Underlying causes and therapeutic targeting of the inflammatory tumor microenvironment

Frontiers in Cell and Developmental Biology

Volumn 6, Issue JUN, 2018, Pages

  Comen, Elizabeth A ^a   Bowman, Robert L ^a   Kleppe, Maria ^a  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

Author keywords

Anti inflammatory drugs; Chronic inflammation; Clonal hematopoiesis; Microenvironment; Oncogenes; Stroma; Tumor suppressors

Indexed keywords

EID: 85049727862     PISSN: None     EISSN: 2296634X     Source Type: Journal    
DOI: 10.3389/fcell.2018.00056     Document Type: Review

References (295)

1. Addadi, Y., Moskovits, N., Granot, D., Lozano, G., Carmi, Y., Apte, R. N., et al. (2010). p53 status in stromal fibroblasts modulates tumor growth in an SDF1-dependent manner. Cancer Res. 70, 9650-9658. doi: 10.1158/0008-5472.CAN-10-1146
2. Agüera-González, S., Burton, O. T., Vázquez-Chávez, E., Cuche, C., Herit, F., Bouchet, J., et al. (2017). Adenomatous polyposis coli defines treg differentiation and anti-inflammatory function through microtubule-mediated NFAT localization. Cell Rep. 21, 181-194. doi: 10.1016/j.celrep.2017.09.020
3. Akeus, P., Langenes, V., von Mentzer, A., Yrlid, U., Sjöling, Å., Saksena, P., et al. (2014). Altered chemokine production and accumulation of regulatory T cells in intestinal adenomas of APC(Min/+) mice. Cancer Immunol. Immunother. 63, 807-819. doi: 10.1007/s00262-014-1555-6
4. Alkhateeb, A. A., Leitzel, K., Ali, S. M., Campbell-Baird, C., Evans, M., Fuchs, E. M., et al. (2012). Elevation in inflammatory serum biomarkers predicts response to trastuzumab-containing therapy. PLoS ONE 7:e51379. doi: 10.1371/journal.pone.0051379
5. Allinen, M., Beroukhim, R., Cai, L., Brennan, C., Lahti-Domenici, J., Huang, H., et al. (2004). Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 6, 17-32. doi: 10.1016/j.ccr.2004.06.010
6. Ara, T., Nakata, R., Sheard, M. A., Shimada, H., Buettner, R., Groshen, S. G., et al. (2013). Critical role of STAT3 in IL-6-mediated drug resistance in human neuroblastoma. Cancer Res. 73, 3852-3864. doi: 10.1158/0008-5472.CAN-12-2353
7. Assi, R., Kantarjian, H. M., Garcia-Manero, G., Cortes, J. E., Pemmaraju, N., Wang, X., et al. (2018). A phase II trial of ruxolitinib in combination with azacytidine in myelodysplastic syndrome/myeloproliferative neoplasms. Am. J. Hematol. 93, 277-285. doi: 10.1002/ajh.24972
8. Bar, J., Feniger-Barish, R., Lukashchuk, N., Shaham, H., Moskovits, N., Goldfinger, N., et al. (2009). Cancer cells suppress p53 in adjacent fibroblasts. Oncogene 28, 933-936. doi: 10.1038/onc.2008.445
9. Barbara, L., Benzi, G., Gaiani, S., Fusconi, F., Zironi, G., Siringo, S., et al. (1992). Natural history of small untreated hepatocellular carcinoma in cirrhosis: a multivariate analysis of prognostic factors of tumor growth rate and patient survival. Hepatology 16, 132-137. doi: 10.1002/hep.1840160122
10. Barbui, T., Barosi, G., Birgegard, G., Cervantes, F., Finazzi, G., Griesshammer, M., et al. (2011). Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J. Clin. Oncol. 29, 761-770. doi: 10.1200/JCO.2010.31.8436
11. Barnes, P. J. (2011). Glucocorticosteroids: current and future directions. Br. J. Pharmacol. 163, 29-43. doi: 10.1111/j.1476-5381.2010.01199.x
12. Barnes, T. A., and Amir, E. (2017). HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer. Br. J. Cancer 117, 451-460. doi: 10.1038/bjc.2017.220
13. Bergers, G., and Benjamin, L. E. (2003). Tumorigenesis and the angiogenic switch. Nat. Rev. Cancer 3, 401-410. doi: 10.1038/nrc1093
14. Bian, Y., Knobloch, T. J., Sadim, M., Kaklamani, V., Raji, A., Yang, G. Y., et al. (2007). Somatic acquisition of TGFBR1*6A by epithelial and stromal cells during head and neck and colon cancer development. Hum. Mol. Genet. 16, 3128-3135. doi: 10.1093/hmg/ddm274
15. Bidwell, B. N., Slaney, C. Y., Withana, N. P., Forster, S., Cao, Y., Loi, S., et al. (2012). Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. Nat. Med. 18, 1224-1231. doi: 10.1038/nm.2830
16. Bigley, A. B., and Simpson, R. J. (2015). NK cells and exercise: implications for cancer immunotherapy and survivorship. Discov. Med. 19, 433-445
17. Bissonnette, R., Papp, K. A., Poulin, Y., Gooderham, M., Raman, M., Mallbris, L., et al. (2016). Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial. Br. J. Dermatol. 175, 902-911. doi: 10.1111/bjd.14871
18. Borsellino, N., Belldegrun, A., and Bonavida, B. (1995). Endogenous interleukin 6 is a resistance factor for cis-diamminedichloroplatinum and etoposide-mediated cytotoxicity of human prostate carcinoma cell lines. Cancer Res. 55, 4633-4639
19. Boursi, B., Haynes, K., Mamtani, R., and Yang, Y. X. (2015). Impact of antibiotic exposure on the risk of colorectal cancer. Pharmacoepidemiol. Drug Saf. 24, 534-542. doi: 10.1002/pds.3765
20. Bowman, R. L., Klemm, F., Akkari, L., Pyonteck, S. M., Sevenich, L., Quail, D. F., et al. (2016). Macrophage ontogeny underlies differences in tumor-specific education in brain malignancies. Cell Rep. 17, 2445-2459. doi: 10.1016/j.celrep.2016.10.052
21. Brentnall, T. A., Crispin, D. A., Rabinovitch, P. S., Haggitt, R. C., Rubin, C. E., Stevens, A. C., et al. (1994). Mutations in the p53 gene: an early marker of neoplastic progression in ulcerative colitis. Gastroenterology 107, 369-378. doi: 10.1016/0016-5085(94)90161-9
22. Bronte, V., Brandau, S., Chen, S. H., Colombo, M. P., Frey, A. B., Greten, T. F., et al. (2016). Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 7:12150. doi: 10.1038/ncomms12150
23. Buchert, M., Burns, C. J., and Ernst, M. (2016). Targeting JAK kinase in solid tumors: emerging opportunities and challenges. Oncogene 35, 939-951. doi: 10.1038/onc.2015.150
24. Burkett, P. R., Koka, R., Chien, M., Chai, S., Boone, D. L., and Ma, A. (2004). Coordinate expression and trans presentation of interleukin (IL)-15Ra and IL-15 supports natural killer cell and memory CD8+ T cell homeostasis. J. Exp. Med. 200, 825-834. doi: 10.1084/jem.20041389
25. Buscarlet, M., Provost, S., Zada, Y. F., Barhdadi, A., Bourgoin, V., Lépine, G., et al. (2017). DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood 130, 753-762. doi: 10.1182/blood-2017-04-777029
26. Busque, L., Patel, J. P., Figueroa, M. E., Vasanthakumar, A., Provost, S., Hamilou, Z., et al. (2012). Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat. Genet. 44, 1179-1181. doi: 10.1038/ng.2413
27. Cancer Genome Atlas Research, N. (2011). Integrated genomic analyses of ovarian carcinoma. Nature 474, 609-615. doi: 10.1038/nature10166
28. Cannarile, M. A., Weisser, M., Jacob, W., Jegg, A. M., Ries, C. H., and Rüttinger, D. (2017). Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J. Immunother. Cancer 5, 53. doi: 10.1186/s40425-017-0257-y
29. Carmona-Fontaine, C., Deforet, M., Akkari, L., Thompson, C. B., Joyce, J. A., and Xavier, J. B. (2017). Metabolic origins of spatial organization in the tumor microenvironment. Proc. Natl. Acad. Sci. U.S.A. 114, 2934-2939. doi: 10.1073/pnas.1700600114
30. Casazza, A., Laoui, D., Wenes, M., Rizzolio, S., Bassani, N., Mambretti, M., et al. (2013). Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 24, 695-709. doi: 10.1016/j.ccr.2013.11.007
31. Cataisson, C., Salcedo, R., Hakim, S., Moffitt, B. A., Wright, L., Yi, M., et al. (2012). IL-1R-MyD88 signaling in keratinocyte transformation and carcinogenesis. J. Exp. Med. 209, 1689-1702. doi: 10.1084/jem.20101355
32. Catanzaro, J. M., Sheshadri, N., Pan, J. A., Sun, Y., Shi, C., Li, J., et al. (2014). Oncogenic ras induces inflammatory cytokine production by upregulating the squamous cell carcinoma antigens SerpinB3/B4. Nat. Commun. 5, 3729. doi: 10.1038/ncomms4729
33. Chae, W. J., and Bothwell, A. L. (2015). Spontaneous intestinal tumorigenesis in Apc (/Min+) mice requires altered T cell development with IL-17A. J. Immunol. Res. 2015:860106. doi: 10.1155/2015/860106
34. Chaput, N., Lepage, P., Coutzac, C., Soularue, E., Le Roux, K., Monot, C., et al. (2017). Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann. Oncol. 28, 1368-1379. doi: 10.1093/annonc/mdx108
