Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Treatment-induced host-mediated mechanisms reducing the efficacy of antitumor therapies

Oncogene volume 33, pages 1341–1347 (2014)Cite this article

Subjects

Abstract

In addition to its direct effects on tumor cells, chemotherapy can rapidly activate various host processes that contribute to therapy resistance and tumor regrowth. The host response to chemotherapy consists of changes in numerous cell types and cytokines. Examples include the acute mobilization and tumor homing of pro-angiogenic bone marrow-derived cells, activation of cells in the tumor microenvironment to produce systemic or paracrine factors, and tissue-specific responses that provide a protective niche for tumor cells. All of these factors reduce chemotherapy efficacy, and blocking the host response at various levels may therefore significantly improve treatment outcome. However, before the combination of conventional chemotherapy with agents blocking specific aspects of the host response can be implemented into clinical practice, a better understanding of the molecular mechanisms behind the host response is required.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Egeblad M, Nakasone ES, Werb Z . Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 2010; 18: 884–901.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 2001; 7: 1194–1201.

    CAS  PubMed  Google Scholar 

  3. Jain RK, Duda DG . Role of bone marrow-derived cells in tumor angiogenesis and treatment. Cancer Cell 2003; 3: 515–516.

    CAS  PubMed  Google Scholar 

  4. Kinzler KW, Vogelstein B . Landscaping the cancer terrain. Science 1998; 280: 1036–1037.

    CAS  PubMed  Google Scholar 

  5. Bissell MJ, Radisky D . Putting tumours in context. Nat Rev Cancer 2001; 1: 46–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hanahan D, Coussens LM . Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 2012; 21: 309–322.

    Article  CAS  PubMed  Google Scholar 

  7. Erez N, Truitt M, Olson P, Arron ST, Hanahan D . Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell 2010; 17: 135–147.

    CAS  PubMed  Google Scholar 

  8. Meads MB, Gatenby RA, Dalton WS . Environment-mediated drug resistance: a major contributor to minimal residual disease. Nat Rev Cancer 2009; 9: 665–674.

    CAS  PubMed  Google Scholar 

  9. Hazlehurst LA, Valkov N, Wisner L, Storey JA, Boulware D, Sullivan DM et al. Reduction in drug-induced DNA double-strand breaks associated with beta1 integrin-mediated adhesion correlates with drug resistance in U937 cells. Blood 2001; 98: 1897–1903.

    CAS  PubMed  Google Scholar 

  10. Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC . Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer 2007; 7: 585–598.

    CAS  PubMed  Google Scholar 

  11. Hartmann TN, Burger JA, Glodek A, Fujii N, Burger M . CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells. Oncogene 2005; 24: 4462–4471.

    CAS  PubMed  Google Scholar 

  12. Frassanito MA, Cusmai A, Iodice G, Dammacco F . Autocrine interleukin-6 production and highly malignant multiple myeloma: relation with resistance to drug-induced apoptosis. Blood 2001; 97: 483–489.

    CAS  PubMed  Google Scholar 

  13. Meads MB, Hazlehurst LA, Dalton WS . The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance. Clin Cancer Res 2008; 14: 2519–2526.

    Article  CAS  PubMed  Google Scholar 

  14. Martin FT, Dwyer RM, Kelly J, Khan S, Murphy JM, Curran C et al. Potential role of mesenchymal stem cells (MSCs) in the breast tumour microenvironment: stimulation of epithelial to mesenchymal transition (EMT). Breast Cancer Res Treat 2010; 124: 317–326.

    CAS  PubMed  Google Scholar 

  15. Giannoni E, Bianchini F, Masieri L, Serni S, Torre E, Calorini L et al. Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness. Cancer Res 2010; 70: 6945–6956.

    CAS  PubMed  Google Scholar 

  16. Klopp AH, Lacerda L, Gupta A, Debeb BG, Solley T, Li L et al. Mesenchymal stem cells promote mammosphere formation and decrease E-cadherin in normal and malignant breast cells. PLoS One 2010; 5: e12180.

    PubMed  PubMed Central  Google Scholar 

  17. Yan XL, Fu CJ, Chen L, Qin JH, Zeng Q, Yuan HF et al. Mesenchymal stem cells from primary breast cancer tissue promote cancer proliferation and enhance mammosphere formation partially via EGF/EGFR/Akt pathway. Breast Cancer Res Treat 2011; 132: 153–164.

