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:

Tumor stroma: a complexity dictated by the hypoxic tumor microenvironment

Abstract

A lot of effort has been done to study how cancer cells react to low-oxygen tension, a condition known as hypoxia. Indeed, abnormal and dysfunctional blood vessels in the tumor are incapable to restore oxygenation, therefore perpetuating hypoxia, which, in turn, will fuel tumor progression, metastasis and resistance to antitumor therapies. Nevertheless, how stromal components including blood and lymphatic endothelial cells, pericytes and fibroblasts, as well as hematopoietic cells, respond to low-oxygen tension in comparison with their normoxic counterparts has been a matter of investigation in the last few years only and, to date, this field of research remains poorly understood. In general, opposing phenotypes can arise from the same stromal component when embedded in different tumor microenvironments, and, vice versa, different stromal components can have opposite reaction to the same tumor microenvironment. In this article, we will discuss the emerging link between tumor stroma and hypoxia, and how this complexity is translated at the molecular level.

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

Access options

Buy this article

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

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Goda F, O'Hara JA, Rhodes ES, Liu KJ, Dunn JF, Bacic G et al. Changes of oxygen tension in experimental tumors after a single dose of X-ray irradiation. Cancer Res 1995; 55: 2249–2252.

    CAS  PubMed  Google Scholar 

  2. Helmlinger G, Yuan F, Dellian M, Jain RK . Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nature Med 1997; 3: 177–182.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  4. De Bock K, Mazzone M, Carmeliet P . Antiangiogenic therapy, hypoxia, and metastasis: risky liaisons, or not? Nat Rev Clin Oncol 2011; 8: 393–404.

    CAS  PubMed  Google Scholar 

  5. Carmeliet P, Jain RK . Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 2011; 10: 417–427.

    CAS  PubMed  Google Scholar 

  6. Mazzone M, Dettori D, Leite de Oliveira R, Loges S, Schmidt T, Jonckx B et al. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 2009; 136: 839–851.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Leite de Oliveira R, Deschoemaeker S, Henze AT, Debackere K, Finisguerra V, Takeda Y et al. Gene-targeting of Phd2 improves tumor response to chemotherapy and prevents side-toxicity. Cancer cell 2012; 22: 263–277.

    CAS  PubMed  Google Scholar 

  8. Leite de Oliveira R, Hamm A, Mazzone M . Growing tumor vessels: more than one way to skin a cat - implications for angiogenesis targeted cancer therapies. Mol Aspects Med 2011; 32: 71–87.

    PubMed  Google Scholar 

  9. Maftei CA, Bayer C, Shi K, Astner ST, Vaupel P . Quantitative assessment of hypoxia subtypes in microcirculatory supply units of malignant tumors using (immuno-)fluorescence techniques. Strahlenther Onkol 2011; 184: 260–266.

    Google Scholar 

  10. Maftei CA, Bayer C, Shi K, Astner ST, Vaupel P . Changes in the fraction of total hypoxia and hypoxia subtypes in human squamous cell carcinomas upon fractionated irradiation: evaluation using pattern recognition in microcirculatory supply units. Radiother Oncol 2011; 101: 209–216.

    CAS  PubMed  Google Scholar 

  11. Chappell JC, Taylor SM, Ferrara N, Bautch VL . Local guidance of emerging vessel sprouts requires soluble Flt-1. Dev Cell 2009; 17: 377–386.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Skuli N, Majmundar AJ, Krock BL, Mesquita RC, Mathew LK, Quinn ZL et al. Endothelial HIF-2alpha regulates murine pathological angiogenesis and revascularization processes. J Clin Invest 2012; 122: 1427–1443.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Graven KK, Farber HW . Endothelial hypoxic stress proteins. Kidney Int 1997; 51: 426–437.

    CAS  PubMed  Google Scholar 

  14. Polet F, Feron O . Endothelial cell metabolism and tumour angiogenesis: glucose and glutamine as essential fuels and lactate as the driving force. J Intern Med 2013; 273: 156–165.

    CAS  PubMed  Google Scholar 

  15. Fraisl P, Aragones J, Carmeliet P . Inhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease. Nat Rev Drug Discov 2009; 8: 139–152.

    CAS  PubMed  Google Scholar 

  16. Wong BW, Kuchnio A, Bruning U, Carmeliet P . Emerging novel functions of the oxygen-sensing prolyl hydroxylase domain enzymes. Trends Biochem Sci 2013; 38: 3–11.

    CAS  PubMed  Google Scholar 

  17. Quintero M, Colombo SL, Godfrey A, Moncada S . Mitochondria as signaling organelles in the vascular endothelium. Proc Natl Acad Sci USA 2006; 103: 5379–5384.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Dutta D, Ray S, Vivian JL, Paul S . Activation of the VEGFR1 chromatin domain: an angiogenic signal-ETS1/HIF-2alpha regulatory axis. J Biol Chem 2008; 283: 25404–25413.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Le Bras A, Lionneton F, Mattot V, Lelievre E, Caetano B, Spruyt N et al. HIF-2alpha specifically activates the VE-cadherin promoter independently of hypoxia and in synergy with Ets-1 through two essential ETS-binding sites. Oncogene 2007; 26: 7480–7489.

    CAS  PubMed  Google Scholar 

  20. Skuli N, Liu L, Runge A, Wang T, Yuan L, Patel S et al. Endothelial deletion of hypoxia-inducible factor-2alpha (HIF-2alpha) alters vascular function and tumor angiogenesis. Blood 2009; 114: 469–477.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Tang N, Wang L, Esko J, Giordano FJ, Huang Y, Gerber HP et al. Loss of HIF-1alpha in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell 2004; 6: 485–495.