35. Cheon, H., Borden, E. C., and Stark, G. R. (2014). Interferons and their stimulated genes in the tumor microenvironment. Semin. Oncol. 41, 156-173. doi: 10.1053/j.seminoncol.2014.02.002
36. Chia, W. K., Ali, R., and Toh, H. C. (2012). Aspirin as adjuvant therapy for colorectal cancer-reinterpreting paradigms. Nat. Rev. Clin. Oncol. 9, 561-570. doi: 10.1038/nrclinonc.2012.137
37. Chiba, T., Marusawa, H., Seno, H., and Watanabe, N. (2008). Mechanism for gastric cancer development by Helicobacter pylori infection. J. Gastroenterol. Hepatol. 23, 1175-1181. doi: 10.1111/j.1440-1746.2008.05472.x
38. Cinti, S., Mitchell, G., Barbatelli, G., Murano, I., Ceresi, E., Faloia, E., et al. (2005). Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J. Lipid Res. 46, 2347-2355. doi: 10.1194/jlr. M500294-JLR200
39. Cleary, M. P., and Grossmann, M. E. (2009). Minireview: obesity and breast cancer: the estrogen connection. Endocrinology 150, 2537-2542. doi: 10.1210/en.2009-0070
40. Colegio, O. R., Chu, N. Q., Szabo, A. L., Chu, T., Rhebergen, A. M., Jairam, V., et al. (2014). Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559-563. doi: 10.1038/nature13490
41. Conley, S. J., Gheordunescu, E., Kakarala, P., Newman, B., Korkaya, H., Heath, A. N., et al. (2012). Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc. Natl. Acad. Sci. U.S.A. 109, 2784-2789. doi: 10.1073/pnas.1018866109
42. Conze, D., Weiss, L., Regen, P. S., Bhushan, A., Weaver, D., Johnson, P., et al. (2001). Autocrine production of interleukin 6 causes multidrug resistance in breast cancer cells. Cancer Res. 61, 8851-8858
43. Cooks, T., Harris, C. C., and Oren, M. (2014). Caught in the cross fire: p53 in inflammation. Carcinogenesis 35, 1680-1690. doi: 10.1093/carcin/bgu134
44. Cooks, T., Pateras, I. S., Tarcic, O., Solomon, H., Schetter, A. J., Wilder, S., et al. (2013). Mutant p53 prolongs NF-kappaB activation and promotes chronic inflammation and inflammation-associated colorectal cancer. Cancer Cell 23, 634-646. doi: 10.1016/j.ccr.2013.03.022
45. Coombs, C. C., Zehir, A., Devlin, S. M., Kishtagari, A., Syed, A., Jonsson, P., et al. (2017). Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell 21, 374.e374-382.e374. doi: 10.1016/j.stem.2017.07.010
46. Coppé, J. P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., Goldstein, J., et al. (2008). Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853-2868. doi: 10.1371/journal.pbio.0060301
47. Coussens, L. M., and Werb, Z. (2002). Inflammation and cancer. Nature 420, 860-867. doi: 10.1038/nature01322
48. Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J., and Der, C. J. (2014). Drugging the undruggable RAS: mission possible? Nat. Rev. Drug Discov. 13, 828-851. doi: 10.1038/nrd4389
49. Cui, W. Y., and Li, M. D. (2010). Nicotinic modulation of innate immune pathways via alpha7 nicotinic acetylcholine receptor. J. Neuroimmune Pharmacol. 5, 479-488. doi: 10.1007/s11481-010-9210-2
50. Cui, Y., and Guo, G. (2016). Immunomodulatory function of the tumor suppressor p53 in host immune response and the tumor microenvironment. Int. J. Mol. Sci. 17:E1942. doi: 10.3390/ijms17111942
51. Daniluk, J., Liu, Y., Deng, D., Chu, J., Huang, H., Gaiser, S., et al. (2012). An NF-kappaB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice. J. Clin. Invest. 122, 1519-1528. doi: 10.1172/JCI59743
52. Das, S., and Marsden, P. A. (2013). Angiogenesis in glioblastoma. N. Engl. J. Med. 369, 1561-1563. doi: 10.1056/NEJMcibr1309402
53. De Boeck, A., Hendrix, A., Maynard, D., Van Bockstal, M., Daniëls, A., Pauwels, P., et al. (2013). Differential secretome analysis of cancer-associated fibroblasts and bone marrow-derived precursors to identify microenvironmental regulators of colon cancer progression. Proteomics 13, 379-388. doi: 10.1002/pmic.201200179
54. De Palma, M., Biziato, D., and Petrova, T. V. (2017). Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer 17, 457-474. doi: 10.1038/nrc.2017.51
55. Deininger, M., Radich, J., Burn, T. C., Huber, R., Paranagama, D., and Verstovsek, S. (2015). The effect of long-term ruxolitinib treatment on JAK2p. V617F allele burden in patients with myelofibrosis. Blood 126, 1551-1554. doi: 10.1182/blood-2015-03-635235
56. DeNardo, D. G., Brennan, D. J., Rexhepaj, E., Ruffell, B., Shiao, S. L., Madden, S. F., et al. (2011). Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 1, 54-67. doi: 10.1158/2159-8274.CD-10-0028
57. Di Minin, G., Bellazzo, A., Dal Ferro, M., Chiaruttini, G., Nuzzo, S., Bicciato, S., et al. (2014). Mutant p53 reprograms TNF signaling in cancer cells through interaction with the tumor suppressor DAB2IP. Mol. Cell 56, 617-629. doi: 10.1016/j.molcel.2014.10.013
58. Dieli-Conwright, C. M., Courneya, K. S., Demark-Wahnefried, W., Sami, N., Lee, K., Buchanan, T. A., et al. (2018). Effects of aerobic and resistance exercise on metabolic syndrome, sarcopenic obesity, and circulating biomarkers in overweight or obese survivors of breast cancer: a randomized controlled Trial. J. Clin. Oncol. 36, 875-883. doi: 10.1200/JCO.2017.75.7526
59. Donnarumma, E., Fiore, D., Nappa, M., Roscigno, G., Adamo, A., Iaboni, M., et al. (2017). Cancer-associated fibroblasts release exosomal microRNAs that dictate an aggressive phenotype in breast cancer. Oncotarget 8, 19592-19608. doi: 10.18632/oncotarget.14752
60. Dvorak, H. F. (1986). Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650-1659. doi: 10.1056/NEJM198612253152606
61. Eghtedar, A., Verstovsek, S., Estrov, Z., Burger, J., Cortes, J., Bivins, C., et al. (2012). Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. Blood 119, 4614-4618. doi: 10.1182/blood-2011-12-400051
62. Elenbaas, B., and Weinberg, R. A. (2001). Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp. Cell Res. 264, 169-184. doi: 10.1006/excr.2000.5133
63. Elinav, E., Nowarski, R., Thaiss, C. A., Hu, B., Jin, C., and Flavell, R. A. (2013). Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer 13, 759-771. doi: 10.1038/nrc3611
64. Elliott, M. J., Maini, R. N., Feldmann, M., Long-Fox, A., Charles, P., Katsikis, P., et al. (1993). Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum. 36, 1681-1690. doi: 10.1002/art.1780361206
65. Erez, N., Truitt, M., Olson, P., Arron, S. T., and Hanahan, D. (2010). Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell 17, 135-147. doi: 10.1016/j.ccr.2009.12.041
66. Falchi, L., Newberry, K. J., and Verstovsek, S. (2015). New therapeutic approaches in polycythemia vera. Clin. Lymphoma Myeloma Leuk. 15(Suppl.), S27-S33. doi: 10.1016/j.clml.2015.02.013
67. Farkona, S., Diamandis, E. P., and Blasutig, I. M. (2016). Cancer immunotherapy: the beginning of the end of cancer? BMC Med. 14:73. doi: 10.1186/s12916-016-0623-5
68. Farmaki, E., Chatzistamou, I., Bourlis, P., Santoukou, E., Trimis, G., Papavassiliou, A. G., et al. (2012). Selection of p53-deficient stromal cells in the tumor microenvironment. Genes Cancer 3, 592-598. doi: 10.1177/1947601912474002
69. Feig, C., Jones, J. O., Kraman, M., Wells, R. J., Deonarine, A., Chan, D. S., et al. (2013). Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl. Acad. Sci. U.S.A. 110, 20212-20217. doi: 10.1073/pnas.1320318110
70. Feldmann, M. (2008). Many cytokines are very useful therapeutic targets in disease. J. Clin. Invest. 118, 3533-3536. doi: 10.1172/JCI37346
71. Feldmann, M., and Maini, R. N. (2001). Anti-TNF a therapy of rheumatoid arthritis: what have we learned? Annu. Rev. Immunol. 19, 163-196. doi: 10.1146/annurev.immunol.19.1.163
72. Ferrara, N., and Adamis, A. P. (2016). Ten years of anti-vascular endothelial growth factor therapy. Nat. Rev. Drug Discov. 15, 385-403. doi: 10.1038/nrd.2015.17
73. Fiedler, U., Reiss, Y., Scharpfenecker, M., Grunow, V., Koidl, S., Thurston, G., et al. (2006). Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat. Med. 12, 235-239. doi: 10.1038/nm1351
74. Flegal, K. M., Carroll, M. D., Ogden, C. L., and Curtin, L. R. (2002). Prevalence and trends in obesity among US adults, 1999-2008. JAMA 303, 235-241. doi: 10.1001/jama.2009.2014
75. Franklin, R. A., Liao, W., Sarkar, A., Kim, M. V., Bivona, M. R., Liu, K., et al. (2014). The cellular and molecular origin of tumor-associated macrophages. Science 344, 921-925. doi: 10.1126/science.1252510
