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Refractory Mechanisms

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Renal Cell Carcinoma

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Abstract

Vascular endothelial growth factor (VEGF)-targeted agents have brought significant progress in pharmacotherapy of advanced renal cell carcinoma (RCC). Some RCCs, however, appear to have innate resistance to treatment. Moreover, majority of patients who primarily respond to VEGF-targeted therapy eventually develop disease progression after prolonged treatment. The mechanism of resistance is supposed to be so multifactorial that it cannot be explained by single molecular events. Despite various factors including cytokines, bone marrow-derived cells, microenvironment, and genetic or epigenetic abnormality could be involved, tumor hypoxia seems to play one of crucial roles in most of the processes. The multiple mechanism in developing drug resistance might just represent the diversity of cellular response to hypoxia and nutrient deprivation, induced by the disruption of the blood vessels. In this chapter we comprehensively review current efforts aiming to clarify these process and to develop pharmacological strategies leading to overcome the drug resistance in RCC.

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References

  1. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134

    Article  CAS  PubMed  Google Scholar 

  2. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124

    Article  CAS  PubMed  Google Scholar 

  3. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370:2103–2111

    Article  PubMed  Google Scholar 

  4. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarba JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28:1061–1068

    Article  CAS  PubMed  Google Scholar 

  5. Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ (2011) Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 378:1931–1939

    Article  CAS  PubMed  Google Scholar 

  6. Busch J, Seidel C, Weikert S, Wolff I, Kempkensteffen C, Weinkauf L, Hinz S, Magheli A, Miller K, Grunwald V (2011) Intrinsic resistance to tyrosine kinase inhibitors is associated with poor clinical outcome in metastatic renal cell carcinoma. BMC Cancer 11:295

    Article  PubMed  PubMed Central  Google Scholar 

  7. Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schoffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R (2009) Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol 10:757–763

    Article  CAS  PubMed  Google Scholar 

  8. Tsuzuki T, Sassa N, Shimoyama Y, Morikawa T, Shiroki R, Kuroda M, Fukatsu A, Kuwahara K, Yoshino Y, Hattori R, Gotoh M (2014) Tyrosine kinase inhibitor-induced vasculopathy in clear cell renal cell carcinoma: an unrecognized antitumour mechanism. Histopathology 64:484–493

    Article  PubMed  Google Scholar 

  9. Fisher R, Larkin J, Swanton C (2012) Inter and intratumour heterogeneity: a barrier to individualized medical therapy in renal cell carcinoma? Front Oncol 2:49

    PubMed  PubMed Central  Google Scholar 

  10. Vasudev NS, Goh V, Juttla JK, Thompson VL, Larkin JM, Gore M, Nathan PD, Reynolds AR (2013) Changes in tumour vessel density upon treatment with anti-angiogenic agents: relationship with response and resistance to therapy. Br J Cancer 109:1230–1242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Smith AD, Lieber ML, Shah SN (2010) Assessing tumor response and detecting recurrence in metastatic renal cell carcinoma on targeted therapy: importance of size and attenuation on contrast-enhanced CT. AJR Am J Roentgenol 194:157–165

    Article  PubMed  Google Scholar 

  12. Hirota K, Semenza GL (2006) Regulation of angiogenesis by hypoxia-inducible factor 1. Crit Rev Oncol Hematol 59:15–26

    Article  PubMed  Google Scholar 

  13. Yu JL, Rak JW, Coomber BL, Hicklin DJ, Kerbel RS (2002) Effect of p53 status on tumor response to antiangiogenic therapy. Science 295:1526–1528

    Article  CAS  PubMed  Google Scholar 

  14. Rapisarda A, Melillo G (2009) Role of the hypoxic tumor microenvironment in the resistance to anti-angiogenic therapies. Drug Resist Updat 12:74–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. O’Hare T, Eide CA, Deininger MW (2007) Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 110:2242–2249

    Article  PubMed  Google Scholar 

  16. Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B (2005) EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786–792

