Escape Mechanisms from Antiangiogenic Therapy: An Immune Cell’s Perspective

Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 772)

Abstract

Neovascularization, the formation of new blood vessels, has become a well-established hallmark of cancer. Its functional importance for the manifestation and progression of tumors has been validated further by the beneficial therapeutic effects of angiogenesis inhibitors, most notably those targeting vascular endothelial growth factor signaling pathways. However, with the transient and short-lived nature of patient response, it has become evident that tumors have the ability to adapt to the pressures of vascular growth restriction. Observations made both in the clinic and at the bench suggest the existence of several escape mechanisms that either reestablish neovascularization in tumors or change tumor behavior to enable propagation and progression without obligate neovascularization. Some of these bypass mechanisms are regulated by low oxygen conditions (hypoxia) caused by therapy-induced vessel regression. Induction of hypoxia and hypoxia-inducible factors regulate a wide range of tumor-promoting pathways, including those of neovascularization, that can upregulate additional proangiogenic factors and drive the recruitment of various bone marrow–derived cells that have the capacity to express proangiogenic factors or directly contribute to neovasculature.

Keywords

Cancer Antiangiogenic therapy Resistance Innate immune cells Macrophages Myeloid-derived suppressor cells (MDSCs) Neovascularization 

References

  1. Bates DO, Hillman NJ, Williams B, Neal CR, Pocock TM (2002) Regulation of microvascular permeability by vascular endothelial growth factors. J Anat 200:581–597PubMedCrossRefGoogle Scholar
  2. Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592–603PubMedCrossRefGoogle Scholar
  3. Bergers G, Song S (2005) The role of pericytes in blood-vessel formation and maintenance. Neuro Oncol 7:452–464PubMedCrossRefGoogle Scholar
  4. Bergers G, Javaherian K, Lo KM, Folkman J, Hanahan D (1999) Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 284:808–812PubMedCrossRefGoogle Scholar
  5. 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 4:133–146PubMedCrossRefGoogle Scholar
  6. Butler JM, Kobayashi H, Rafii S (2010) Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nat Rev Cancer 10:138–146PubMedCrossRefGoogle Scholar
  7. 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: 299–309PubMedCrossRefGoogle Scholar
  8. Chung AS, Lee J, Ferrara N (2010) Targeting the tumour vasculature: insights from physiological angiogenesis. Nat Rev Cancer 10:505–514PubMedCrossRefGoogle Scholar
  9. Cooke VG, Lebleu VS, Keskin D, Khan Z, O’Connell JT, Teng Y, Duncan MB, Xie L, Maeda G, Vong S et al (2012) Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell 21:66–81PubMedCrossRefGoogle Scholar
  10. 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 8:211–226PubMedCrossRefGoogle Scholar
  11. De Palma M, Murdoch C, Venneri MA, Naldini L, Lewis CE (2007) Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications. Trends Immunol 28:519–524PubMedCrossRefGoogle Scholar
  12. Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ (2009) Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 58:49–59PubMedCrossRefGoogle Scholar
  13. Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegue E, Song H, Vandenberg S, Johnson RS, Werb Z et al (2008a) HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13:206–220PubMedCrossRefGoogle Scholar