76. Frassanito, M. A., Cusmai, A., Iodice, G., and Dammacco, F. (2001). Autocrine interleukin-6 production and highly malignant multiple myeloma: relation with resistance to drug-induced apoptosis. Blood 97, 483-489. doi: 10.1182/blood. V97.2.483
77. Freedman, N. D., Silverman, D. T., Hollenbeck, A. R., Schatzkin, A., and Abnet, C. C. (2011). Association between smoking and risk of bladder cancer among men and women. JAMA 306, 737-745. doi: 10.1001/jama.2011.1142
78. Fuentes-Mattei, E., Velazquez-Torres, G., Phan, L., Zhang, F., Chou, P. C., Shin, J. H., et al. (2014). Effects of obesity on transcriptomic changes and cancer hallmarks in estrogen receptor-positive breast cancer. J. Natl. Cancer Inst. 106:dju158. doi: 10.1093/jnci/dju158
79. Fukuyama, T., Ehling, S., Cook, E., and Bäumer, W. (2015). Topically administered janus-kinase inhibitors tofacitinib and oclacitinib display impressive antipruritic and anti-inflammatory responses in a model of allergic dermatitis. J. Pharmacol. Exp. Ther. 354, 394-405. doi: 10.1124/jpet.115.223784
80. Fuster, J. J., MacLauchlan, S., Zuriaga, M. A., Polackal, M. N., Ostriker, A. C., Chakraborty, R., et al. (2017). Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355, 842-847. doi: 10.1126/science.aag1381
81. Galon, J., Costes, A., Sanchez-Cabo, F., Kirilovsky, A., Mlecnik, B., Lagorce-Pagès, C., et al. (2006). Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960-1964. doi: 10.1126/science.1129139
82. Garrett, W. S. (2015). Cancer and the microbiota. Science 348, 80-86. doi: 10.1126/science.aaa4972
83. Genovese, G., Kähler, A. K., Handsaker, R. E., Lindberg, J., Rose, S. A., Bakhoum, S. F., et al. (2014). Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477-2487. doi: 10.1056/NEJMoa1409405
84. Geyer, H. L., Dueck, A. C., Scherber, R. M., and Mesa, R. A. (2015). Impact of inflammation on myeloproliferative neoplasm symptom development. Mediators Inflamm. 2015, 284706. doi: 10.1155/2015/284706
85. Ghandadi, M., and Sahebkar, A. (2016). Interleukin-6: a critical cytokine in cancer multidrug resistance. Curr. Pharm. Des. 22, 518-526. doi: 10.2174/1381612822666151124234417
86. Ghoreschi, K., Jesson, M. I., Li, X., Lee, J. L., Ghosh, S., Alsup, J. W., et al. (2011). Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J. Immunol. 186, 4234-4243. doi: 10.4049/jimmunol.1003668
87. Glass, C. K., and Natoli, G. (2016). Molecular control of activation and priming in macrophages. Nat. Immunol. 17, 26-33. doi: 10.1038/ni.3306
88. Godwin, P., Baird, A. M., Heavey, S., Barr, M. P., O'Byrne, K. J., and Gately, K. (2013). Targeting nuclear factor-kappa B to overcome resistance to chemotherapy. Front. Oncol. 3:120. doi: 10.3389/fonc.2013.00120
89. Goel, S., Wyrwicz, L., Choi, M., Coveler, A. L., Ucar, A., Brown, A. W., et al. (2016). Phase III double-blinded, placebo-controlled study of MABp1 for improving survival in metastatic colorectal cancer. J. Clin. Oncol. 34:TPS784. doi: 10.1200/jco.2016.34.4_suppl.tps784
90. Gomez Perdiguero, E., Klapproth, K., Schulz, C., Busch, K., Azzoni, E., Crozet, L., et al. (2015). Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547-551. doi: 10.1038/nature13989
91. Gopalakrishnan, V., Spencer, C. N., Nezi, L., Reuben, A., Andrews, M. C., Karpinets, T. V., et al. (2018). Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97-103. doi: 10.1126/science.aan4236
92. Gounaris, E., Blatner, N. R., Dennis, K., Magnusson, F., Gurish, M. F., Strom, T. B., et al. (2009). T-regulatory cells shift from a protective anti-inflammatory to a cancer-promoting proinflammatory phenotype in polyposis. Cancer Res. 69, 5490-5497. doi: 10.1158/0008-5472.CAN-09-0304
93. Greiner, J. W., Hand, P. H., Noguchi, P., Fisher, P. B., Pestka, S., and Schlom, J. (1984). Enhanced expression of surface tumor-associated antigens on human breast and colon tumor cells after recombinant human leukocyte a-interferon treatment. Cancer Res. 44, 3208-3214
94. Greten, F. R., and Karin, M. (2004). The IKK/NF-kappaB activation pathway-a target for prevention and treatment of cancer. Cancer Lett. 206, 193-199. doi: 10.1016/j.canlet.2003.08.029
95. Grivennikov, S. I., and Karin, M. (2011). Inflammatory cytokines in cancer: tumour necrosis factor and interleukin 6 take the stage. Ann. Rheum. Dis. 70(Suppl 1), i104-i108. doi: 10.1136/ard.2010.140145
96. Grivennikov, S. I., Greten, F. R., and Karin, M. (2010). Immunity, inflammation, and cancer. Cell 140, 883-899. doi: 10.1016/j.cell.2010.01.025
97. Grivennikov, S. I., Wang, K., Mucida, D., Stewart, C. A., Schnabl, B., Jauch, D., et al. (2012). Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491, 254-258. doi: 10.1038/nature11465
98. Groden, J., Thliveris, A., Samowitz, W., Carlson, M., Gelbert, L., Albertsen, H., et al. (1991). Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66, 589-600. doi: 10.1016/0092-8674(81)90021-0
99. Guo, G., Marrero, L., Rodriguez, P., Del Valle, L., Ochoa, A., and Cui, Y. (2013). Trp53 inactivation in the tumor microenvironment promotes tumor progression by expanding the immunosuppressive lymphoid-like stromal network. Cancer Res. 73, 1668-1675. doi: 10.1158/0008-5472.CAN-12-3810
100. Hammerl, D., Smid, M., Timmermans, A. M., Sleijfer, S., Martens, J. W. M., and Debets, R. (2017). Breast cancer genomics and immuno-oncological markers to guide immune therapies. Semin. Cancer Biol. doi: 10.1016/j.semcancer.2017.11.003. [Epub ahead of print]
101. Hanahan, D., and Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell 144, 646-674. doi: 10.1016/j.cell.2011.02.013
102. Harney, A. S., Arwert, E. N., Entenberg, D., Wang, Y., Guo, P., Qian, B. Z., et al. (2015). Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2hi macrophage-derived VEGFA. Cancer Discov. 5, 932-943. doi: 10.1158/2159-8290.CD-15-0012
103. Harris, R. E., Chlebowski, R. T., Jackson, R. D., Frid, D. J., Ascenseo, J. L., Anderson, G., et al. (2003). Breast cancer and nonsteroidal anti-inflammatory drugs: prospective results from the Women's Health Initiative. Cancer Res. 63, 6096-6101
104. He, W., Luistro, L., Carvajal, D., Smith, M., Nevins, T., Yin, X., et al. (2011). High tumor levels of IL6 and IL8 abrogate preclinical efficacy of the gamma-secretase inhibitor, RO4929097. Mol. Oncol. 5, 292-301. doi: 10.1016/j.molonc.2011.01.001
105. Hellmann, M., Rizvi, N., Wolchok, J. D., and Chan, T. A. (2016). Genomic profile, smoking, and response to anti-PD-1 therapy in non-small cell lung carcinoma. Mol. Cell Oncol. 3:e1048929. doi: 10.1080/23723556.2015.1048929
106. Heo, T. H., Wahler, J., and Suh, N. (2016). Potential therapeutic implications of IL-6/IL-6R/gp130-targeting agents in breast cancer. Oncotarget 7, 15460-15473. doi: 10.18632/oncotarget.7102
107. Hervas-Stubbs, S., Perez-Gracia, J. L., Rouzaut, A., Sanmamed, M. F., Le Bon, A., and Melero, I. (2011). Direct effects of type I interferons on cells of the immune system. Clin. Cancer Res. 17, 2619-2627. doi: 10.1158/1078-0432.CCR-10-1114
108. Hill, R., Song, Y., Cardiff, R. D., and Van Dyke, T. (2005). Selective evolution of stromal mesenchyme with p53 loss in response to epithelial tumorigenesis. Cell 123, 1001-1011. doi: 10.1016/j.cell.2005.09.030
109. Hong, D. S., Hui, D., Bruera, E., Janku, F., Naing, A., Falchook, G. S., et al. (2014). MABp1, a first-in-class true human antibody targeting interleukin-1a in refractory cancers: an open-label, phase 1 dose-escalation and expansion study. Lancet Oncol. 15, 656-666. doi: 10.1016/S1470-2045(14)70155-X
110. Hu, M., Yao, J., Cai, L., Bachman, K. E., van den Brûle, F., Velculescu, V., et al. (2005). Distinct epigenetic changes in the stromal cells of breast cancers. Nat. Genet. 37, 899-905. doi: 10.1038/ng1596
111. Hu, N., Wang, C., Hu, Y., Yang, H. H., Kong, L. H., Lu, N., et al. (2006). Genome-wide loss of heterozygosity and copy number alteration in esophageal squamous cell carcinoma using the Affymetrix GeneChip Mapping 10 K array. BMC Genomics 7:299. doi: 10.1186/1471-2164-7-299
