLoS ONE 2012, 7:e32584.
9. Huang B., Yang X.-D., Lamb A., Chen L.-F. Posttranslational modifications of NF-kappaB: another layer of regulation for NF-kappaB signaling pathway. Cell. Signal. 2010, 22:1282-1290.
10. Johnson R.F., Witzel I.-I., Perkins N.D. p53-dependent regulation of mitochondrial energy production by the RelA subunit of NF-κB. Cancer Res. 2011, 71:5588-5597.
11. Copland J.A., Sheffield-Moore M., Koldzic-Zivanovic N., Gentry S., et al. Sex steroid receptors in skeletal differentiation and epithelial neoplasia: is tissue-specific intervention possible?. Bioessays 2009, 31:629-641.
12. Vlahopoulos S., Boldogh I., Casola A., Brasier A.R. Nuclear factor-kappaB-dependent induction of interleukin-8 gene expression by tumor necrosis factor alpha: evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation. Blood 1999, 94:1878-1889.
13. Gerondakis S., Siebenlist U. Roles of the NF-kappaB pathway in lymphocyte development and function. Cold Spring Harb. Perspect. Biol. 2010, 2:a000182.
14. Tornatore L., Thotakura A.K., Bennett J., Moretti M., et al. The nuclear factor kappa B signaling pathway: integrating metabolism with inflammation. Trends Cell Biol. 2012, 22:557-566.
15. Ma Z., Vocadlo D.J., Vosseller K. Hyper-O-GlcNAcylation is anti-apoptotic and maintains constitutive NF-κB activity in pancreatic cancer cells. J. Biol. Chem. 2013, 288:15121-15130.
16. Msaki A., Sánchez A.M., Koh L.F., Barré B., et al. The role of RelA (p65) threonine 505 phosphorylation in the regulation of cell growth, survival, and migration. Mol. Biol. Cell 2011, 22:3032-3040.
17. Yang J., Mitra A., Dojer N., Fu S., et al. A probabilistic approach to learn chromatin architecture and accurate inference of the NF-κB/RelA regulatory network using ChIP-Seq. Nucleic Acids Res. 2013, 41:7240-7259.
18. Basak S., Shih V.F.-S., Hoffmann A. Generation and activation of multiple dimeric transcription factors within the NF-kappaB signaling system. Mol. Cell. Biol. 2008, 28:3139-3150.
19. Xiao G., Fu J. NF-κB and cancer: a paradigm of Yin-Yang. Am. J. Cancer Res. 2011, 1:192-221.
20. Toruner M., Fernandez-Zapico M., Sha J.J., Pham L., et al. Antianoikis effect of nuclear factor-kappaB through up-regulated expression of osteoprotegerin, BCL-2, and IAP-1. J. Biol. Chem. 2006, 281:8686-8696.
21. Lambrou G.I., Papadimitriou L., Chrousos G.P., Vlahopoulos S.A. Glucocorticoid and proteasome inhibitor impact on the leukemic lymphoblast: multiple, diverse signals converging on a few key downstream regulators. Mol. Cell. Endocrinol. 2012, 351:142-151.
22. Wright C.J., Agboke F., Muthu M., Michaelis K.A., et al. Nuclear factor-κB (NF-κB) inhibitory protein IκBβ determines apoptotic cell death following exposure to oxidative stress. J. Biol. Chem. 2012, 287:6230-6239.
23. McKay L.I., Cidlowski J.A. Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways. Endocr. Rev. 1999, 20:435-459.
24. Grivennikov S.I., Karin M. Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. 2010, 21:11-19.
25. Wang W., Shao S., Jiao Z., Guo M., et al. The Th17/Treg imbalance and cytokine environment in peripheral blood of patients with rheumatoid arthritis. Rheumatol. Int. 2012, 32:887-893.
26. De Santis E., Di Vito M., Perrone G.A., Mari E., et al. Overexpression of pro-inflammatory genes and down-regulation of SOCS-1 in human PTC and in hypoxic BCPAP cells. Biomed. Pharmacother. 2013, 67:7-16.
27. Anders H.-J., Romagnani P., Mantovani A. Pathomechanisms: homeostatic chemokines in health, tissue regeneration, and progressive diseases. Trends Mol. Med. 2014, 20:154-165.
28. Agelopoulos M., Thanos D. Epigenetic determination of a cell-specific gene expression program by ATF-2 and the histone variant macroH2A. EMBO J. 2006, 25:4843-4853.