    PubMed  Google Scholar 

  18. Chaffer CL, Weinberg RA . A perspective on cancer cell metastasis. Science 2011; 331: 1559–1564.

    CAS  PubMed  Google Scholar 

  19. Li HJ, Reinhardt F, Herschman HR, Weinberg RA . Cancer-stimulated mesenchymal stem cells create a carcinoma stem cell niche via prostaglandin E2 signaling. Cancer Discov 2012; 2: 840–855.

    CAS  PubMed  Google Scholar 

  20. Tredan O, Galmarini CM, Patel K, Tannock IF . Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 2007; 99: 1441–1454.

    CAS  PubMed  Google Scholar 

  21. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009; 324: 1457–1461.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Neesse A, Michl P, Frese KK, Feig C, Cook N, Jacobetz MA et al. Stromal biology and therapy in pancreatic cancer. Gut 2011; 60: 861–868.

    PubMed  Google Scholar 

  23. Kobayashi H, Man S, Graham CH, Kapitain SJ, Teicher BA, Kerbel RS . Acquired multicellular-mediated resistance to alkylating agents in cancer. Proc Natl Acad Sci USA 1993; 90: 3294–3298.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Waldman T, Zhang Y, Dillehay L, Yu J, Kinzler K, Vogelstein B et al. Cell-cycle arrest versus cell death in cancer therapy. Nat Med 1997; 3: 1034–1036.

    CAS  PubMed  Google Scholar 

  25. Samson DJ, Seidenfeld J, Ziegler K, Aronson N . Chemotherapy sensitivity and resistance assays: a systematic review. J Clin Oncol 2004; 22: 3618–3630.

    CAS  PubMed  Google Scholar 

  26. Green SK, Frankel A, Kerbel RS . Adhesion-dependent multicellular drug resistance. Anticancer Drug Des 1999; 14: 153–168.

    CAS  PubMed  Google Scholar 

  27. Farmer P, Bonnefoi H, Anderle P, Cameron D, Wirapati P, Becette V et al. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat Med 2009; 15: 68–74.

    CAS  PubMed  Google Scholar 

  28. Stupp R, Ruegg C . Integrin inhibitors reaching the clinic. J Clin Oncol 2007; 25: 1637–1638.

    CAS  PubMed  Google Scholar 

  29. Low JA, de Sauvage FJ . Clinical experience with Hedgehog pathway inhibitors. J Clin Oncol 2010; 28: 5321–5326.

    CAS  PubMed  Google Scholar 

  30. Madden JI . Infinity Reports Update from Phase 2 Study of Saridegib Plus Gemcitabine in Patients with Metastatic Pancreatic Cancer 27 January 2012.

  31. Cerniglia GJ, Pore N, Tsai JH, Schultz S, Mick R, Choe R et al. Epidermal growth factor receptor inhibition modulates the microenvironment by vascular normalization to improve chemotherapy and radiotherapy efficacy. PLoS One 2009; 4: e6539.

    PubMed  PubMed Central  Google Scholar 

  32. Kitadai Y, Sasaki T, Kuwai T, Nakamura T, Bucana CD, Fidler IJ . Targeting the expression of platelet-derived growth factor receptor by reactive stroma inhibits growth and mQetastasis of human colon carcinoma. Am J Pathol 2006; 169: 2054–2065.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Pietras K, Pahler J, Bergers G, Hanahan D . Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLoS Med 2008; 5: e19.

    PubMed  PubMed Central  Google Scholar 

  34. Sumida T, Kitadai Y, Shinagawa K, Tanaka M, Kodama M, Ohnishi M et al. Anti-stromal therapy with imatinib inhibits growth and metastasis of gastric carcinoma in an orthotopic nude mouse model. Int J Cancer 2011; 128: 2050–2062.

    CAS  PubMed  Google Scholar 

  35. Browder T, Butterfield CE, Kraling BM, Marshall B, O'Reilly MS, Folkman J . Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 2000; 60: 1878–1886.

    CAS  PubMed  Google Scholar 

  36. Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 2000; 105: R15–R24.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Kerbel RS, Kamen BA . The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 2004; 4: 423–436.

    CAS  PubMed  Google Scholar 

  38. Hanahan D, Bergers G, Bergsland E . Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 2000; 105: 1045–1047.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Le DT, Jaffee EM . Regulatory T-cell modulation using cyclophosphamide in vaccine approaches: a current perspective. Cancer Res 2012; 72: 3439–3444.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Apetoh L, Vegran F, Ladoire S, Ghiringhelli F . Restoration of antitumor immunity through selective inhibition of myeloid derived suppressor cells by anticancer therapies. Curr Mol Med 2011; 11: 365–372.

    CAS  PubMed  Google Scholar 

  41. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 2007; 13: 1050–1059.