    Article  CAS  PubMed  Google Scholar 

  17. Hammers HJ, Verheul HM, Salumbides B, Sharma R, Rudek M, Jaspers J, Shah P, Ellis L, Shen L, Paesante S, Dykema K, Furge K, Teh BT, Netto G, Pili R (2010) Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma: evidence from a xenograft study. Mol Cancer Ther 9:1525–1535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhang L, Bhasin M, Schor-Bardach R, Wang X, Collins MP, Panka D, Putheti P, Signoretti S, Alsop DC, Libermann T, Atkins MB, Mier JW, Goldberg SN, Bhatt RS (2011) Resistance of renal cell carcinoma to sorafenib is mediated by potentially reversible gene expression. PLoS One 6:e19144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. St Croix B, Rago C, Velculescu V, Traverso G, Romans KE, Montgomery E, Lal A, Riggins GJ, Lengauer C, Vogelstein B, Kinzler KW (2000) Genes expressed in human tumor endothelium. Science 289:1197–1202

    Article  CAS  PubMed  Google Scholar 

  20. Bussolati B, Deambrosis I, Russo S, Deregibus MC, Camussi G (2003) Altered angiogenesis and survival in human tumor-derived endothelial cells. FASEB J 17:1159–1161

    CAS  PubMed  Google Scholar 

  21. Allport JR, Weissleder R (2003) Murine Lewis lung carcinoma-derived endothelium expresses markers of endothelial activation and requires tumor-specific extracellular matrix in vitro. Neoplasia 5:205–217

    Article  PubMed  PubMed Central  Google Scholar 

  22. Streubel B, Chott A, Huber D, Exner M, Jager U, Wagner O, Schwarzinger I (2004) Lymphoma-specific genetic aberrations in microvascular endothelial cells in B-cell lymphomas. N Engl J Med 351:250–259

    Article  CAS  PubMed  Google Scholar 

  23. Hida K, Hida Y, Amin DN, Flint AF, Panigrahy D, Morton CC, Klagsbrun M (2004) Tumor-associated endothelial cells with cytogenetic abnormalities. Cancer Res 64:8249–8255

    Article  CAS  PubMed  Google Scholar 

  24. Hida K, Klagsbrun M (2005) A new perspective on tumor endothelial cells: unexpected chromosome and centrosome abnormalities. Cancer Res 65:2507–2510

    Article  CAS  PubMed  Google Scholar 

  25. Rubenstein JL, Kim J, Ozawa T, Zhang M, Westphal M, Deen DF, Shuman MA (2000) Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia 2:306–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kunkel P, Ulbricht U, Bohlen P, Brockmann MA, Fillbrandt R, Stavrou D, Westphal M, Lamszus K (2001) Inhibition of glioma angiogenesis and growth in vivo by systemic treatment with a monoclonal antibody against vascular endothelial growth factor receptor-2. Cancer Res 61:6624–6628

    CAS  PubMed  Google Scholar 

  27. Blouw B, Song H, Tihan T, Bosze J, Ferrara N, Gerber HP, Johnson RS, Bergers G (2003) The hypoxic response of tumors is dependent on their microenvironment. Cancer Cell 4:133–146

    Article  CAS  PubMed  Google Scholar 

  28. Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, Inoue M, Bergers G, Hanahan D, Casanovas O (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15:220–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS (2009) Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15:232–239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lu KV, Chang JP, Parachoniak CA, Pandika MM, Aghi MK, Meyronet D, Isachenko N, Fouse SD, Phillips JJ, Cheresh DA, Park M, Bergers G (2012) VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell 22:21–35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sennino B, Ishiguro-Oonuma T, Wei Y, Naylor RM, Williamson CW, Bhagwandin V, Tabruyn SP, You WK, Chapman HA, Christensen JG, Aftab DT, McDonald DM (2012) Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov 2:270–287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shojaei F, Lee JH, Simmons BH, Wong A, Esparza CO, Plumlee PA, Feng J, Stewart AE, Hu-Lowe DD, Christensen JG (2010) HGF/c-Met acts as an alternative angiogenic pathway in sunitinib-resistant tumors. Cancer Res 70:10090–10100

    Article  CAS  PubMed  Google Scholar 

  33. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, Qian F, Chu F, Bentzien F, Cancilla B, Orf J, You A, Laird AD, Engst S, Lee L, Lesch J, Chou YC, Joly AH (2011) Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 10:2298–2308

    Article  CAS  PubMed  Google Scholar 

  34. Choueiri TK, Pal SK, McDermott DF, Morrissey S, Ferguson KC, Holland J, Kaelin WG, Dutcher JP (2014) A phase I study of cabozantinib (XL184) in patients with renal cell cancer. Ann Oncol 25:1603–1608