29. Natoli G. NF-κB and chromatin: ten years on the path from basic mechanisms to candidate drugs. Immunol. Rev. 2012, 246:183-192.
30. Hajishengallis G., Chavakis T. Endogenous modulators of inflammatory cell recruitment. Trends Immunol. 2013, 34:1-6.
31. Sica A., Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest. 2012, 122:787-795.
32. Garding A., Bhattacharya N., Claus R., Ruppel M., et al. Epigenetic upregulation of lncRNAs at 13q14.3 in leukemia is linked to the In Cis downregulation of a gene cluster that targets NF-κB. PLoS Genet. 2013, 9:e1003373.
33. Chua H.L., Bhat-Nakshatri P., Clare S.E., Morimiya A., et al. NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2. Oncogene 2007, 26:711-724.
34. Zhang Y., Liu J., Yao S., Li F., et al. Nuclear factor kappa B signaling initiates early differentiation of neural stem cells. Stem Cells 2012, 30:510-524.
35. Lee J., Sayed N., Hunter A., Au K.F., et al. Activation of innate immunity is required for efficient nuclear reprogramming. Cell 2012, 151:547-558.
36. Salminen A., Kauppinen A., Kaarniranta K. Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP). Cell. Signal. 2012, 24:835-845.
37. Noll J.E., Williams S.A., Purton L.E., Zannettino A.C.W. Tug of war in the haematopoietic stem cell niche: do myeloma plasma cells compete for the HSC niche?. Blood Cancer J. 2012, 2:e91.
38. Bonavida B. RKIP-mediated chemo-immunosensitization of resistant cancer cells via disruption of the NF-κB/Snail/YY1/RKIP resistance-driver loop. Crit. Rev. Oncog. 2014, 19:431-445.
39. Spirina L.V., Kondakova I.V., Choynzonov E.L., Chigevskaya S.Y., et al. Expression of vascular endothelial growth factor and transcription factors HIF-1, NF-κB expression in squamous cell carcinoma of head and neck; association with proteasome and calpain activities. J. Cancer Res. Clin. Oncol. 2013, 139:625-633.
40. Ko Y.J., Balk S.P. Targeting steroid hormone receptor pathways in the treatment of hormone dependent cancers. Curr. Pharm. Biotechnol. 2004, 5:459-470.
41. Yang C., Atkinson S.P., Vilella F., Lloret M., et al. Opposing putative roles for canonical and noncanonical NFκB signaling on the survival, proliferation, and differentiation potential of human embryonic stem cells. Stem Cells 2010, 28:1970-1980.
42. Zhang Y., Hu W. NFκB signaling regulates embryonic and adult neurogenesis. Front. Biol. 2012, 7.
43. Takase O., Yoshikawa M., Idei M., Hirahashi J., et al. The role of NF-κB signaling in the maintenance of pluripotency of human induced pluripotent stem cells. PLOS ONE 2013, 8:e56399.
44. Gugasyan R., Horat E., Kinkel S.A., Ross F., et al. The NF-κB1 transcription factor prevents the intrathymic development of CD8 T cells with memory properties. EMBO J. 2012, 31:692-706.
45. Saccani S., Pantano S., Natoli G. Modulation of NF-kappaB activity by exchange of dimers. Mol. Cell 2003, 11:1563-1574.
46. Hayashi F., Yanagawa Y., Onoé K., Iwabuchi K. Dendritic cell differentiation with prostaglandin E results in selective attenuation of the extracellular signal-related kinase pathway and decreased interleukin-23 production. Immunology 2010, 131:67-76.
47. Sharma S., Stolina M., Yang S.-C., Baratelli F., et al. Tumor cyclooxygenase 2-dependent suppression of dendritic cell function. Clin. Cancer Res. 2003, 9:961-968.
48. Ullrich E., Ménard C., Flament C., Terme M., et al. Dendritic cells and innate defense against tumor cells. Cytokine Growth Factor Rev. 2008, 19:79-92.
49. Zhao J.L., Rao D.S., Boldin M.P., Taganov K.D., et al. NF-kappaB dysregulation in microRNA-146a-deficient mice drives the development of myeloid malignancies. Proc. Natl. Acad. Sci. U. S. A. 2011, 108:9184-9189.