112. Huang, S., Mills, L., Mian, B., Tellez, C., McCarty, M., Yang, X. D., et al. (2002). Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am. J. Pathol. 161, 125-134. doi: 10.1016/S0002-9440(10)64164-8
113. Hussain, S. P., Amstad, P., Raja, K., Ambs, S., Nagashima, M., Bennett, W. P., et al. (2000). Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res. 60, 3333-3337
114. Iida, N., Dzutsev, A., Stewart, C. A., Smith, L., Bouladoux, N., Weingarten, R. A., et al. (2013). Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342, 967-970. doi: 10.1126/science.1240527
115. Ishiguro, K., Yoshida, T., Yagishita, H., Numata, Y., and Okayasu, T. (2006). Epithelial and stromal genetic instability contributes to genesis of colorectal adenomas. Gut 55, 695-702. doi: 10.1136/gut.2005.079459
116. Iyengar, N. M., Brown, K. A., Zhou, X. K., Gucalp, A., Subbaramaiah, K., Giri, D. D., et al. (2017). Metabolic obesity, adipose inflammation and elevated breast aromatase in women with normal body mass index. Cancer Prev. Res. 10, 235-243. doi: 10.1158/1940-6207.CAPR-16-0314
117. Iyengar, N. M., Gucalp, A., Dannenberg, A. J., and Hudis, C. A. (2016). Obesity and cancer mechanisms: tumor microenvironment and inflammation. J. Clin. Oncol. 34, 4270-4276. doi: 10.1200/JCO.2016.67.4283
118. Iyengar, N. M., Hudis, C. A., and Dannenberg, A. J. (2015). Obesity and cancer: local and systemic mechanisms. Annu. Rev. Med. 66, 297-309. doi: 10.1146/annurev-med-050913-022228
119. Iyengar, N. M., Kochhar, A., Morris, P. G., Morris, L. G., Zhou, X. K., Ghossein, R. A. G., et al. (2014). Impact of obesity on the survival of patients with early-stage squamous cell carcinoma of the oral tongue. Cancer 120, 983-991. doi: 10.1002/cncr.28532
120. Jackstadt, R., and Sansom, O. J. (2016). Mouse models of intestinal cancer. J. Pathol. 238, 141-151. doi: 10.1002/path.4645
121. Jaiswal, S., Fontanillas, P., Flannick, J., Manning, A., Grauman, P. V., Mar, B. G., et al. (2014). Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488-2498. doi: 10.1056/NEJMoa1408617
122. Jaiswal, S., Natarajan, P., and Ebert, B. L. (2017a). Clonal hematopoiesis and atherosclerosis. N. Engl. J. Med. 377, 1401-1402. doi: 10.1056/NEJMc1710381
123. Jaiswal, S., Natarajan, P., Silver, A. J., Gibson, C. J., Bick, A. G., Shvartz, E., et al. (2017b). Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N. Engl. J. Med. 377, 111-121. doi: 10.1056/NEJMoa1701719
124. Ji, B., Tsou, L., Wang, H., Gaiser, S., Chang, D. Z., Daniluk, J., et al. (2009). Ras activity levels control the development of pancreatic diseases. Gastroenterology 137, 1072-1082, 1082.e1-6. doi: 10.1053/j.gastro.2009.05.052
125. Johnson, C. C., Hayes, R. B., Schoen, R. E., Gunter, M. J., and Huang, W. Y. (2010). Non-steroidal anti-inflammatory drug use and colorectal polyps in the prostate, lung, colorectal, and ovarian cancer screening trial. Am. J. Gastroenterol. 105, 2646-2655. doi: 10.1038/ajg.2010.349
126. Jones, V. S., Huang, R. Y., Chen, L. P., Chen, Z. S., Fu, L., and Huang, R. P. (2016). Cytokines in cancer drug resistance: cues to new therapeutic strategies. Biochim. Biophys. Acta 1865, 255-265. doi: 10.1016/j.bbcan.2016.03.005
127. Joshua, A. M., Vukovic, B., Braude, I., Hussein, S., Zielenska, M., Srigley, J., et al. (2007). Telomere attrition in isolated high-grade prostatic intraepithelial neoplasia and surrounding stroma is predictive of prostate cancer. Neoplasia 9, 81-89. doi: 10.1593/neo.06745
128. Kalluri, R. (2016). The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582-598. doi: 10.1038/nrc.2016.73
129. Khandelwal, P., Teusink-Cross, A., Davies, S. M., Nelson, A. S., Dandoy, C. E., El-Bietar, J., et al. (2017). Ruxolitinib as salvage therapy in steroid-refractory acute graft-versus-host disease in pediatric hematopoietic stem cell transplant patients. Biol. Blood Marrow Transplant. 23, 1122-1127. doi: 10.1016/j.bbmt.2017.03.029
130. Kim, G., Ouzounova, M., Quraishi, A. A., Davis, A., Tawakkol, N., Clouthier, S. G., et al. (2015). SOCS3-mediated regulation of inflammatory cytokines in PTEN and p53 inactivated triple negative breast cancer model. Oncogene 34, 671-680. doi: 10.1038/onc.2014.4
131. Kim, H. S., Lim, H. S., Lee, S. H., Lee, J. W., Nam, S. W., Park, W. S., et al. (2006). Mitochondrial microsatellite instability of colorectal cancer stroma. Int. J. Cancer 119, 2607-2611. doi: 10.1002/ijc.22244
132. Kioi, M., Vogel, H., Schultz, G., Hoffman, R. M., Harsh, G. R., and Brown, J. M. (2010). Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J. Clin. Invest. 120, 694-705. doi: 10.1172/JCI40283
133. Kirkwood, J. (2002). Cancer immunotherapy: the interferon-alpha experience. Semin. Oncol. 29, 18-26. doi: 10.1053/sonc.2002.33078
134. Kleppe, M., Comen, E., Wen, H. Y., Bastian, L., Blum, B., Rapaport, F. T., et al. (2015a). Somatic mutations in leukocytes infiltrating primary breast cancers. NPJ Breast Cancer 1, 15005. doi: 10.1038/npjbcancer.2015.5
135. Kleppe, M., Kwak, M., Koppikar, P., Riester, M., Keller, M., Bastian, L., et al. (2015b). JAK-STAT pathway activation in malignant and nonmalignant cells contributes to MPN pathogenesis and therapeutic response. Cancer Discov. 5, 316-331. doi: 10.1158/2159-8290.CD-14-0736
136. Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., et al. (2016). Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12, 1-222. doi: 10.1080/15548627.2015.1100356
137. Kloepper, J., Riedemann, L., Amoozgar, Z., Seano, G., Susek, K., Yu, V., et al. (2016). Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proc. Natl. Acad. Sci. U.S.A. 113, 4476-4481. doi: 10.1073/pnas.1525360113
138. Knüpfer, H., and Preiss, R. (2007). Significance of interleukin-6 (IL-6) in breast cancer (review). Breast Cancer Res. Treat. 102, 129-135. doi: 10.1007/s10549-006-9328-3
139. Koelwyn, G. J., Quail, D. F., Zhang, X., White, R. M., and Jones, L. W. (2017). Exercise-dependent regulation of the tumour microenvironment. Nat. Rev. Cancer 17, 620-632. doi: 10.1038/nrc.2017.78
140. Koelwyn, G. J., Wennerberg, E., Demaria, S., and Jones, L. W. (2015). Exercise in regulation of inflammation-immune axis function in cancer initiation and progression. Oncology 29, 908-920, 922
141. Komarova, E. A., Diatchenko, L., Rokhlin, O. W., Hill, J. E., Wang, Z. J., Krivokrysenko, V. I., et al. (1998). Stress-induced secretion of growth inhibitors: a novel tumor suppressor function of p53. Oncogene 17, 1089-1096. doi: 10.1038/sj.onc.1202303
142. Komarova, E. A., Krivokrysenko, V., Wang, K., Neznanov, N., Chernov, M. V., Komarov, P. G., et al. (2005). p53 is a suppressor of inflammatory response in mice. FASEB J. 19, 1030-1032. doi: 10.1096/fj.04-3213fje
143. Kontzias, A., Kotlyar, A., Laurence, A., Changelian, P., and O'Shea, J. J. (2012). Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease. Curr. Opin. Pharmacol. 12, 464-470. doi: 10.1016/j.coph.2012.06.008
144. Korkaya, H., Kim, G. I., Davis, A., Malik, F., Henry, N. L., Ithimakin, S., et al. (2012). Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol. Cell 47, 570-584. doi: 10.1016/j.molcel.2012.06.014
145. Kraman, M., Bambrough, P. J., Arnold, J. N., Roberts, E. W., Magiera, L., Jones, J. O., et al. (2010). Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 330, 827-830. doi: 10.1126/science.1195300
146. Krock, B. L., Skuli, N., and Simon, M. C. (2011). Hypoxia-induced angiogenesis: good and evil. Genes Cancer 2, 1117-1133. doi: 10.1177/1947601911423654
147. Kroemer, G., and Zitvogel, L. (2018). Cancer immunotherapy in 2017: the breakthrough of the microbiota. Nat. Rev. Immunol. 18, 87-88. doi: 10.1038/nri.2018.4
148. Kudlacz, E., Conklyn, M., Andresen, C., Whitney-Pickett, C., and Changelian, P. (2008). The JAK-3 inhibitor CP-690550 is a potent anti-inflammatory agent in a murine model of pulmonary eosinophilia. Eur. J. Pharmacol. 582, 154-161. doi: 10.1016/j.ejphar.2007.12.024
149. Kumar, V., Donthireddy, L., Marvel, D., Condamine, T., Wang, F., Lavilla-Alonso, S., et al. (2017). Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell 32, 654.e655-668.e655. doi: 10.1016/j.ccell.2017.10.005
150. Kuper, H., Adami, H. O., and Trichopoulos, D. (2000). Infections as a major preventable cause of human cancer. J. Intern. Med. 248, 171-183. doi: 10.1046/j.1365-2796.2000.00742.x