  14. Du R, Petritsch C, Lu K, Liu P, Haller A, Ganss R, Song H, Vandenberg S, Bergers G (2008b) Matrix metalloproteinase-2 regulates vascular patterning and growth affecting tumor cell survival and invasion in GBM. Neuro-oncology 10:254–264PubMedCrossRefGoogle Scholar
  15. Ebos JM, Kerbel RS (2011) Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat Rev Clin Oncol 8:210–221PubMedCrossRefGoogle Scholar
  16. 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 15:232–239PubMedCrossRefGoogle Scholar
  17. Ferrara N (2002) VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2:795–803PubMedCrossRefGoogle Scholar
  18. Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25:581–611PubMedCrossRefGoogle Scholar
  19. Ferrara N, Hillan KJ, Novotny W (2005) Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 333:328–335PubMedCrossRefGoogle Scholar
  20. Filipazzi P, Valenti R, Huber V, Pilla L, Canese P, Iero M, Castelli C, Mariani L, Parmiani G, Rivoltini L (2007) Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol Off J Am Soc Clin Oncol 25:2546–2553CrossRefGoogle Scholar
  21. Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, Chorianopoulos E, Liesenborghs L, Koch M, De Mol M et al (2007) Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131:463–475PubMedCrossRefGoogle Scholar
  22. Folkman J (2007) Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6:273–286PubMedCrossRefGoogle Scholar
  23. Folkman J, Merler E, Abernathy C, Williams G (1971) Isolation of a tumor factor responsible for angiogenesis. J Exp Med 133:275–288PubMedCrossRefGoogle Scholar
  24. Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16:4604–4613PubMedGoogle Scholar
  25. Gao D, Nolan DJ, Mellick AS, Bambino K, McDonnell K, Mittal V (2008) Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science 319:195–198PubMedCrossRefGoogle Scholar
  26. Gorre ME, Sawyers CL (2002) Molecular mechanisms of resistance to STI571 in chronic myeloid leukemia. Curr Opin Hematol 9:303–307PubMedCrossRefGoogle Scholar
  27. Greenberg JI, Shields DJ, Barillas SG, Acevedo LM, Murphy E, Huang J, Scheppke L, Stockmann C, Johnson RS, Angle N et al (2008) A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456:809–813PubMedCrossRefGoogle Scholar
  28. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364PubMedCrossRefGoogle Scholar
  29. Hillen F, Griffioen AW (2007) Tumour vascularization: sprouting angiogenesis and beyond. Cancer Metastasis Rev 26:489–502PubMedCrossRefGoogle Scholar
  30. Hlushchuk R, Riesterer O, Baum O, Wood J, Gruber G, Pruschy M, Djonov V (2008) Tumor recovery by angiogenic switch from sprouting to intussusceptive angiogenesis after treatment with PTK787/ZK222584 or ionizing radiation. Am J Pathol 173:1173–1185PubMedCrossRefGoogle Scholar
  31. Hlushchuk R, Makanya AN, Djonov V (2011) Escape mechanisms after antiangiogenic treatment, or why are the tumors growing again? Int J Dev Biol 55:563–567PubMedCrossRefGoogle Scholar
  32. Jain RK (2005a) Antiangiogenic therapy for cancer: current and emerging concepts. Oncology 19:7–16PubMedGoogle Scholar
  33. Jain RK (2005b) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62PubMedCrossRefGoogle Scholar
  34. Keith B, Johnson RS, Simon MC (2011) HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12:9–22PubMedGoogle Scholar
  35. Kelly BD, Hackett SF, Hirota K, Oshima Y, Cai Z, Berg-Dixon S, Rowan A, Yan Z, Campochiaro PA, Semenza GL (2003) Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1. Circ Res 93:1074–1081PubMedCrossRefGoogle Scholar
  36. Ku DD, Zaleski JK, Liu S, Brock TA (1993) Vascular endothelial growth factor induces EDRF-dependent relaxation in coronary arteries. Am J Physiol 265:H586–H592PubMedGoogle Scholar