50. Prasad S., Ravindran J., Aggarwal B.B. NF-kappaB and cancer: how intimate is this relationship. Mol. Cell. Biochem. 2010, 336:25-37.
51. Wang D.J., Ratnam N.M., Byrd J.C., Guttridge D.C. NF-κB functions in tumor initiation by suppressing the surveillance of both innate and adaptive immune cells. Cell Rep. 2014, 9:90-103.
52. Aggarwal B.B., Kunnumakkara A.B., Harikumar K.B., Gupta S.R., et al. Signal transducer and activator of transcription-3, inflammation, and cancer: how intimate is the relationship?. Ann. N. Y. Acad. Sci. 2009, 1171:59-76.
53. Helm O., Held-Feindt J., Grage-Griebenow E., Reiling N., et al. Tumor-associated macrophages exhibit pro- and anti-inflammatory properties by which they impact on pancreatic tumorigenesis. Int. J. Cancer 2014, 135:843-861.
54. Vlahopoulos S., Zoumpourlis V.C. JNK: a key modulator of intracellular signaling. Biochemistry 2004, 69:844-854.
55. Ndlovu M.N., Van Lint C., Van Wesemael K., Callebert P., et al. Hyperactivated NF-{kappa}B and AP-1 transcription factors promote highly accessible chromatin and constitutive transcription across the interleukin-6 gene promoter in metastatic breast cancer cells. Mol. Cell. Biol. 2009, 29:5488-5504.
56. Kodama K., Ozasa K., Okubo T. Radiation and cancer risk in atomic-bomb survivors. J. Radiol. Prot. 2012, 32:N51-N54.
57. Muthuswamy R., Berk E., Junecko B.F., Zeh H.J., et al. NF-κB hyperactivation in tumor tissues allows tumor-selective reprogramming of the chemokine microenvironment to enhance the recruitment of cytolytic T effector cells. Cancer Res. 2012, 72:3735-3743.
58. Zhao L., Yang J., Wang H.-P., Liu R.-Y. Imbalance in the Th17/Treg and cytokine environment in peripheral blood of patients with adenocarcinoma and squamous cell carcinoma. Med. Oncol. 2013, 30:461.
59. Baccelli I., Trumpp A. The evolving concept of cancer and metastasis stem cells. J. Cell Biol. 2012, 198:281-293.
60. Cowell C.F., Weigelt B., Sakr R.A., Ng C.K.Y., et al. Progression from ductal carcinoma in situ to invasive breast cancer: revisited. Mol. Oncol. 2013, 7:859-869.
61. Malouf G.G., Job S., Paradis V., Fabre M., et al. Transcriptional profiling of pure fibrolamellar hepatocellular carcinoma reveals an endocrine signature. Hepatology 2014, 59:2228-2237.
62. Mia-Jan K., Munkhdelger J., Lee M.-R., Ji S.-Y., et al. Expression of CD133 in neuroendocrine neoplasms of the digestive tract: a detailed immunohistochemical analysis. Tohoku J. Exp. Med. 2013, 229:301-309.
63. Rahal R., Frick M., Romero R., Korn J.M., et al. Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma. Nat. Med. 2014, 20:87-92.
64. Peri S., Devarajan K., Yang D.-H., Knudson A.G., et al. Meta-analysis identifies NF-κB as a therapeutic target in renal cancer. PLOS ONE 2013, 8:e76746.
65. Armstrong M.D., Von Hoff D., Barber B., Marlow L.A., et al. An effective personalized approach to a rare tumor: prolonged survival in metastatic pancreatic acinar cell carcinoma based on genetic analysis and cell line development. J. Cancer 2011, 2:142-152.
66. Renner C., Zinzani P.L., Gressin R., Klingbiel D., et al. A multicenter phase II trial (SAKK 36/06) of single-agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma. Haematologica 2012, 97:1085-1091.
67. Chaturvedi N.K., Rajule R.N., Shukla A., Radhakrishnan P., et al. Novel treatment for mantle cell lymphoma including therapy-resistant tumor by NF-κB and mTOR dual-targeting approach. Mol. Cancer Ther. 2013, 12:2006-2017.
68. Lee H., Deng J., Xin H., Liu Y., et al. A requirement of STAT3 DNA binding precludes Th-1 immunostimulatory gene expression by NF-κB in tumors. Cancer Res. 2011, 71:3772-3780.