151. Kurose, K., Gilley, K., Matsumoto, S., Watson, P. H., Zhou, X. P., and Eng, C. (2002). Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nat. Genet. 32, 355-357. doi: 10.1038/ng1013
152. Kurose, K., Hoshaw-Woodard, S., Adeyinka, A., Lemeshow, S., Watson, P. H., and Eng, C. (2001). Genetic model of multi-step breast carcinogenesis involving the epithelium and stroma: clues to tumour-microenvironment interactions. Hum. Mol. Genet. 10, 1907-1913. doi: 10.1093/hmg/10.18.1907
153. Lasry, A., Zinger, A., and Ben-Neriah, Y. (2016). Inflammatory networks underlying colorectal cancer. Nat. Immunol. 17, 230-240. doi: 10.1038/ni.3384
154. Le, D. T., Uram, J. N., Wang, H., Bartlett, B. R., Kemberling, H., Eyring, A. D., et al. (2015). PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509-2520. doi: 10.1056/NEJMoa1500596
155. Lee, H. J., Zhuang, G., Cao, Y., Du, P., Kim, H. J., and Settleman, J. (2014). Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell 26, 207-221. doi: 10.1016/j.ccr.2014.05.019
156. Lee, T. L., Yang, X. P., Yan, B., Friedman, J., Duggal, P., Bagain, L., et al. (2007). A novel nuclear factor-kappaB gene signature is differentially expressed in head and neck squamous cell carcinomas in association with TP53 status. Clin. Cancer Res. 13, 5680-5691. doi: 10.1158/1078-0432.CCR-07-0670
157. Leoni, C., Montagner, S., Rinaldi, A., Bertoni, F., Polletti, S., Balestrieri, C., et al. (2017). Dnmt3a restrains mast cell inflammatory responses. Proc. Natl. Acad. Sci. U.S.A. 114, E1490-E1499. doi: 10.1073/pnas.1616420114
158. Leslie, N. R., and Downes, C. P. (2004). PTEN function: how normal cells control it and tumour cells lose it. Biochem. J. 382, 1-11. doi: 10.1042/BJ20040825
159. Li, F., and Sethi, G. (2010). Targeting transcription factor NF-kappaB to overcome chemoresistance and radioresistance in cancer therapy. Biochim. Biophys. Acta 1805, 167-180. doi: 10.1016/j.bbcan.2010.01.002
160. Li, P., Shan, J. X., Chen, X. H., Zhang, D., Su, L. P., Huang, X. Y., et al. (2015). Epigenetic silencing of microRNA-149 in cancer-associated fibroblasts mediates prostaglandin E2/interleukin-6 signaling in the tumor microenvironment. Cell Res. 25, 588-603. doi: 10.1038/cr.2015.51
161. Li, X., Zhang, Q., Ding, Y., Liu, Y., Zhao, D., Zhao, K., et al. (2016). Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity. Nat. Immunol. 17, 806-815. doi: 10.1038/ni.3464
162. Ligibel, J. A., Alfano, C. M., Courneya, K. S., Demark-Wahnefried, W., Burger, R. A., Chlebowski, R. T., et al. (2014). American Society of Clinical Oncology position statement on obesity and cancer. J. Clin. Oncol. 32, 3568-3574. doi: 10.1200/JCO.2014.58.4680
163. Lin, K. T., and Wang, L. H. (2016). New dimension of glucocorticoids in cancer treatment. Steroids 111, 84-88. doi: 10.1016/j.steroids.2016.02.019
164. Lin, Y., Bai, L., Chen, W., and Xu, S. (2010). The NF-kappaB activation pathways, emerging molecular targets for cancer prevention and therapy. Expert Opin. Ther. Targets 14, 45-55. doi: 10.1517/14728220903431069
165. Linderholm, B., Lindh, B., Tavelin, B., Grankvist, K., and Henriksson, R. (2000). p53 and vascular-endothelial-growth-factor (VEGF) expression predicts outcome in 833 patients with primary breast carcinoma. Int. J. Cancer 89, 51-62. doi: 10.1002/(SICI)1097-0215(20000120)89:1<51::AID-IJC9>3.0.CO;2-8
166. Liu, L. Y., Craiglow, B. G., Dai, F., and King, B. A. (2017). Tofacitinib for the treatment of severe alopecia areata and variants: a study of 90 patients. J. Am. Acad. Dermatol. 76, 22-28. doi: 10.1016/j.jaad.2016.09.007
167. LoConte, N. K., Brewster, A. M., Kaur, J. S., Merrill, J. K., and Alberg, A. J. (2018). Alcohol and cancer: a statement of the American Society of Clinical Oncology. J. Clin. Oncol. 36, 83-93. doi: 10.1200/JCO.2017.76.1155
168. Longo, V., Brunetti, O., Gnoni, A., Cascinu, S., Gasparini, G., Lorusso, V., et al. (2016). Angiogenesis in pancreatic ductal adenocarcinoma: a controversial issue. Oncotarget 7, 58649-58658. doi: 10.18632/oncotarget.10765
169. Lu, J., Ye, X., Fan, F., Xia, L., Bhattacharya, R., Bellister, S., et al. (2013). Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1. Cancer Cell 23, 171-185. doi: 10.1016/j.ccr.2012.12.021
170. Lu, L. M., Zavitz, C. C., Chen, B., Kianpour, S., Wan, Y., and Stämpfli, M. R. (2007). Cigarette smoke impairs NK cell-dependent tumor immune surveillance. J. Immunol. 178, 936-943. doi: 10.4049/jimmunol.178.2.936
171. Lu, M., Zhang, W., Li, Y., Berenzon, D., Wang, X., Wang, J., et al. (2010). Interferon-a targets JAK2V617F-positive hematopoietic progenitor cells and acts through the p38 MAPK pathway. Exp. Hematol. 38, 472-480. doi: 10.1016/j.exphem.2010.03.005
172. Lujambio, A., Akkari, L., Simon, J., Grace, D., Tschaharganeh, D. F., Bolden, J. E., et al. (2013). Non-cell-autonomous tumor suppression by p53. Cell 153, 449-460. doi: 10.1016/j.cell.2013.03.020
173. Lust, J. A., Lacy, M. Q., Zeldenrust, S. R., Dispenzieri, A., Gertz, M. A., Witzig, T. E., et al. (2009). Induction of a chronic disease state in patients with smoldering or indolent multiple myeloma by targeting interleukin 1(β)-induced interleukin 6 production and the myeloma proliferative component. Mayo Clin. Proc. 84, 114-122. doi: 10.4065/84.2.114
174. Luttges, J., Diederichs, A., Menke, M. A., Vogel, I., Kremer, B., and Klöppel, G. (2000). Ductal lesions in patients with chronic pancreatitis show K-ras mutations in a frequency similar to that in the normal pancreas and lack nuclear immunoreactivity for p53. Cancer 88, 2495-2504. doi: 10.1002/1097-0142(20000601)88:11<2495::AID-CNCR10>3.0.CO;2-B
175. Mackay-Wiggan, J., Jabbari, A., Nguyen, N., Cerise, J. E., Clark, C., Ulerio, G., et al. (2016). Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata. JCI Insight 1:e89790. doi: 10.1172/jci.insight.89790
176. Man, Y., Mannion, C., Kuhls, E., Moinfar, F., Bratthauer, G. L., Albores-Saavedra, J., et al. (2001). Allelic losses at 3p and 11p are detected in both epithelial and stromal components of cervical small-cell neuroendocrine carcinoma. Appl. Immunohistochem. Mol. Morphol. 9, 340-345. doi: 10.1097/00129039-200112000-00009
177. Maxwell, P. J., Neisen, J., Messenger, J., and Waugh, D. J. (2014). Tumor-derived CXCL8 signaling augments stroma-derived CCL2-promoted proliferation and CXCL12-mediated invasion of PTEN-deficient prostate cancer cells. Oncotarget 5, 4895-4908. doi: 10.18632/oncotarget.2052
178. McGuire, S. (2016). World Cancer Report 2014. World Health Organization; International Agency for Research on Cancer, Geneva
179. McKerrell, T., Park, N., Moreno, T., Grove, C. S., Ponstingl, H., Stephens, J., et al. (2015). Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep. 10, 1239-1245. doi: 10.1016/j.celrep.2015.02.005
180. Michalaki, V., Syrigos, K., Charles, P., and Waxman, J. (2004). Serum levels of IL-6 and TNF-a correlate with clinicopathological features and patient survival in patients with prostate cancer. Br. J. Cancer 90, 2312-2316. doi: 10.1038/sj.bjc.6601814
181. Milara, J., and Cortijo, J. (2012). Tobacco, inflammation, and respiratory tract cancer. Curr. Pharm. Des. 18, 3901-3938. doi: 10.2174/138161212802083743
182. Moinfar, F., Man, Y. G., Arnould, L., Bratthauer, G. L., Ratschek, M., and Tavassoli, F. A. (2000). Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. Cancer Res. 60, 2562-2566
183. Mondet, J., Hussein, K., and Mossuz, P. (2015). Circulating cytokine levels as markers of inflammation in philadelphia negative myeloproliferative neoplasms: diagnostic and prognostic interest. Mediators Inflamm. 2015:670580. doi: 10.1155/2015/670580
184. Moore, P. S., and Chang, Y. (2010). Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nat. Rev. Cancer 10, 878-889. doi: 10.1038/nrc2961
185. Mori, Y., Ikeda, K., Inomata, T., Yoshimoto, G., Fujii, N., Ago, H., et al. (2016). Ruxolitinib treatment for GvHD in patients with myelofibrosis. Bone Marrow Transplant. 51, 1584-1587. doi: 10.1038/bmt.2016.256