  37. Kuhnert F, Kirshner JR, Thurston G (2011) Dll4-Notch signaling as a therapeutic target in tumor angiogenesis. Vas Cell 3:20CrossRefGoogle Scholar
  38. Kujawski M, Kortylewski M, Lee H, Herrmann A, Kay H, Yu H (2008) Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. J Clin Invest 118:3367–3377PubMedCrossRefGoogle Scholar
  39. LeCouter J, Kowalski J, Foster J, Hass P, Zhang Z, Dillard-Telm L, Frantz G, Rangell L, DeGuzman L, Keller GA et al (2001) Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature 412:877–884PubMedCrossRefGoogle Scholar
  40. Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL (1996) Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56:4625–4629PubMedGoogle Scholar
  41. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309PubMedCrossRefGoogle Scholar
  42. Li C, Shintani S, Terakado N, Nakashiro K, Hamakawa H (2002) Infiltration of tumor-associated macrophages in human oral squamous cell carcinoma. Oncol Rep 9:1219–1223PubMedGoogle Scholar
  43. Lin EY, Nguyen AV, Russell RG, Pollard JW (2001) Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193:727–740PubMedCrossRefGoogle Scholar
  44. Lin EY, Li JF, Gnatovskiy L, Deng Y, Zhu L, Grzesik DA, Qian H, Xue XN, Pollard JW (2006) Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 66:11238–11246PubMedCrossRefGoogle Scholar
  45. Lu KV, Chang JP, Parachoniak CA, Pandika MM, Aghi MK, Meyronet D, Isachenko N, Fouse SD, Phillips JJ, Cheresh DA et al (2012) VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell 22:21–35PubMedCrossRefGoogle Scholar
  46. Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A, Heissig B, Marks W, Witte L et al (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7:1194–1201PubMedCrossRefGoogle Scholar
  47. Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe’er J, Trent JM, Meltzer PS, Hendrix MJ (1999) Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 155:739–752PubMedCrossRefGoogle Scholar
  48. Mazzieri R, Pucci F, Moi D, Zonari E, Ranghetti A, Berti A, Politi LS, Gentner B, Brown JL, Naldini L et al (2011) Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 19:512–526PubMedCrossRefGoogle Scholar
  49. Milan SA, Yeo CJ (2012) Neuroendocrine tumors of the pancreas. Curr Opin Oncol 24:46–55PubMedCrossRefGoogle Scholar
  50. Mirza N, Fishman M, Fricke I, Dunn M, Neuger AM, Frost TJ, Lush RM, Antonia S, Gabrilovich DI (2006) All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res 66:9299–9307PubMedCrossRefGoogle Scholar
  51. Movahedi K, Guilliams M, Van den Bossche J, Van den Bergh R, Gysemans C, Beschin A, De Baetselier P, Van Ginderachter JA (2008) Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 111:4233–4244PubMedCrossRefGoogle Scholar
  52. Murdoch C, Muthana M, Coffelt SB, Lewis CE (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8:618–631PubMedCrossRefGoogle Scholar
  53. O’Connor R, Clynes M, Dowling P, O’Donovan N, O’Driscoll L (2007) Drug resistance in cancer – searching for mechanisms, markers and therapeutic agents. Expert Opin Drug Metab Toxicol 3:805–817PubMedCrossRefGoogle Scholar
  54. Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182:4499–4506PubMedCrossRefGoogle Scholar
  55. 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 15:220–231PubMedCrossRefGoogle Scholar
  56. Pan PY, Wang GX, Yin B, Ozao J, Ku T, Divino CM, Chen SH (2008) Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function. Blood 111:219–228PubMedCrossRefGoogle Scholar
  57. Pandit R, Lathers DM, Beal NM, Garrity T, Young MR (2000) CD34+ immune suppressive cells in the peripheral blood of patients with head and neck cancer. Ann Otol Rhinol Laryngol 109:749–754PubMedGoogle Scholar