    CAS  PubMed  Google Scholar 

  42. Bruchard M, Mignot G, Derangere V, Chalmin F, Chevriaux A, Vegran F et al. Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat Med 2013; 19: 57–64.

    CAS  PubMed  Google Scholar 

  43. Gingis-Velitski S, Loven D, Benayoun L, Munster M, Bril R, Voloshin T et al. Host response to short-term, single-agent chemotherapy induces matrix metalloproteinase-9 expression and accelerates metastasis in mice. Cancer Res 2011; 71: 6986–6996.

    CAS  PubMed  Google Scholar 

  44. Roodhart JM, Langenberg MH, Vermaat JS, Lolkema MP, Baars A, Giles RH et al. Late release of circulating endothelial cells and endothelial progenitor cells after chemotherapy predicts response and survival in cancer patients. Neoplasia 2010; 12: 87–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Shaked Y, Henke E, Roodhart JM, Mancuso P, Langenberg MH, Colleoni M et al. Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell 2008; 14: 263–273.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. De Palma M, Venneri MA, Galli R, Sergi SL, Politi LS, Sampaolesi M et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 2005; 8: 211–226.

    CAS  PubMed  Google Scholar 

  47. Jin DK, Shido K, Kopp HG, Petit I, Shmelkov SV, Young LM et al. Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes. Nat Med 2006; 12: 557–567.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Roodhart JM, He H, Daenen LG, Barber CL, Mv Amersfoort, Hoffman J et al Notch regulates the egression of angio-supportive bone marrow-derived cells after chemotherapy AACR Annual Meeting, Abstract 1022 2012.

  49. Shree T, Olson OC, Elie BT, Kester JC, Garfall AL, Simpson K et al. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev 2011; 25: 2465–2479.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 2011; 1: 54–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Ebos JM, Lee CR, Christensen JG, Mutsaers AJ, Kerbel RS . Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci USA 2007; 104: 17069–17074.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Lindauer A, Di GP, Kanefendt F, Tomalik-Scharte D, Kinzig M, Rodamer M et al. Pharmacokinetic/pharmacodynamic modeling of biomarker response to sunitinib in healthy volunteers. Clin Pharmacol Ther 2010; 87: 601–608.

    CAS  PubMed  Google Scholar 

  53. Ebos JM, Lee CR, Kerbel RS . Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin Cancer Res 2009; 15: 5020–5025.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Kerbel RS, Ebos JM . Peering into the aftermath: the inhospitable host? Nat Med 2010; 16: 1084–1085.

    CAS  PubMed  Google Scholar 

  55. Norden-Zfoni A, Desai J, Manola J, Beaudry P, Force J, Maki R et al. Blood-based biomarkers of SU11248 activity and clinical outcome in patients with metastatic imatinib-resistant gastrointestinal stromal tumor. Clin Cancer Res 2007; 13: 2643–2650.

    CAS  PubMed  Google Scholar 

  56. Deprimo SE, Bello CL, Smeraglia J, Baum CM, Spinella D, Rini BI et al. Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins. J Transl Med 2007; 5: 32.

    PubMed  PubMed Central  Google Scholar 

  57. Lewis CE, De PM, Naldini L . Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2. Cancer Res 2007; 67: 8429–8432.

    CAS  PubMed  Google Scholar 

  58. Joyce JA, Pollard JW . Microenvironmental regulation of metastasis. Nat Rev Cancer 2009; 9: 239–252.

    CAS  PubMed  Google Scholar 

  59. Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat Biotechnol 2007; 25: 911–920.

    CAS  PubMed  Google Scholar 

  60. Shojaei F, Wu X, Qu X, Kowanetz M, Yu L, Tan M et al. G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc Natl Acad Sci USA 2009; 106: 6742–6747.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Abdullah SE, Perez-Soler R . Mechanisms of resistance to vascular endothelial growth factor blockade. Cancer 2012; 118: 3455–3467.

    CAS  PubMed  Google Scholar 

  62. Shaked Y, Tang T, Woloszynek J, Daenen LG, Man S, Xu P et al. Contribution of granulocyte colony-stimulating factor to the acute mobilization of endothelial precursor cells by vascular disrupting agents. Cancer Res 2009; 69: 7524–7528.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Shaked Y, Ciarrocchi A, Franco M, Lee CR, Man S, Cheung AM et al. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 2006; 313: 1785–1787.

    CAS  PubMed  Google Scholar 

  64. Farace F, Massard C, Borghi E, Bidart JM, Soria JC . Vascular disrupting therapy-induced mobilization of circulating endothelial progenitor cells. Ann Oncol 2007; 18: 1421–1422.