    Article  CAS  PubMed  Google Scholar 

  35. Casanovas O, Hicklin DJ, Bergers G, Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8:299–309

    Article  CAS  PubMed  Google Scholar 

  36. Welti JC, Gourlaouen M, Powles T, Kudahetti SC, Wilson P, Berney DM, Reynolds AR (2011) Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib. Oncogene 30:1183–1193

    Article  CAS  PubMed  Google Scholar 

  37. Bello E, Colella G, Scarlato V, Oliva P, Berndt A, Valbusa G, Serra SC, D’Incalci M, Cavalletti E, Giavazzi R, Damia G, Camboni G (2011) E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models. Cancer Res 71:1396–1405

    Article  CAS  PubMed  Google Scholar 

  38. Motzer RJ, Porta C, Vogelzang NJ, Sternberg CN, Szczylik C, Zolnierek J, Kollmannsberger C, Rha SY, Bjarnason GA, Melichar B, De Giorgi U, Grunwald V, Davis ID, Lee JL, Esteban E, Urbanowitz G, Cai C, Squires M, Marker M, Shi MM, Escudier B (2014) Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol 15:286–296

    Article  CAS  PubMed  Google Scholar 

  39. Richard S, Gardie B, Couve S, Gad S (2013) Von Hippel-Lindau: how a rare disease illuminates cancer biology. Semin Cancer Biol 23:26–37

    Article  CAS  PubMed  Google Scholar 

  40. Mizukami Y, Jo WS, Duerr EM, Gala M, Li J, Zhang X, Zimmer MA, Iliopoulos O, Zukerberg LR, Kohgo Y, Lynch MP, Rueda BR, Chung DC (2005) Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cells. Nat Med 11:992–997

    CAS  PubMed  Google Scholar 

  41. Wysoczynski M, Shin DM, Kucia M, Ratajczak MZ (2010) Selective upregulation of interleukin-8 by human rhabdomyosarcomas in response to hypoxia: therapeutic implications. Int J Cancer 126:371–381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Huang D, Ding Y, Zhou M, Rini BI, Petillo D, Qian CN, Kahnoski R, Futreal PA, Furge KA, Teh BT (2010) Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res 70:1063–1071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676

    Article  CAS  PubMed  Google Scholar 

  44. Loges S, Schmidt T, Carmeliet P (2009) “Antimyeloangiogenic” therapy for cancer by inhibiting PlGF. Clin Cancer Res 15:3648–3653

    Article  CAS  PubMed  Google Scholar 

  45. Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, Wu Y, Bono F, Devy L, Beck H, Scholz D, Acker T, DiPalma T, Dewerchin M, Noel A, Stalmans I, Barra A, Blacher S, VandenDriessche T, Ponten A, Eriksson U, Plate KH, Foidart JM, Schaper W, Charnock-Jones DS, Hicklin DJ, Herbert JM, Collen D, Persico MG (2001) Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 7:575–583

    Article  CAS  PubMed  Google Scholar 

  46. Luttun A, Brusselmans K, Fukao H, Tjwa M, Ueshima S, Herbert JM, Matsuo O, Collen D, Carmeliet P, Moons L (2002) Loss of placental growth factor protects mice against vascular permeability in pathological conditions. Biochem Biophys Res Commun 295:428–434

    Article  CAS  PubMed  Google Scholar 

  47. Luttun A, Tjwa M, Moons L, Wu Y, Angelillo-Scherrer A, Liao F, Nagy JA, Hooper A, Priller J, De Klerck B, Compernolle V, Daci E, Bohlen P, Dewerchin M, Herbert JM, Fava R, Matthys P, Carmeliet G, Collen D, Dvorak HF, Hicklin DJ, Carmeliet P (2002) Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 8:831–840

    CAS  PubMed  Google Scholar 

  48. Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, Chorianopoulos E, Liesenborghs L, Koch M, De Mol M, Autiero M, Wyns S, Plaisance S, Moons L, van Rooijen N, Giacca M, Stassen JM, Dewerchin M, Collen D, Carmeliet P (2007) Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131:463–475

    Article  CAS  PubMed  Google Scholar 

  49. Rini BI, Michaelson MD, Rosenberg JE, Bukowski RM, Sosman JA, Stadler WM, Hutson TE, Margolin K, Harmon CS, DePrimo SE, Kim ST, Chen I, George DJ (2008) Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol 26:3743–3748