69. Oh H.-M., Yu C.-R., Golestaneh N., Amadi-Obi A., et al. STAT3 protein promotes T-cell survival and inhibits interleukin-2 production through up-regulation of Class O Forkhead transcription factors. J. Biol. Chem. 2011, 286:30888-30897.
70. Chung S.S., Aroh C., Vadgama J.V. Constitutive activation of STAT3 signaling regulates hTERT and promotes stem cell-like traits in human breast cancer cells. PLOS ONE 2013, 8:e83971.
71. Murphy S.H., Suzuki K., Downes M., Welch G.L., et al. Tumor suppressor protein (p)53, is a regulator of NF-kappaB repression by the glucocorticoid receptor. Proc. Natl. Acad. Sci. U. S. A. 2011, 108:17117-17122.
72. Mantel C., Messina-Graham S., Moh A., Cooper S., et al. Mouse hematopoietic cell-targeted STAT3 deletion: stem/progenitor cell defects, mitochondrial dysfunction, ROS overproduction, and a rapid aging-like phenotype. Blood 2012, 120:2589-2599.
73. Yu X., Harris S.L., Levine A.J. The regulation of exosome secretion: a novel function of the p53 protein. Cancer Res. 2006, 66:4795-4801.
74. Stam R.W., Den Boer M.L., Schneider P., de Boer J., et al. Association of high-level MCL-1 expression with in vitro and in vivo prednisone resistance in MLL-rearranged infant acute lymphoblastic leukemia. Blood 2010, 115:1018-1025.
75. Lerebours F., Vacher S., Andrieu C., Espie M., et al. NF-kappa B genes have a major role in inflammatory breast cancer. BMC Cancer 2008, 8:41.
76. Iliopoulos D., Hirsch H.A., Struhl K. An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 2009, 139:693-706.
77. Xiang M., Birkbak N.J., Vafaizadeh V., Walker S.R., et al. STAT3 induction of miR-146b forms a feedback loop to inhibit the NF-κB to IL-6 signaling axis and STAT3-driven cancer phenotypes. Sci. Signal. 2014, 7:ra11.
78. Rosenbloom K.R., Sloan C.A., Malladi V.S., Dreszer T.R., et al. ENCODE data in the UCSC Genome Browser: year 5 update. Nucleic Acids Res. 2013, 41:D56-D63.
79. Nikulenkov F., Spinnler C., Li H., Tonelli C., et al. Insights into p53 transcriptional function via genome-wide chromatin occupancy and gene expression analysis. Cell Death Differ. 2012, 19:1992-2002.
80. Yan S., Li Z., Thiele C.J. Inhibition of STAT3 with orally active JAK inhibitor, AZD1480, decreases tumor growth in neuroblastoma and pediatric sarcomas in vitro and in vivo. Oncotarget 2013, 4:433-445.
81. Han S.-S., Yun H., Son D.-J., Tompkins V.S., et al. NF-kappaB/STAT3/PI3K signaling crosstalk in iMyc E mu B lymphoma. Mol. Cancer 2010, 9:97.
82. Hosoi H., Dilling M.B., Liu L.N., Danks M.K., et al. Studies on the mechanism of resistance to rapamycin in human cancer cells. Mol. Pharmacol. 1998, 54:815-824.
83. Blandino G., Valerio M., Cioce M., Mori F., et al. Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC. Nat. Commun. 2012, 3:865.
84. Son D.-S., Kabir S.M., Dong Y.-L., Lee E., et al. Inhibitory effect of tumor suppressor p53 on proinflammatory chemokine expression in ovarian cancer cells by reducing proteasomal degradation of IκB. PLoS ONE 2012, 7:e51116.
85. Gurova K.V., Hill J.E., Guo C., Prokvolit A., et al. Small molecules that reactivate p53 in renal cell carcinoma reveal a NF-kappaB-dependent mechanism of p53 suppression in tumors. Proc. Natl. Acad. Sci. U. S. A. 2005, 102:17448-17453.
86. Jeong S.-J., Pise-Masison C.A., Radonovich M.F., Park H.U., et al. A novel NF-kappaB pathway involving IKKbeta and p65/RelA Ser-536 phosphorylation results in p53 Inhibition in the absence of NF-kappaB transcriptional activity. J. Biol. Chem. 2005, 280:10326-10332.
87. Kawauchi K., Araki K., Tobiume K., Tanaka N. Activated p53 induces NF-kappaB DNA binding but suppresses its transcriptional activation. Biochem. Biophys. Res. Commun. 2008, 372:137-141.