    CAS  PubMed  Google Scholar 

  65. Taylor M, Billiot F, Marty V, Rouffiac V, Cohen P, Tournay E et al. Reversing resistance to vascular-disrupting agents by blocking late mobilization of circulating endothelial progenitor cells. Cancer Discov 2012; 2: 434–449.

    CAS  PubMed  Google Scholar 

  66. Welford AF, Biziato D, Coffelt SB, Nucera S, Fisher M, Pucci F et al. TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice. J Clin Invest 2011; 121: 1969–1973.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Bono A, Bianchi P, Locatelli A, Calleri A, Quarna J, Antoniott P et al. Angiogenic cells, macroparticles and RNA transcripts in laparoscopic vs open surgery for colorectal cancer. Cancer Biol Ther 2010; 10: 682–685.

    CAS  PubMed  Google Scholar 

  68. Voloshin T, Gingis-Velitski S, Shaked Y . The angiogenic profile of colorectal cancer patients following open or laparoscopic colectomy. Cancer Biol Ther 2010; 10: 686–688.

    PubMed  Google Scholar 

  69. Langenberg MH, Nijkamp MW, Roodhart JM, Snoeren N, Tang T, Shaked Y et al. Liver surgery induces an immediate mobilization of progenitor cells in liver cancer patients: a potential role for G-CSF. Cancer Biol Ther 2010; 9: 743–748.

    CAS  PubMed  Google Scholar 

  70. Sofia Vala I, Martins LR, Imaizumi N, Nunes RJ, Rino J, Kuonen F et al. Low doses of ionizing radiation promote tumor growth and metastasis by enhancing angiogenesis. PLoS One 2010; 5: e11222.

    PubMed  PubMed Central  Google Scholar 

  71. Nguyen DH, Oketch-Rabah HA, Illa-Bochaca I, Geyer FC, Reis-Filho JS, Mao JH et al. Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type. Cancer Cell 2011; 19: 640–651.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Ahn GO, Tseng D, Liao CH, Dorie MJ, Czechowicz A, Brown JM . Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment. Proc Natl Acad Sci USA 2010; 107: 8363–8368.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Klopp AH, Spaeth EL, Dembinski JL, Woodward WA, Munshi A, Meyn RE et al. Tumor irradiation increases the recruitment of circulating mesenchymal stem cells into the tumor microenvironment. Cancer Res 2007; 67: 11687–11695.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Bian ZY, Li G, Gan YK, Hao YQ, Xu WT, Tang TT . Increased number of mesenchymal stem cell-like cells in peripheral blood of patients with bone sarcomas. Arch Med Res 2009; 40: 163–168.

    CAS  PubMed  Google Scholar 

  75. Roodhart JM, Daenen LG, Stigter EC, Prins HJ, Gerrits J, Houthuijzen JM et al. Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer Cell 2011; 20: 370–383.

    CAS  PubMed  Google Scholar 

  76. Orimo A, Gupta PB, Sgroi DC, renzana-Seisdedos F, Delaunay T, Naeem R et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005; 121: 335–348.

    CAS  PubMed  Google Scholar 

  77. Sun Y, Campisi J, Higano C, Beer TM, Porter P, Coleman I et al. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med 2012; 18: 1359–1368.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Gilbert LA, Hemann MT . DNA damage-mediated induction of a chemoresistant niche. Cell 2010; 143: 355–366.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Campisi J . Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 2005; 120: 513–522.

    CAS  PubMed  Google Scholar 

  80. Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 2008; 6: 2853–2868.

    CAS  PubMed  Google Scholar 

  81. Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP, Raza SR et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol 2009; 11: 973–979.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Kuilman T, Peeper DS . Senescence-messaging secretome: SMS-ing cellular stress. Nat Rev Cancer 2009; 9: 81–94.

    CAS  PubMed  Google Scholar 

  83. Sotgia F, Martinez-Outschoorn UE, Pavlides S, Howell A, Pestell RG, Lisanti MP . Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment. Breast Cancer Res 2011; 13: 213.

    PubMed  PubMed Central  Google Scholar 

  84. Carmel RJ, Brown JM . The effect of cyclophosphamide and other drugs on the incidence of pulmonary metastases in mice. Cancer Res 1977; 37: 145–151.

    CAS  PubMed  Google Scholar 

  85. Hanna N, Burton RC . Definitive evidence that natural killer (NK) cells inhibit experimental tumor metastases in vivo. J Immunol 1981; 127: 1754–1758.