  58. Peters BA, Diaz LA, Polyak K, Meszler L, Romans K, Guinan EC, Antin JH, Myerson D, Hamilton SR, Vogelstein B et al (2005) Contribution of bone marrow-derived endothelial cells to human tumor vasculature. Nat Med 11:261–262PubMedCrossRefGoogle Scholar
  59. Potente M, Gerhardt H, Carmeliet P (2011) Basic and therapeutic aspects of angiogenesis. Cell 146:873–887PubMedCrossRefGoogle Scholar
  60. Priceman SJ, Sung JL, Shaposhnik Z, Burton JB, Torres-Collado AX, Moughon DL, Johnson M, Lusis AJ, Cohen DA, Iruela-Arispe ML et al (2010) Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy. Blood 115:1461–1471PubMedCrossRefGoogle Scholar
  61. Reddy GR, Kuo CC, Tan UK, Coumar MS, Chang CY, Chiang YK, Lai MJ, Yeh JY, Wu SY, Chang JY et al (2008) Synthesis and structure-activity relationships of 2-amino-1-aroylnaphthalene and 2-hydroxy-1-aroylnaphthalenes as potent antitubulin agents. J Med Chem 51: 8163–8167PubMedCrossRefGoogle Scholar
  62. Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T, Maira G, Parati EA, Stassi G, Larocca LM et al (2010) Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468:824–828PubMedCrossRefGoogle Scholar
  63. Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C, Squadrito ML, Segura I, Li X, Knevels E et al (2011) HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19:31–44PubMedCrossRefGoogle Scholar
  64. Schmid MC, Avraamides CJ, Dippold HC, Franco I, Foubert P, Ellies LG, Acevedo LM, Manglicmot JR, Song X, Wrasidlo W et al (2011) Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kgamma, a single convergent point promoting tumor inflammation and progression. Cancer Cell 19:715–727PubMedCrossRefGoogle Scholar
  65. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985PubMedCrossRefGoogle Scholar
  66. Sharma N, Seftor RE, Seftor EA, Gruman LM, Heidger PM Jr, Cohen MB, Lubaroff DM, Hendrix MJ (2002) Prostatic tumor cell plasticity involves cooperative interactions of distinct phenotypic subpopulations: role in vasculogenic mimicry. Prostate 50:189–201PubMedCrossRefGoogle Scholar
  67. Shirakawa K, Kobayashi H, Heike Y, Kawamoto S, Brechbiel MW, Kasumi F, Iwanaga T, Konishi F, Terada M, Wakasugi H (2002) Hemodynamics in vasculogenic mimicry and angiogenesis of inflammatory breast cancer xenograft. Cancer Res 62:560–566PubMedGoogle Scholar
  68. Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S, Fuh G, Gerber HP, Ferrara N (2007a) Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat Biotechnol 25:911–920PubMedCrossRefGoogle Scholar
  69. Shojaei F, Wu X, Zhong C, Yu L, Liang XH, Yao J, Blanchard D, Bais C, Peale FV, van Bruggen N et al (2007b) Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450:825–831PubMedCrossRefGoogle Scholar
  70. Shojaei F, Singh M, Thompson JD, Ferrara N (2008) Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression. Proc Natl Acad Sci USA 105:2640–2645PubMedCrossRefGoogle Scholar
  71. Shojaei F, Wu X, Qu X, Kowanetz M, Yu L, Tan M, Meng YG, Ferrara N (2009) G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc Natl Acad Sci USA 106:6742–6747PubMedCrossRefGoogle Scholar
  72. Sica A, Larghi P, Mancino A, Rubino L, Porta C, Totaro MG, Rimoldi M, Biswas SK, Allavena P, Mantovani A (2008) Macrophage polarization in tumour progression. Semin Cancer Biol 18:349–355PubMedCrossRefGoogle Scholar
  73. Simon MP, Tournaire R, Pouyssegur J (2008) The angiopoietin-2 gene of endothelial cells is up-regulated in hypoxia by a HIF binding site located in its first intron and by the central factors GATA-2 and Ets-1. J Cell Physiol 217:809–818PubMedCrossRefGoogle Scholar