    Article  CAS  PubMed  Google Scholar 

  50. Bessho H, Wong B, Huang D, Siew EY, Tan J, Ong CK, Tan SY, Matsumoto K, Iwamura M, Teh BT (2015) Inhibition of placental growth factor in renal cell carcinoma. Anticancer Res 35:531–541

    CAS  PubMed  Google Scholar 

  51. Augustin HG, Koh GY, Thurston G, Alitalo K (2009) Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol 10:165–177

    Article  CAS  PubMed  Google Scholar 

  52. Rigamonti N, Kadioglu E, Keklikoglou I, Wyser Rmili C, Leow CC, De Palma M (2014) Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade. Cell Rep 8:696–706

    Article  CAS  PubMed  Google Scholar 

  53. Hashizume H, Falcon BL, Kuroda T, Baluk P, Coxon A, Yu D, Bready JV, Oliner JD, McDonald DM (2010) Complementary actions of inhibitors of angiopoietin-2 and VEGF on tumor angiogenesis and growth. Cancer Res 70:2213–2223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Leow CC, Coffman K, Inigo I, Breen S, Czapiga M, Soukharev S, Gingles N, Peterson N, Fazenbaker C, Woods R, Jallal B, Ricketts SA, Lavallee T, Coats S, Chang Y (2012) MEDI3617, a human anti-angiopoietin 2 monoclonal antibody, inhibits angiogenesis and tumor growth in human tumor xenograft models. Int J Oncol 40:1321–1330

    CAS  PubMed  Google Scholar 

  55. Wang X, Bullock AJ, Zhang L, Wei L, Yu D, Mahagaokar K, Alsop DC, Mier JW, Atkins MB, Coxon A, Oliner J, Bhatt RS (2014) The role of angiopoietins as potential therapeutic targets in renal cell carcinoma. Transl Oncol 7:188–195

    Article  PubMed  PubMed Central  Google Scholar 

  56. Bergers G, Song S (2005) The role of pericytes in blood-vessel formation and maintenance. Neuro-Oncology 7:452–464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Helfrich I, Schadendorf D (2011) Blood vessel maturation, vascular phenotype and angiogenic potential in malignant melanoma: one step forward for overcoming anti-angiogenic drug resistance? Mol Oncol 5:137–149

    Article  CAS  PubMed  Google Scholar 

  58. Helfrich I, Scheffrahn I, Bartling S, Weis J, von Felbert V, Middleton M, Kato M, Ergun S, Augustin HG, Schadendorf D (2010) Resistance to antiangiogenic therapy is directed by vascular phenotype, vessel stabilization, and maturation in malignant melanoma. J Exp Med 207:491–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592–603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Pietras K, Hanahan D (2005) A multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol 23:939–952

    Article  CAS  PubMed  Google Scholar 

  61. Xian X, Hakansson J, Stahlberg A, Lindblom P, Betsholtz C, Gerhardt H, Semb H (2006) Pericytes limit tumor cell metastasis. J Clin Invest 116:642–651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hainsworth JD, Spigel DR, Sosman JA, Burris HA 3rd, Farley C, Cucullu H, Yost K, Hart LL, Sylvester L, Waterhouse DM, Greco FA (2007) Treatment of advanced renal cell carcinoma with the combination bevacizumab/erlotinib/imatinib: a phase I/II trial. Clin Genitourin Cancer 5:427–432

    Article  CAS  PubMed  Google Scholar 

  63. Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. De Palma M, Venneri MA, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, Naldini L (2005) Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8:211–226

    Article  CAS  PubMed  Google Scholar 

  65. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y, Matrisian LM, Carbone DP, Lin PC (2004) Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6:409–421

    Article  CAS  PubMed  Google Scholar 

  67. Bunt SK, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S (2006) Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression. J Immunol 176:284–290

    Article  CAS  PubMed  Google Scholar 

  68. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858–864

    Article  CAS  PubMed  Google Scholar 

  69. Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegue E, Song H, Vandenberg S, Johnson RS, Werb Z, Bergers G (2008) HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13:206–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Shaked Y, Ciarrocchi A, Franco M, Lee CR, Man S, Cheung AM, Hicklin DJ, Chaplin D, Foster FS, Benezra R, Kerbel RS (2006) Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 313:1785–1787