88. Liu X., Wang X., Zhang J., Lam E.K.Y., et al. Warburg effect revisited: an epigenetic link between glycolysis and gastric carcinogenesis. Oncogene 2010, 29:442-450.
89. Leung C.T. Epithelial cell translocation: new insights into mechanisms of tumor initiation. Bioessays 2013, 35:80-83.
90. Sheng W.-Y., Chen Y.-R., Wang T-C.V. A major role of PKC theta and NFkappaB in the regulation of hTERT in human T lymphocytes. FEBS Lett. 2006, 580:6819-6824.
91. Liang S., Mele J., Wu Y., Buffenstein R., et al. Resistance to experimental tumorigenesis in cells of a long-lived mammal, the naked mole-rat (Heterocephalus glaber). Aging Cell 2010, 9:626-635.
92. Lewis K.N., Mele J., Hornsby P.J., Buffenstein R. Stress resistance in the naked mole-rat: the bare essentials - a mini-review. Gerontology 2012, 58:453-462.
93. Yang L., Karin M. Roles of tumor suppressors in regulating tumor-associated inflammation. Cell Death Differ. 2014, 21:1677-1686.
94. McGranahan N., Favero F., de Bruin E.C., Birkbak N.J., et al. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution. Sci. Transl. Med. 2015, 7:283ra54.
95. Poltz R., Naumann M. Dynamics of p53 and NF-κB regulation in response to DNA damage and identification of target proteins suitable for therapeutic intervention. BMC Syst. Biol. 2012, 6:125.
96. Di Minin G., Bellazzo A., Dal Ferro M., Chiaruttini G., et al. Mutant p53 reprograms TNF signaling in cancer cells through interaction with the tumor suppressor DAB2IP. Mol. Cell 2014, 56:617-629.
97. Malaquin N., Carrier-Leclerc A., Dessureault M., Rodier F. DDR-mediated crosstalk between DNA-damaged cells and their microenvironment. Front. Genet. 2015, 6:94.
98. Leibovich-Rivkin T., Buganim Y., Solomon H., Meshel T., et al. Tumor-promoting circuits that regulate a cancer-related chemokine cluster: dominance of inflammatory mediators over oncogenic alterations. Cancers 2012, 4:55-76.
99. Leibovich-Rivkin T., Liubomirski Y., Meshel T., Abashidze A., et al. The inflammatory cytokine TNFα cooperates with Ras in elevating metastasis and turns WT-Ras to a tumor-promoting entity in MCF-7 cells. BMC Cancer 2014, 14:158.
100. Yu P., Fu Y.-X. Targeting tumors with LIGHT to generate metastasis-clearing immunity. Cytokine Growth Factor Rev. 2008, 19:285-294.
101. Zhu G., Tang Y., Geng N., Zheng M., et al. HIF-α/MIF and NF-κB/IL-6 axes contribute to the recruitment of CD11b+Gr-1+ myeloid cells in hypoxic microenvironment of HNSCC. Neoplasia 2014, 16:168-179.
102. Ying H., Elpek K.G., Vinjamoori A., Zimmerman S.M., et al. PTEN is a major tumor suppressor in pancreatic ductal adenocarcinoma and regulates an NF-κB-cytokine network. Cancer Discov. 2011, 1:158-169.
103. Abrahamsson J., Påhlman M., Mellander L. Interleukin 6, but not tumour necrosis factor-alpha, is a good predictor of severe infection in febrile neutropenic and non-neutropenic children with malignancy. Acta Paediatr. 1997, 86:1059-1064.
104. Mace T.A., Ameen Z., Collins A., Wojcik S., et al. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res. 2013, 73:3007-3018.
105. Knoop R.F., Sparn M., Waldmann J., Plassmeier L., et al. Chronic pancreatitis and systemic inflammatory response syndrome prevent impact of chemotherapy with gemcitabine in a genetically engineered mouse model of pancreatic cancer. Neoplasia 2014, 16:463-470.
106. Brandi G., Tavolari S., Guarnieri T., Di Marco M., et al. Antiprotease strategy in pancreatic cancer treatment: emergence from a preclinical study. Pancreas 2014, 43:53-63.
107. Yang S., Huang F.-K., Huang J., Chen S., et al. Molecular mechanism of fascin function in filopodial formation. J. Biol. Chem. 2013, 288:274-284.