186. Morris, P. G., Hudis, C. A., Giri, D., Morrow, M., Falcone, D. J., Zhou, X. K., et al. (2011). Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer. Cancer Prev. Res. 4, 1021-1029. doi: 10.1158/1940-6207.CAPR-11-0110
187. Moser, A. R., Mattes, E. M., Dove, W. F., Lindstrom, M. J., Haag, J. D., and Gould, M. N. (1993). ApcMin, a mutation in the murine Apc gene, predisposes to mammary carcinomas and focal alveolar hyperplasias. Proc. Natl. Acad. Sci. U.S.A. 90, 8977-8981. doi: 10.1073/pnas.90.19.8977
188. Moser, A. R., Pitot, H. C., and Dove, W. F. (1990). A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247, 322-324. doi: 10.1126/science.2296722
189. Moskovits, N., Kalinkovich, A., Bar, J., Lapidot, T., and Oren, M. (2006). p53 Attenuates cancer cell migration and invasion through repression of SDF-1/CXCL12 expression in stromal fibroblasts. Cancer Res. 66, 10671-10676. doi: 10.1158/0008-5472.CAN-06-2323
190. Murray, P. J., Allen, J. E., Biswas, S. K., Fisher, E. A., Gilroy, D. W., Goerdt, S., et al. (2014). Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14-20. doi: 10.1016/j.immuni.2014.06.008
191. Nakanishi, C., and Toi, M. (2005). Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs. Nat. Rev. Cancer 5, 297-309. doi: 10.1038/nrc1588
192. Nguyen, K. B., Salazar-Mather, T. P., Dalod, M. Y., Van Deusen, J. B., Wei, X. Q., Liew, F. Y., et al. (2002). Coordinated and distinct roles for IFN-α β, IL-12, and IL-15 regulation of NK cell responses to viral infection. J. Immunol. 169, 4279-4287. doi: 10.4049/jimmunol.169.8.4279
193. Norton, S. E., Ward-Hartstonge, K. A., Taylor, E. S., and Kemp, R. A. (2015). Immune cell interplay in colorectal cancer prognosis. World J. Gastrointest. Oncol. 7, 221-232. doi: 10.4251/wjgo.v7.i10.221
194. Noy, R., and Pollard, J. W. (2014). Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49-61. doi: 10.1016/j.immuni.2014.06.010
195. öhlund, D., Elyada, E., and Tuveson, D. (2014). Fibroblast heterogeneity in the cancer wound. J. Exp. Med. 211, 1503-1523. doi: 10.1084/jem.20140692
196. Okabe, Y., and Medzhitov, R. (2016). Tissue biology perspective on macrophages. Nat. Immunol. 17, 9-17. doi: 10.1038/ni.3320
197. Olive, K. P., Jacobetz, M. A., Davidson, C. J., Gopinathan, A., McIntyre, D., Honess, D., et al. (2009). Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457-1461. doi: 10.1126/science.1171362
198. Olson, O. C., and Joyce, J. A. (2015). Cysteine cathepsin proteases: regulators of cancer progression and therapeutic response. Nat. Rev. Cancer 15, 712-729. doi: 10.1038/nrc4027
199. Olson, O. C., Kim, H., Quail, D. F., Foley, E. A., and Joyce, J. A. (2017). Tumor-associated macrophages suppress the cytotoxic activity of antimitotic agents. Cell Rep. 19, 101-113. doi: 10.1016/j.celrep.2017.03.038
200. O'Shea, J. J., Kontzias, A., Yamaoka, K., Tanaka, Y., and Laurence, A. (2013). Janus kinase inhibitors in autoimmune diseases. Ann. Rheum. Dis. 72(Suppl. 2), ii111-ii115. doi: 10.1136/annrheumdis-2012-202576
201. Oskarsson, T., Acharyya, S., Zhang, X. H., Vanharanta, S., Tavazoie, S. F., Morris, P. G., et al. (2011). Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat. Med. 17, 867-874. doi: 10.1038/nm.2379
202. Palumbo, A. Jr., Da Costa Nde, O., Bonamino, M. H., Pinto, L. F., and Nasciutti, L. E. (2015). Genetic instability in the tumor microenvironment: a new look at an old neighbor. Mol. Cancer 14, 145. doi: 10.1186/s12943-015-0409-y
203. Parker, B. S., Rautela, J., and Hertzog, P. J. (2016). Antitumour actions of interferons: implications for cancer therapy. Nat. Rev. Cancer 16, 131-144. doi: 10.1038/nrc.2016.14
204. Parkin, D. M. (2006). The global health burden of infection-associated cancers in the year 2002. Int. J. Cancer 118, 3030-3044. doi: 10.1002/ijc.21731
205. Passamonti, F., Maffioli, M., Caramazza, D., and Cazzola, M. (2011). Myeloproliferative neoplasms: from JAK2 mutations discovery to JAK2 inhibitor therapies. Oncotarget 2, 485-490. doi: 10.18632/oncotarget.281
206. Paterson, R. F., Ulbright, T. M., MacLennan, G. T., Zhang, S., Pan, C. X., Sweeney, C. J., et al. (2003). Molecular genetic alterations in the laser-capture-microdissected stroma adjacent to bladder carcinoma. Cancer 98, 1830-1836. doi: 10.1002/cncr.11747
207. Patocs, A., Zhang, L., Xu, Y., Weber, F., Caldes, T., Mutter, G. L., et al. (2007). Breast-cancer stromal cells with TP53 mutations and nodal metastases. N. Engl. J. Med. 357, 2543-2551. doi: 10.1056/NEJMoa071825
208. Paunescu, V., Bojin, F. M., Tatu, C. A., Gavriliuc, O. I., Rosca, A., Gruia, A. T., et al. (2011). Tumour-associated fibroblasts and mesenchymal stem cells: more similarities than differences. J. Cell. Mol. Med. 15, 635-646. doi: 10.1111/j.1582-4934.2010.01044.x
209. Pemmaraju, N., Kantarjian, H., Kadia, T., Cortes, J., Borthakur, G., Newberry, K., et al. (2015). A phase I/II study of the Janus kinase (JAK)1 and 2 inhibitor ruxolitinib in patients with relapsed or refractory acute myeloid leukemia. Clin. Lymphoma Myeloma Leuk. 15, 171-176. doi: 10.1016/j.clml.2014.08.003
210. Peng, D. F., Kanai, Y., Sawada, M., Ushijima, S., Hiraoka, N., Kosuge, T., et al. (2005). Increased DNA methyltransferase 1 (DNMT1) protein expression in precancerous conditions and ductal carcinomas of the pancreas. Cancer Sci. 96, 403-408. doi: 10.1111/j.1349-7006.2005.00071.x
211. Peng, W., Chen, J. Q., Liu, C., Malu, S., Creasy, C., Tetzlaff, M. T., et al. (2016). Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 6, 202-216. doi: 10.1158/2159-8290.CD-15-0283
212. Perretti, M., and Ahluwalia, A. (2000). The microcirculation and inflammation: site of action for glucocorticoids. Microcirculation 7, 147-161. doi: 10.1111/j.1549-8719.2000.tb00117.x
213. Peterson, T. E., Kirkpatrick, N. D., Huang, Y., Farrar, C. T., Marijt, K. A., Kloepper, J., et al. (2016). Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages. Proc. Natl. Acad. Sci. U.S.A. 113, 4470-4475. doi: 10.1073/pnas.1525349113
214. Pfeifer, G. P., Denissenko, M. F., Olivier, M., Tretyakova, N., Hecht, S. S., and Hainaut, P. (2002). Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene 21, 7435-7451. doi: 10.1038/sj.onc.1205803
215. Platanias, L. C. (2013). Interferons and their antitumor properties. J. Interferon Cytokine Res. 33, 143-144. doi: 10.1089/jir.2013.0019
216. Pleasance, E. D., Stephens, P. J., O'Meara, S., McBride, D. J., Meynert, A., Jones, D., et al. (2010). A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature 463, 184-190. doi: 10.1038/nature08629
217. Plimack, E. R., Lorusso, P. M., McCoon, P., Tang, W., Krebs, A. D., Curt, G., et al. (2013). AZD1480: a phase I study of a novel JAK2 inhibitor in solid tumors. Oncologist 18, 819-820. doi: 10.1634/theoncologist.2013-0198
218. Postow, M. A., and Hellmann, M. D. (2018). Adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 378, 1165. doi: 10.1056/NEJMc1801663
219. Postow, M. A., Sidlow, R., and Hellmann, M. D. (2018). Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 378, 158-168. doi: 10.1056/NEJMra1703481
220. Propper, D. J., Chao, D., Braybrooke, J. P., Bahl, P., Thavasu, P., Balkwill, F., et al. (2003). Low-dose IFN-gamma induces tumor MHC expression in metastatic malignant melanoma. Clin. Cancer Res. 9, 84-92
221. Pyonteck, S. M., Akkari, L., Schuhmacher, A. J., Bowman, R. L., Sevenich, L., Quail, D. F., et al. (2013). CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19, 1264-1272. doi: 10.1038/nm.3337
222. Qian, B. Z., Li, J., Zhang, H., Kitamura, T., Zhang, J., Campion, L. R., et al. (2011). CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222-225. doi: 10.1038/nature10138
223. Quail, D. F., and Joyce, J. A. (2013). Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423-1437. doi: 10.1038/nm.3394
224. Quail, D. F., Bowman, R. L., Akkari, L., Quick, M. L., Schuhmacher, A. J., Huse, J. T., et al. (2016). The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science 352:aad3018. doi: 10.1126/science.aad3018
225. Quintás-Cardama, A., Kantarjian, H., Cortes, J., and Verstovsek, S. (2011). Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat. Rev. Drug Discov. 10, 127-140. doi: 10.1038/nrd3264