    Article  CAS  PubMed  Google Scholar 

  71. Zagzag D, Krishnamachary B, Yee H, Okuyama H, Chiriboga L, Ali MA, Melamed J, Semenza GL (2005) Stromal cell-derived factor-1alpha and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor. Cancer Res 65:6178–6188

    Article  CAS  PubMed  Google Scholar 

  72. Pan J, Mestas J, Burdick MD, Phillips RJ, Thomas GV, Reckamp K, Belperio JA, Strieter RM (2006) Stromal derived factor-1 (SDF-1/CXCL12) and CXCR4 in renal cell carcinoma metastasis. Mol Cancer 5:56

    Article  PubMed  PubMed Central  Google Scholar 

  73. Panka DJ, Liu Q, Geissler AK, Mier JW (2013) Effects of HDM2 antagonism on sunitinib resistance, p53 activation, SDF-1 induction, and tumor infiltration by CD11b+/Gr-1+ myeloid derived suppressor cells. Mol Cancer 12:17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Tsai YP, Wu KJ (2014) Epigenetic regulation of hypoxia-responsive gene expression: focusing on chromatin and DNA modifications. Int J Cancer 134:249–256

    Article  PubMed  Google Scholar 

  75. Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A, Davies H, Edkins S, Hardy C, Latimer C, Teague J, Andrews J, Barthorpe S, Beare D, Buck G, Campbell PJ, Forbes S, Jia M, Jones D, Knott H, Kok CY, Lau KW, Leroy C, Lin ML, McBride DJ, Maddison M, Maguire S, McLay K, Menzies A, Mironenko T, Mulderrig L, Mudie L, O’Meara S, Pleasance E, Rajasingham A, Shepherd R, Smith R, Stebbings L, Stephens P, Tang G, Tarpey PS, Turrell K, Dykema KJ, Khoo SK, Petillo D, Wondergem B, Anema J, Kahnoski RJ, Teh BT, Stratton MR, Futreal PA (2010) Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463:360–363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gibbs RA, Marston LW (2013) Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499:43–49

    Article  Google Scholar 

  77. Sato Y, Yoshizato T, Shiraishi Y, Maekawa S, Okuno Y, Kamura T, Shimamura T, Sato-Otsubo A, Nagae G, Suzuki H, Nagata Y, Yoshida K, Kon A, Suzuki Y, Chiba K, Tanaka H, Niida A, Fujimoto A, Tsunoda T, Morikawa T, Maeda D, Kume H, Sugano S, Fukayama M, Aburatani H, Sanada M, Miyano S, Homma Y, Ogawa S (2013) Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet 45:860–867

    Article  CAS  PubMed  Google Scholar 

  78. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366:883–892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhou VW, Goren A, Bernstein BE (2011) Charting histone modifications and the functional organization of mammalian genomes. Nat Rev Genet 12:7–18

    Article  PubMed  Google Scholar 

  80. Rogenhofer S, Kahl P, Mertens C, Hauser S, Hartmann W, Buttner R, Muller SC, von Ruecker A, Ellinger J (2012) Global histone H3 lysine 27 (H3K27) methylation levels and their prognostic relevance in renal cell carcinoma. BJU Int 109:459–465

    Article  CAS  PubMed  Google Scholar 

  81. Kanao K, Mikami S, Mizuno R, Shinojima T, Murai M, Oya M (2008) Decreased acetylation of histone H3 in renal cell carcinoma: a potential target of histone deacetylase inhibitors. J Urol 180:1131–1136

    Article  CAS  PubMed  Google Scholar 

  82. Ellinger J, Kahl P, Mertens C, Rogenhofer S, Hauser S, Hartmann W, Bastian PJ, Buttner R, Muller SC, von Ruecker A (2010) Prognostic relevance of global histone H3 lysine 4 (H3K4) methylation in renal cell carcinoma. Int J Cancer 127:2360–2366

    Article  CAS  PubMed  Google Scholar 

  83. Pollard PJ, Loenarz C, Mole DR, McDonough MA, Gleadle JM, Schofield CJ, Ratcliffe PJ (2008) Regulation of Jumonji-domain-containing histone demethylases by hypoxia-inducible factor (HIF)-1alpha. Biochem J 416:387–394