108. Snyder M., Huang J., Huang X.-Y., Zhang J.J. A STAT3/NFκB complex is necessary for the expression of fascin in metastatic breast cancer cells in response to IL-6 and TNF-α. J. Biol. Chem. 2014, 289:30082-30089.
109. Sun J., He H., Pillai S., Xiong Y., et al. GATA3 transcription factor abrogates Smad4 transcription factor-mediated fascin overexpression, invadopodium formation, and breast cancer cell invasion. J. Biol. Chem. 2013, 288:36971-36982.
110. Wong V., Ching D., McCrea P.D., Firestone G.L. Glucocorticoid down-regulation of fascin protein expression is required for the steroid-induced formation of tight junctions and cell-cell interactions in rat mammary epithelial tumor cells. J. Biol. Chem. 1999, 274:5443-5453.
111. Owens M.B., Hill A.D., Hopkins A.M. Ductal barriers in mammary epithelium. Tissue Barriers 2013, 1:e25933.
112. Yang L., Pang Y., Moses H.L. TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 2010, 31:220-227.
113. Ellermeier J., Wei J., Duewell P., Hoves S., et al. Therapeutic efficacy of bifunctional siRNA combining TGF-β1 silencing with RIG-I activation in pancreatic cancer. Cancer Res. 2013, 73:1709-1720.
114. Balanis N., Wendt M.K., Schiemann B.J., Wang Z., et al. Epithelial to mesenchymal transition promotes breast cancer progression via a fibronectin-dependent STAT3 signaling pathway. J. Biol. Chem. 2013, 288:17954-17967.
115. Pang Y., Gara S.K., Achyut B.R., Li Z., et al. TGF-β signaling in myeloid cells is required for tumor metastasis. Cancer Discov. 2013, 3:936-951.
116. López-Novoa J.M., Nieto M.A. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol. Med. 2009, 1:303-314.
117. Cufí S., Vazquez-Martin A., Oliveras-Ferraros C., Martin-Castillo B., et al. Metformin against TGFβ-induced epithelial-to-mesenchymal transition (EMT): from cancer stem cells to aging-associated fibrosis. Cell Cycle 2010, 9:4461-4468.
118. Zubeldia I.G., Bleau A.-M., Redrado M., Serrano D., et al. Epithelial to mesenchymal transition and cancer stem cell phenotypes leading to liver metastasis are abrogated by the novel TGFβ1-targeting peptides P17 and P144. Exp. Cell Res. 2013, 319:12-22.
119. Sun J., He H., Xiong Y., Lu S., et al. Fascin protein is critical for transforming growth factor β protein-induced invasion and filopodia formation in spindle-shaped tumor cells. J. Biol. Chem. 2011, 286:38865-38875.
120. Maier H.J., Wirth T., Beug H. Epithelial-mesenchymal transition in pancreatic carcinoma. Cancers 2010, 2:2058-2083.
121. Kim H., Choi J.-A., Kim J.-H. Ras promotes transforming growth factor-β (TGF-β)-induced epithelial-mesenchymal transition via a leukotriene B4 receptor-2-linked cascade in mammary epithelial cells. J. Biol. Chem. 2014, 289:22151-22160.
122. Dews M., Tan G.S., Hultine S., Raman P., et al. Masking epistasis between MYC and TGF-β pathways in antiangiogenesis-mediated colon cancer suppression. J. Natl. Cancer Inst. 2014, 106:dju043.
123. Novitskiy S.V., Pickup M.W., Chytil A., Polosukhina D., et al. Deletion of TGF-β signaling in myeloid cells enhances their anti-tumorigenic properties. J. Leukoc. Biol. 2012, 92:641-651.
124. Li J., Favata M., Kelley J.A., Caulder E., et al. INCB16562, a JAK1/2 selective inhibitor, is efficacious against multiple myeloma cells and reverses the protective effects of cytokine and stromal cell support. Neoplasia 2010, 12:28-38.
125. Ivanov V.N., Wen G., Hei T.K. Sodium arsenite exposure inhibits AKT and Stat3 activation, suppresses self-renewal and induces apoptotic death of embryonic stem cells. Apoptosis 2013, 18:188-200.
126. Canino C., Mori F., Cambria A., Diamantini A., et al. SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells. Oncogene 2012, 31:3148-3163.