    CAS  PubMed  Google Scholar 

  86. Yamauchi K, Yang M, Hayashi K, Jiang P, Yamamoto N, Tsuchiya H et al. Induction of cancer metastasis by cyclophosphamide pretreatment of host mice: an opposite effect of chemotherapy. Cancer Res 2008; 68: 516–520.

    CAS  PubMed  Google Scholar 

  87. Daenen LG, Roodhart JM, van AM, Dehnad M, Roessingh W, Ulfman LH et al. Chemotherapy enhances metastasis formation via VEGFR-1-expressing endothelial cells. Cancer Res 2011; 71: 6976–6985.

    CAS  PubMed  Google Scholar 

  88. Daenen LG, Shaked Y, Man S, Xu P, Voest EE, Hoffman RM et al. Low-dose metronomic cyclophosphamide combined with vascular disrupting therapy induces potent antitumor activity in preclinical human tumor xenograft models. Mol Cancer Ther 2009; 8: 2872–2881.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Kim JJ, Tannock IF . Repopulation of cancer cells during therapy: an important cause of treatment failure. Nat Rev Cancer 2005; 5: 516–525.

    CAS  PubMed  Google Scholar 

  91. Davis AJ, Tannock JF . Repopulation of tumour cells between cycles of chemotherapy: a neglected factor. Lancet Oncol 2000; 1: 86–93.

    CAS  PubMed  Google Scholar 

  92. Bertolini F, Paul S, Mancuso P, Monestiroli S, Gobbi A, Shaked Y et al. Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res 2003; 63: 4342–4346.

    CAS  PubMed  Google Scholar 

  93. Emmenegger U, Francia G, Chow A, Shaked Y, Kouri A, Man S et al. Tumors that acquire resistance to low-dose metronomic cyclophosphamide retain sensitivity to maximum tolerated dose cyclophosphamide. Neoplasia 2011; 13: 40–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Pietras K, Hanahan D . 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 2005; 23: 939–952.

    CAS  PubMed  Google Scholar 

  95. Dellapasqua S, Bertolini F, Bagnardi V, Campagnoli E, Scarano E, Torrisi R et al. Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer. J Clin Oncol 2008.

  96. Garcia AA, Hirte H, Fleming G, Yang D, Tsao-Wei DD, Roman L et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol 2008; 26: 76–82.

    CAS  PubMed  Google Scholar 

  97. Bottini A, Generali D, Brizzi MP, Fox SB, Bersiga A, Bonardi S et al. Randomized phase II trial of letrozole and letrozole plus low-dose metronomic oral cyclophosphamide as primary systemic treatment in elderly breast cancer patients. J Clin Oncol 2006; 24: 3623–3628.

    CAS  PubMed  Google Scholar 

  98. Penel N, Adenis A, Bocci G . Cyclophosphamide-based metronomic chemotherapy: after 10 years of experience, where do we stand and where are we going? Crit Rev Oncol Hematol 2012; 82: 40–50.

    PubMed  Google Scholar 

  99. Loven D, Hasnis E, Bertolini F, Shaked Y . Low-dose metronomic chemotherapy: from past experience to new paradigms in the treatment of cancer. Drug Discov Today 2012; 18: 193–201.

    PubMed  Google Scholar 

  100. Kato H, Ichinose Y, Ohta M, Hata E, Tsubota N, Tada H et al. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 2004; 350: 1713–1721.

    CAS  PubMed  Google Scholar 

  101. Watanabe T, Sano M, Takashima S, Kitaya T, Tokuda Y, Yoshimoto M et al. Oral uracil and tegafur compared with classic cyclophosphamide, methotrexate, fluorouracil as postoperative chemotherapy in patients with node-negative, high-risk breast cancer: National Surgical Adjuvant Study for Breast Cancer 01 Trial. J Clin Oncol 2009; 27: 1368–1374.

    CAS  PubMed  Google Scholar 

  102. Brown JM, Wilson WR . Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 2004; 4: 437–447.

    CAS  PubMed  Google Scholar 

  103. Kerbel RS . Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science 2006; 312: 1171–1175.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands

    L G M Daenen, J M Houthuijzen, G A Cirkel, J M L Roodhart & E E Voest

  2. Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion, Haifa, Israel

    Y Shaked

Authors
  1. L G M Daenen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J M Houthuijzen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G A Cirkel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J M L Roodhart
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Shaked
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E E Voest
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E E Voest.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Daenen, L., Houthuijzen, J., Cirkel, G. et al. Treatment-induced host-mediated mechanisms reducing the efficacy of antitumor therapies. Oncogene 33, 1341–1347 (2014). https://doi.org/10.1038/onc.2013.94

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.94

Keywords

This article is cited by

Search

Advanced search

Quick links