    Article  CAS  PubMed  Google Scholar 

  84. Beyer S, Kristensen MM, Jensen KS, Johansen JV, Staller P (2008) The histone demethylases JMJD1A and JMJD2B are transcriptional targets of hypoxia-inducible factor HIF. J Biol Chem 283:36542–36552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Xia X, Lemieux ME, Li W, Carroll JS, Brown M, Liu XS, Kung AL (2009) Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis. Proc Natl Acad Sci U S A 106:4260–4265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Krieg AJ, Rankin EB, Chan D, Razorenova O, Fernandez S, Giaccia AJ (2010) Regulation of the histone demethylase JMJD1A by hypoxia-inducible factor 1 alpha enhances hypoxic gene expression and tumor growth. Mol Cell Biol 30:344–353

    Article  CAS  PubMed  Google Scholar 

  87. Osawa T, Tsuchida R, Muramatsu M, Shimamura T, Wang F, Suehiro J, Kanki Y, Wada Y, Yuasa Y, Aburatani H, Miyano S, Minami T, Kodama T, Shibuya M (2013) Inhibition of histone demethylase JMJD1A improves anti-angiogenic therapy and reduces tumor-associated macrophages. Cancer Res 73:3019–3028

    Article  CAS  PubMed  Google Scholar 

  88. Gotink KJ, Broxterman HJ, Labots M, de Haas RR, Dekker H, Honeywell RJ, Rudek MA, Beerepoot LV, Musters RJ, Jansen G, Griffioen AW, Assaraf YG, Pili R, Peters GJ, Verheul HM (2011) Lysosomal sequestration of sunitinib: a novel mechanism of drug resistance. Clin Cancer Res 17:7337–7346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Mikami S, Oya M, Mizuno R, Kosaka T, Katsube K, Okada Y (2014) Invasion and metastasis of renal cell carcinoma. Med Mol Morphol 47:63–67

    Article  CAS  PubMed  Google Scholar 

  90. Mikami S, Katsube K, Oya M, Ishida M, Kosaka T, Mizuno R, Mukai M, Okada Y (2011) Expression of Snail and Slug in renal cell carcinoma: E-cadherin repressor Snail is associated with cancer invasion and prognosis. Lab Investig 91:1443–1458

    Article  CAS  PubMed  Google Scholar 

  91. Frederick BA, Helfrich BA, Coldren CD, Zheng D, Chan D, Bunn PA Jr, Raben D (2007) Epithelial to mesenchymal transition predicts gefitinib resistance in cell lines of head and neck squamous cell carcinoma and non-small cell lung carcinoma. Mol Cancer Ther 6:1683–1691

    Article  CAS  PubMed  Google Scholar 

  92. Kajiyama H, Shibata K, Terauchi M, Yamashita M, Ino K, Nawa A, Kikkawa F (2007) Chemoresistance to paclitaxel induces epithelial-mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cells. Int J Oncol 31:277–283

    CAS  PubMed  Google Scholar 

  93. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704–715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Santisteban M, Reiman JM, Asiedu MK, Behrens MD, Nassar A, Kalli KR, Haluska P, Ingle JN, Hartmann LC, Manjili MH, Radisky DC, Ferrone S, Knutson KL (2009) Immune-induced epithelial to mesenchymal transition in vivo generates breast cancer stem cells. Cancer Res 69:2887–2895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, Hilsenbeck SG, Pavlick A, Zhang X, Chamness GC, Wong H, Rosen J, Chang JC (2008) Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 100:672–679

    Article  CAS  PubMed  Google Scholar 

  96. Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29:4741–4751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Mikami S, Mizuno R, Kosaka T, Saya H, Oya M, Okada Y (2015) Expression of TNF-alpha and CD44 is implicated in poor prognosis, cancer cell invasion, metastasis and resistance to the sunitinib treatment in clear cell renal cell carcinomas. Int J Cancer 136:1504–1514

    Article  CAS  PubMed  Google Scholar 

  98. Padera TP, Stoll BR, Tooredman JB, Capen D, di Tomaso E, Jain RK (2004) Pathology: cancer cells compress intratumour vessels. Nature 427:695

    Article  CAS  PubMed  Google Scholar 

  99. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Mototsugu Oya, Toshiaki Shinojima & Ryuichi Mizuno

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  1. Mototsugu Oya
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  2. Toshiaki Shinojima
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  3. Ryuichi Mizuno
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Correspondence to Mototsugu Oya .

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    Mototsugu Oya

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Oya, M., Shinojima, T., Mizuno, R. (2017). Refractory Mechanisms. In: Oya, M. (eds) Renal Cell Carcinoma. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55531-5_15

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