226. Raedler, L. A. (2015). Jakafi(Ruxolitinib): first FDA-approved medication for the treatment of patients with polycythemia vera. Am. Health Drug Benefits 8, 75-79
227. Rahnamoun, H., Lu, H., Duttke, S. H., Benner, C., Glass, C. K., and Lauberth, S. M. (2017). Mutant p53 shapes the enhancer landscape of cancer cells in response to chronic immune signaling. Nat. Commun. 8, 754. doi: 10.1038/s41467-017-01117-y
228. Ridker, P. M., Everett, B. M., Thuren, T., MacFadyen, J. G., Chang, W. H., Ballantyne, C., et al. (2017a). Antiinflammatory therapy with canakinumab for Atherosclerotic disease. N. Engl. J. Med. 377, 1119-1131. doi: 10.1056/NEJMoa1707914
229. Ridker, P. M., MacFadyen, J. G., Thuren, T., Everett, B. M., Libby, P., Glynn, R. J., et al. (2017b). Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet 390, 1833-1842. doi: 10.1016/S0140-6736(17)32247-X
230. Robinson, B. D., and Jones, J. G. (2009). Tumor microenvironment of metastasis (TMEM): a novel tissue-based assay for metastatic risk in breast cancer. Future Oncol. 5, 919-921. doi: 10.2217/fon.09.79
231. Rock, C. L., Flatt, S. W., Thomson, C. A., Stefanick, M. L., Newman, V. A., Jones, L. A., et al. (2004). Effects of a high-fiber, low-fat diet intervention on serum concentrations of reproductive steroid hormones in women with a history of breast cancer. J. Clin. Oncol. 22, 2379-2387. doi: 10.1200/JCO.2004.09.025
232. Rønnov-Jessen, L., Petersen, O. W., and Bissell, M. J. (1996). Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol. Rev. 76, 69-125. doi: 10.1152/physrev.1996.76.1.69
233. Salgado, R., Junius, S., Benoy, I., Van Dam, P., Vermeulen, P., Van Marck, E., et al. (2003). Circulating interleukin-6 predicts survival in patients with metastatic breast cancer. Int. J. Cancer 103, 642-646. doi: 10.1002/ijc.10833
234. Sanchez-Alvarez, R., Martinez-Outschoorn, U. E., Lin, Z., Lamb, R., Hulit, J., Howell, A., et al. (2013). Ethanol exposure induces the cancer-associated fibroblast phenotype and lethal tumor metabolism: implications for breast cancer prevention. Cell Cycle 12, 289-301. doi: 10.4161/cc.23109
235. Schäfer, M., and Werner, S. (2008). Cancer as an overhealing wound: an old hypothesis revisited. Nat. Rev. Mol. Cell Biol. 9, 628-638. doi: 10.1038/nrm2455
236. Schmittnaegel, M., Rigamonti, N., Kadioglu, E., Cassará, A., Wyser Rmili, C., Kiialainen, A., et al. (2017). Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci. Transl. Med. 9:eaak9670. doi: 10.1126/scitranslmed.aak9670
237. Schreiner, B., Mitsdoerffer, M., Kieseier, B. C., Chen, L., Hartung, H. P., Weller, M., et al. (2004). Interferon-β enhances monocyte and dendritic cell expression of B7-H1 (PD-L1), a strong inhibitor of autologous T-cell activation: relevance for the immune modulatory effect in multiple sclerosis. J. Neuroimmunol. 155, 172-182. doi: 10.1016/j.jneuroim.2004.06.013
238. Seitz, H. K., and Becker, P. (2007). Alcohol metabolism and cancer risk. Alcohol Res. Health 30, 38-41, 44-37
239. Sevenich, L., Bowman, R. L., Mason, S. D., Quail, D. F., Rapaport, F., Elie, B. T., et al. (2014). Analysis of tumour-and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S. Nat. Cell Biol. 16, 876-888. doi: 10.1038/ncb3011
240. Shaked, H., Hofseth, L. J., Chumanevich, A., Chumanevich, A. A., Wang, J., Wang, Y., et al. (2012). Chronic epithelial NF-kappaB activation accelerates APC loss and intestinal tumor initiation through iNOS up-regulation. Proc. Natl. Acad. Sci. U.S.A. 109, 14007-14012. doi: 10.1073/pnas.1211509109
241. Sharma, P., and Allison, J. P. (2015). Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205-214. doi: 10.1016/j.cell.2015.03.030
242. Shi, Z., Yang, W. M., Chen, L. P., Yang, D. H., Zhou, Q., Zhu, J., et al. (2012). Enhanced chemosensitization in multidrug-resistant human breast cancer cells by inhibition of IL-6 and IL-8 production. Breast Cancer Res. Treat. 135, 737-747. doi: 10.1007/s10549-012-2196-0
243. Shiao, S. L., Ruffell, B., DeNardo, D. G., Faddegon, B. A., Park, C. C., and Coussens, L. M. (2015). TH2-Polarized CD4(+) T Cells and macrophages limit efficacy of radiotherapy. Cancer Immunol. Res. 3, 518-525. doi: 10.1158/2326-6066.CIR-14-0232
244. Shiels, M. S., Katki, H. A., Freedman, N. D., Purdue, M. P., Wentzensen, N., Trabert, B., et al. (2014). Cigarette smoking and variations in systemic immune and inflammation markers. J. Natl. Cancer Inst. 106:dju294. doi: 10.1093/jnci/dju294
245. Shlush, L. I., Zandi, S., Mitchell, A., Chen, W. C., Brandwein, J. M., Gupta, V., et al. (2014). Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 506, 328-333. doi: 10.1038/nature13038
246. Singha, B., Gatla, H. R., Manna, S., Chang, T. P., Sanacora, S., Poltoratsky, V., et al. (2014). Proteasome inhibition increases recruitment of IkappaB kinase beta (IKKbeta), S536P-p65, and transcription factor EGR1 to interleukin-8 (IL-8) promoter, resulting in increased IL-8 production in ovarian cancer cells. J. Biol. Chem. 289, 2687-2700. doi: 10.1074/jbc. M113.502641
247. Snyder, A., Makarov, V., Merghoub, T., Yuan, J., Zaretsky, J. M., Desrichard, A., et al. (2014). Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189-2199. doi: 10.1056/NEJMoa1406498
248. Song, M., and Chan, A. T. (2017). Diet, gut microbiota, and colorectal cancer prevention: a review of potential mechanisms and promising targets for future research. Curr. Colorectal Cancer Rep. 13, 429-439. doi: 10.1007/s11888-017-0389-y
249. Sopori, M. (2002). Effects of cigarette smoke on the immune system. Nat. Rev. Immunol. 2, 372-377. doi: 10.1038/nri803
250. Spranger, S., Bao, R., and Gajewski, T. F. (2015). Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523, 231-235. doi: 10.1038/nature14404
251. Stein, B. L., and Tiu, R. V. (2013). Biological rationale and clinical use of interferon in the classical BCR-ABL-negative myeloproliferative neoplasms. J. Interferon Cytokine Res. 33, 145-153. doi: 10.1089/jir.2012.0120
252. Tada, M., Ohashi, M., Shiratori, Y., Okudaira, T., Komatsu, Y., Kawabe, T., et al. (1996). Analysis of K-ras gene mutation in hyperplastic duct cells of the pancreas without pancreatic disease. Gastroenterology 110, 227-231. doi: 10.1053/gast.1996.v110.pm8536861
253. Talmadge, J. E., and Gabrilovich, D. I. (2013). History of myeloid-derived suppressor cells. Nat. Rev. Cancer 13, 739-752. doi: 10.1038/nrc3581
254. Talpaz, M., Hehlmann, R., Quintas-Cardama, A., Mercer, J., and Cortes, J. (2013). Re-emergence of interferon-a in the treatment of chronic myeloid leukemia. Leukemia 27, 803-812. doi: 10.1038/leu.2012.313
255. Tarafdar, A., Hopcroft, L. E., Gallipoli, P., Pellicano, F., Cassels, J., Hair, A., et al. (2017). CML cells actively evade host immune surveillance through cytokine-mediated downregulation of MHC-II expression. Blood 129, 199-208. doi: 10.1182/blood-2016-09-742049
256. Tian, H., Callahan, C. A., DuPree, K. J., Darbonne, W. C., Ahn, C. P., Scales, S. J., et al. (2009). Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc. Natl. Acad. Sci. U.S.A. 106, 4254-4259. doi: 10.1073/pnas.0813203106
257. Tsai, W. L., and Chung, R. T. (2010). Viral hepatocarcinogenesis. Oncogene 29, 2309-2324. doi: 10.1038/onc.2010.36
258. Tuhkanen, H., Anttila, M., Kosma, V. M., Ylä-Herttuala, S., Heinonen, S., Kuronen, A., et al. (2004). Genetic alterations in the peritumoral stromal cells of malignant and borderline epithelial ovarian tumors as indicated by allelic imbalance on chromosome 3p. Int. J. Cancer 109, 247-252. doi: 10.1002/ijc.11733
259. Ulrich, C. M., Bigler, J., and Potter, J. D. (2006). Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics. Nat. Rev. Cancer 6, 130-140. doi: 10.1038/nrc1801
260. Underhill, D. M., and Goodridge, H. S. (2012). Information processing during phagocytosis. Nat. Rev. Immunol. 12, 492-502. doi: 10.1038/nri3244
261. United States Public Health Service, and Office of the Surgeon General. (2010). How Tobacco Smoke Causes Disease: the Biology and Behavioral Basis for Smoking-Attributable Disease: a Report of the Surgeon General. (Rockville, MD; Washington, DC: U.S. Dept. of Health and Human Services; Public Health Service For sale by the Supt. of Docs U.S. G.P.O.)