127. Van Dommelen S.M., Vader P., Lakhal S., Kooijmans S.A.A., et al. Microvesicles and exosomes: opportunities for cell-derived membrane vesicles in drug delivery. J. Control. Release 2012, 161:635-644.
128. Lambrou G.I., Vlahopoulos S., Papathanasiou C., Papanikolaou M., et al. Prednisolone exerts late mitogenic and biphasic effects on resistant acute lymphoblastic leukemia cells: relation to early gene expression. Leuk. Res. 2009, 33:1684-1695.
129. Sonabend R.Y., McKay S.V., Okcu M.F., Yan J., et al. Hyperglycemia during induction therapy is associated with poorer survival in children with acute lymphocytic leukemia. J. Pediatr. 2009, 155:73-78.
130. Hulleman E., Kazemier K.M., Holleman A., VanderWeele D.J., et al. Inhibition of glycolysis modulates prednisolone resistance in acute lymphoblastic leukemia cells. Blood 2009, 113:2014-2021.
131. Langlais D., Couture C., Balsalobre A., Drouin J. Regulatory network analyses reveal genome-wide potentiation of LIF signaling by glucocorticoids and define an innate cell defense response. PLoS Genet. 2008, 4:e1000224.
132. Lam L.T., Wright G., Davis R.E., Lenz G., et al. Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-{kappa}B pathways in subtypes of diffuse large B-cell lymphoma. Blood 2008, 111:3701-3713.
133. Ando M., Uehara I., Kogure K., Asano Y., et al. Interleukin 6 enhances glycolysis through expression of the glycolytic enzymes hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3. J. Nippon Med. Sch. 2010, 77:97-105.
134. Kang K.Y., Kim Y.-K., Yi H., Kim J., et al. Metformin downregulates Th17 cells differentiation and attenuates murine autoimmune arthritis. Int. Immunopharmacol. 2013, 16:85-92.
135. Grimaldi C., Chiarini F., Tabellini G., Ricci F., et al. AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications. Leukemia 2012, 26:91-100.
136. Griner L.N., McGraw K.L., Johnson J.O., List A.F., et al. JAK2-V617F-mediated signalling is dependent on lipid rafts and statins inhibit JAK2-V617F-dependent cell growth. Br. J. Haematol. 2013, 160:177-187.
137. Pugliese L., Bernardini I., Pacifico N., Peverini M., et al. Severe hypocholesterolaemia is often neglected in haematological malignancies. Eur. J. Cancer 2010, 46:1735-1743.
138. Kunnumakkara A.B., Guha S., Krishnan S., Diagaradjane P., et al. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res. 2007, 67:3853-3861.
139. Märten A., Zeiss N., Serba S., Mehrle S., et al. Bortezomib is ineffective in an orthotopic mouse model of pancreatic adenocarcinoma. Mol. Cancer Ther. 2008, 7:3624-3631.
140. Zhou H., Liu Y., Cheung L.H., Kim S., et al. Characterization and mechanistic studies of a novel melanoma-targeting construct containing IκBa for specific inhibition of nuclear factor-κB activity. Neoplasia 2010, 12:766-777.
141. Friedmann-Morvinski D., Bushong E.A., Ke E., Soda Y., et al. Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science 2012, 338:1080-1084.
142. Xie Y. Structure, assembly and homeostatic regulation of the 26S proteasome. J. Mol. Cell Biol. 2010, 2:308-317.
143. Li Y., de Magalhães J.P. Accelerated protein evolution analysis reveals genes and pathways associated with the evolution of mammalian longevity. Age (Dordr.) 2013, 35:301-314.
144. Dai Y., Chen S., Wang L., Pei X.-Y., et al. Disruption of IkappaB kinase (IKK)-mediated RelA serine 536 phosphorylation sensitizes human multiple myeloma cells to histone deacetylase (HDAC) inhibitors. J. Biol. Chem. 2011, 286:34036-34050.
145. Vlahopoulos S., Critselis E., Voutsas I.F., Perez S.A., et al. New use for old drugs? Prospective targets of chloroquines in cancer therapy. Curr. Drug Targets 2014, 15:843-851.
146. Loberg R.D., Bradley D.A., Tomlins S.A., Chinnaiyan A.M., et al. The lethal phenotype of cancer: the molecular basis of death due to malignancy. CA Cancer J. Clin. 2007, 57:225-241.