  74. Smith JK, Mamoon NM, Duhe RJ (2004) Emerging roles of targeted small molecule protein-tyrosine kinase inhibitors in cancer therapy. Oncol Res 14:175–225PubMedGoogle Scholar
  75. Soda Y, Marumoto T, Friedmann-Morvinski D, Soda M, Liu F, Michiue H, Pastorino S, Yang M, Hoffman RM, Kesari S et al (2011) Transdifferentiation of glioblastoma cells into vascular endothelial cells. Proc Natl Acad Sci USA 108:4274–4280PubMedCrossRefGoogle Scholar
  76. Song S, Ewald AJ, Stallcup W, Werb Z, Bergers G (2005) PDGFRbeta+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat Cell Biol 7:870–879PubMedCrossRefGoogle Scholar
  77. Srivastava MK, Bosch JJ, Thompson JA, Ksander BR, Edelman MJ, Ostrand-Rosenberg S (2008) Lung cancer patients’ CD4(+) T cells are activated in vitro by MHC II cell-based vaccines despite the presence of myeloid-derived suppressor cells. Cancer Immunol Immunother 57:1493–1504PubMedCrossRefGoogle Scholar
  78. Sun B, Zhang S, Zhao X, Zhang W, Hao X (2004) Vasculogenic mimicry is associated with poor survival in patients with mesothelial sarcomas and alveolar rhabdomyosarcomas. Int J Oncol 25:1609–1614PubMedGoogle Scholar
  79. Takanami I, Takeuchi K, Kodaira S (1999) Tumor-associated macrophage infiltration in pulmonary adenocarcinoma: association with angiogenesis and poor prognosis. Oncology 57:138–142PubMedCrossRefGoogle Scholar
  80. Venneri MA, De Palma M, Ponzoni M, Pucci F, Scielzo C, Zonari E, Mazzieri R, Doglioni C, Naldini L (2007) Identification of proangiogenic TIE2-expressing monocytes (TEMs) in human peripheral blood and cancer. Blood 109:5276–5285PubMedCrossRefGoogle Scholar
  81. Wang R, Chadalavada K, Wilshire J, Kowalik U, Hovinga KE, Geber A, Fligelman B, Leversha M, Brennan C, Tabar V (2010) Glioblastoma stem-like cells give rise to tumour endothelium. Nature 468:829–833PubMedCrossRefGoogle Scholar
  82. Welford AF, Biziato D, Coffelt SB, Nucera S, Fisher M, Pucci F, Di Serio C, Naldini L, De Palma M, Tozer GM et al (2011) TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice. J Clin Invest 121:1969–1973PubMedCrossRefGoogle Scholar
  83. 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 6:409–421PubMedCrossRefGoogle Scholar
  84. Yang L, Huang J, Ren X, Gorska AE, Chytil A, Aakre M, Carbone DP, Matrisian LM, Richmond A, Lin PC et al (2008) Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 13:23–35PubMedCrossRefGoogle Scholar
  85. Youn JI, Nagaraj S, Collazo M, Gabrilovich DI (2008) Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol 181:5791–5802PubMedGoogle Scholar
  86. Zeisberger SM, Odermatt B, Marty C, Zehnder-Fjallman AH, Ballmer-Hofer K, Schwendener RA (2006) Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach. Brit J Cancer 95:272–281PubMedCrossRefGoogle Scholar
  87. Zumsteg A, Christofori G (2009) Corrupt policemen: inflammatory cells promote tumor angiogenesis. Curr Opin Oncol 21:60–70PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Lee Rivera
    • 1
    • 2
  • Melissa Pandika
    • 1
    • 2
  • Gabriele Bergers
    • 1
    • 2
    • 3
    • 4
  1. 1.Departments of Neurological SurgeryUniversity of California, Helen Diller Family Cancer Research CenterSan FranciscoUSA
  2. 2.Brain Tumor Research CenterUniversity of California, Helen Diller Family Cancer Research CenterSan FranciscoUSA
  3. 3.AnatomyUniversity of California, Helen Diller Family Cancer Research CenterSan FranciscoUSA
  4. 4.UCSF Comprehensive Cancer CenterUniversity of California, Helen Diller Family Cancer Research CenterSan FranciscoUSA

Personalised recommendations