262. Vang, R., Levine, D. A., Soslow, R. A., Zaloudek, C., Shih Ie, M., and Kurman, R. J. (2016). Molecular alterations of TP53 are a defining feature of ovarian high-grade serous carcinoma: a rereview of cases lacking TP53 mutations in The Cancer Genome Atlas Ovarian Study. Int. J. Gynecol. Pathol. 35, 48-55. doi: 10.1097/PGP.0000000000000207
263. Vanharanta, S., Shu, W., Brenet, F., Hakimi, A. A., Heguy, A., Viale, A., et al. (2013). Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer. Nat. Med. 19, 50-56. doi: 10.1038/nm.3029
264. Varol, C., and Sagi, I. (2017). Phagocyte-extracellular matrix crosstalk empowers tumor development and dissemination. FEBS J. 285, 734-751. doi: 10.1111/febs.14317
265. Velicer, C. M., Heckbert, S. R., Lampe, J. W., Potter, J. D., Robertson, C. A., and Taplin, S. H. (2004). Antibiotic use in relation to the risk of breast cancer. JAMA 291, 827-835. doi: 10.1001/jama.291.7.827
266. Verstovsek, S., Kantarjian, H., Mesa, R. A., Pardanani, A. D., Cortes-Franco, J., Thomas, D. A., et al. (2010). Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N. Engl. J. Med. 363, 1117-1127. doi: 10.1056/NEJMoa1002028
267. Viaud, S., Saccheri, F., Mignot, G., Yamazaki, T., Daillère, R., Hannani, D., et al. (2013). The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342, 971-976. doi: 10.1126/science.1240537
268. Vlantis, K., Wullaert, A., Sasaki, Y., Schmidt-Supprian, M., Rajewsky, K., Roskams, T., et al. (2011). Constitutive IKK2 activation in intestinal epithelial cells induces intestinal tumors in mice. J. Clin. Invest. 121, 2781-2793. doi: 10.1172/JCI45349
269. Voorhees, P. M., Chen, Q., Kuhn, D. J., Small, G. W., Hunsucker, S. A., Strader, J. S., et al. (2007). Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma. Clin. Cancer Res. 13, 6469-6478. doi: 10.1158/1078-0432.CCR-07-1293
270. Wang, K., and Karin, M. (2015). Tumor-elicited inflammation and colorectal cancer. Adv. Cancer Res. 128, 173-196. doi: 10.1016/bs.acr.2015.04.014
271. Warren, G. W., and Cummings, K. M. (2013). Tobacco and lung cancer: risks, trends, and outcomes in patients with cancer. Am. Soc. Clin. Oncol. 359-364. doi: 10.1200/EdBook_AM.2013.33.359
272. Weber, F., Xu, Y., Zhang, L., Patocs, A., Shen, L., Platzer, P., et al. (2007). Microenvironmental genomic alterations and clinicopathological behavior in head and neck squamous cell carcinoma. JAMA 297, 187-195. doi: 10.1001/jama.297.2.187
273. Wyckoff, J., Wang, W., Lin, E. Y., Wang, Y., Pixley, F., Stanley, E. R., et al. (2004). A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res. 64, 7022-7029. doi: 10.1158/0008-5472.CAN-04-1449
274. Xiao, Q., Zhou, D., Rucki, A. A., Williams, J., Zhou, J., Mo, G., et al. (2016). Cancer-associated fibroblasts in pancreatic cancer are reprogrammed by tumor-induced alterations in genomic DNA methylation. Cancer Res. 76, 5395-5404. doi: 10.1158/0008-5472.CAN-15-3264
275. Xie, K. (2001). Interleukin-8 and human cancer biology. Cytokine Growth Factor Rev. 12, 375-391. doi: 10.1016/S1359-6101(01)00016-8
276. Xu, M., Chen, G., Fu, W., Liao, M., Frank, J. A., Bower, K. A., et al. (2012). Ethanol disrupts vascular endothelial barrier: implication in cancer metastasis. Toxicol. Sci. 127, 42-53. doi: 10.1093/toxsci/kfs087
277. Xue, J., Schmidt, S. V., Sander, J., Draffehn, A., Krebs, W., Quester, I., et al. (2014). Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40, 274-288. doi: 10.1016/j.immuni.2014.01.006
278. Yagishita, H., Yoshida, T., Ishiguro, K., Numata, Y., and Okayasu, I. (2008). Epithelial and stromal genetic instability linked to tumor suppressor genes in ulcerative colitis-associated tumorigenesis. Scand. J. Gastroenterol. 43, 559-566. doi: 10.1080/00365520701817419
279. Yan, D., Kowal, J., Akkari, L., Schuhmacher, A. J., Huse, J. T., West, B. L., et al. (2017). Inhibition of colony stimulating factor-1 receptor abrogates microenvironment-mediated therapeutic resistance in gliomas. Oncogene 36, 6049-6058. doi: 10.1038/onc.2017.261
280. Yan, L., Anderson, G. M., DeWitte, M., and Nakada, M. T. (2006). Therapeutic potential of cytokine and chemokine antagonists in cancer therapy. Eur. J. Cancer 42, 793-802. doi: 10.1016/j.ejca.2006.01.013
281. Yang, L., and Karin, M. (2014). Roles of tumor suppressors in regulating tumor-associated inflammation. Cell Death Differ. 21, 1677-1686. doi: 10.1038/cdd.2014.131
282. Yang, X. D., Corvalan, J. R., Wang, P., Roy, C. M., and Davis, C. G. (1999). Fully human anti-interleukin-8 monoclonal antibodies: potential therapeutics for the treatment of inflammatory disease states. J. Leukoc. Biol. 66, 401-410. doi: 10.1002/jlb.66.3.401
283. Yang, X., Wang, X., Liu, D., Yu, L., Xue, B., and Shi, H. (2014). Epigenetic regulation of macrophage polarization by DNA methyltransferase 3b. Mol. Endocrinol. 28, 565-574. doi: 10.1210/me.2013-1293
284. Yin, J., Harpaz, N., Tong, Y., Huang, Y., Laurin, J., Greenwald, B. D., et al. (1993). p53 point mutations in dysplastic and cancerous ulcerative colitis lesions. Gastroenterology 104, 1633-1639. doi: 10.1016/0016-5085(93)90639-T
285. Ying, H., Elpek, K. G., Vinjamoori, A., Zimmerman, S. M., Chu, G. C., Yan, H., et al. (2011). PTEN is a major tumor suppressor in pancreatic ductal adenocarcinoma and regulates an NF-kappaB-cytokine network. Cancer Discov. 1, 158-169. doi: 10.1158/2159-8290.CD-11-0031
286. Young, A. L., Challen, G. A., Birmann, B. M., and Druley, T. E. (2016). Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat. Commun. 7:12484. doi: 10.1038/ncomms12484
287. Zahreddine, H., and Borden, K. L. (2013). Mechanisms and insights into drug resistance in cancer. Front. Pharmacol. 4:28. doi: 10.3389/fphar.2013.00028
288. Zeisberg, E. M., and Zeisberg, M. (2013). The role of promoter hypermethylation in fibroblast activation and fibrogenesis. J. Pathol. 229, 264-273. doi: 10.1002/path.4120
289. Zeiser, R., Burchert, A., Lengerke, C., Verbeek, M., Maas-Bauer, K., Metzelder, S. K., et al. (2015). Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia 29, 2062-2068. doi: 10.1038/leu.2015.212
290. Zhang, G. J., and Adachi, I. (1999). Serum interleukin-6 levels correlate to tumor progression and prognosis in metastatic breast carcinoma. Anticancer Res. 19, 1427-1432
291. Zhang, Q., Zhao, K., Shen, Q., Han, Y., Gu, Y., Li, X., et al. (2015). Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 525, 389-393. doi: 10.1038/nature15252
292. Zhao, X., Xu, Z., and Li, H. (2017). NSAIDs use and reduced metastasis in cancer patients: results from a meta-analysis. Sci. Rep. 7:1875. doi: 10.1038/s41598-017-01644-0
293. Zhu, T. S., Costello, M. A., Talsma, C. E., Flack, C. G., Crowley, J. G., Hamm, L. L., et al. (2011). Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells. Cancer Res. 71, 6061-6072. doi: 10.1158/0008-5472.CAN-10-4269
294. Zhu, Y., Herndon, J. M., Sojka, D. K., Kim, K. W., Knolhoff, B. L., Zuo, C., et al. (2017). Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity 47, 597. doi: 10.1016/j.immuni.2017.08.018
295. Zhu, Y., Knolhoff, B. L., Meyer, M. A., Nywening, T. M., West, B. L., Luo, J., et al. (2014). CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 74, 5057-5069. doi: 10.1158/0008-5472.CAN-13-3723