    CAS  PubMed  Google Scholar 

  22. Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 2003; 161: 1163–1177.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 2007; 445: 776–780.

    PubMed  Google Scholar 

  24. Jakobsson L, Franco CA, Bentley K, Collins RT, Ponsioen B, Aspalter IM et al. Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting. Nature Cell Biol 2010; 12: 943–953.

    CAS  PubMed  Google Scholar 

  25. Koivunen P, Hirsila M, Gunzler V, Kivirikko KI, Myllyharju J . Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases. J Biol Chem 2004; 279: 9899–9904.

    CAS  PubMed  Google Scholar 

  26. Branco-Price C, Zhang N, Schnelle M, Evans C, Katschinski DM, Liao D et al. Endothelial cell HIF-1alpha and HIF-2alpha differentially regulate metastatic success. Cancer Cell 2012; 21: 52–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Schoppmann SF, Birner P, Studer P, Breiteneder-Geleff S . Lymphatic microvessel density and lymphovascular invasion assessed by anti-podoplanin immunostaining in human breast cancer. Anticancer Res 2001; 21: 2351–2355.

    CAS  PubMed  Google Scholar 

  28. Ran S, Volk L, Hall K, Flister MJ . Lymphangiogenesis and lymphatic metastasis in breast cancer. Pathophysiology 2010; 17: 229–251.

    PubMed  Google Scholar 

  29. Schito L, Rey S, Tafani M, Zhang H, Wong CC, Russo A et al. Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells. Proc Natl Acad Sci USA 2012; 109: E2707–E2716.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Schoppmann SF, Fenzl A, Schindl M, Bachleitner-Hofmann T, Nagy K, Gnant M et al. Hypoxia inducible factor-1alpha correlates with VEGF-C expression and lymphangiogenesis in breast cancer. Breast Cancer Res Treat 2006; 99: 135–141.

    CAS  PubMed  Google Scholar 

  31. Ohta Y, Shridhar V, Bright RK, Kalemkerian GP, Du W, Carbone M et al. VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours. Br J Cancer 1999; 81: 54–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Liang X, Yang D, Hu J, Hao X, Gao J, Mao Z . Hypoxia inducible factor-alpha expression correlates with vascular endothelial growth factor-C expression and lymphangiogenesis/angiogenesis in oral squamous cell carcinoma. Anticancer Res 2008; 28: 1659–1666.

    PubMed  Google Scholar 

  33. Spinella F, Garrafa E, Di Castro V, Rosano L, Nicotra MR, Caruso A et al. Endothelin-1 stimulates lymphatic endothelial cells and lymphatic vessels to grow and invade. Cancer Res 2009; 69: 2669–2676.

    CAS  PubMed  Google Scholar 

  34. Irigoyen M, Anso E, Martinez E, Garayoa M, Martinez-Irujo JJ, Rouzaut A . Hypoxia alters the adhesive properties of lymphatic endothelial cells. A transcriptional and functional study. Biochim Biophys Acta 2007; 1773: 880–890.

    CAS  PubMed  Google Scholar 

  35. Ota H, Katsube K, Ogawa J, Yanagishita M . Hypoxia/Notch signaling in primary culture of rat lymphatic endothelial cells. FEBS Lett 2007; 581: 5220–5226.

    CAS  PubMed  Google Scholar 

  36. Geudens I, Herpers R, Hermans K, Segura I, Ruiz de Almodovar C, Bussmann J et al. Role of delta-like-4/Notch in the formation and wiring of the lymphatic network in zebrafish. Arterioscler Thromb Vasc Biol 2010; 30: 1695–1702.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Hangai-Hoger N, Cabrales P, Briceno JC, Tsai AG, Intaglietta M . Microlymphatic and tissue oxygen tension in the rat mesentery. Am J Physiol Heart Circ Physiol 2004; 286: H878–H883.

    CAS  PubMed  Google Scholar 

  38. Dore-Duffy P, LaManna JC . Physiologic angiodynamics in the brain. Antioxid Redox Signal 2007; 9: 1363–1371.

    CAS  PubMed  Google Scholar 

  39. Lynch CN, Wang YC, Lund JK, Chen YW, Leal JA, Wiley SR . TWEAK induces angiogenesis and proliferation of endothelial cells. J Biol Chem 1999; 274: 8455–8459.

    CAS  PubMed  Google Scholar 

  40. Donohue PJ, Richards CM, Brown SA, Hanscom HN, Buschman J, Thangada S et al. TWEAK is an endothelial cell growth and chemotactic factor that also potentiates FGF-2 and VEGF-A mitogenic activity. Arterioscler Thromb Vasc Biol 2003; 23: 594–600.

    CAS  PubMed  Google Scholar 

  41. Pouyssegur J, Dayan F, Mazure NM . Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 2006; 441: 437–443.

    CAS  PubMed  Google Scholar 

  42. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D . Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 2003; 111: 1287–1295.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Cooke VG, LeBleu VS, Keskin D, Khan Z, O'Connell JT, Teng Y et al. Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell 2012; 21: 66–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Ozerdem U . Targeting of pericytes diminishes neovascularization and lymphangiogenesis in prostate cancer. Prostate 2006; 66: 294–304.

    CAS  PubMed  Google Scholar 

  45. Xian X, Hakansson J, Stahlberg A, Lindblom P, Betsholtz C, Gerhardt H et al. Pericytes limit tumor cell metastasis. J Clin Invest 2006; 116: 642–651.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Elfiky AA, Sonpavde G . Novel molecular targets for the therapy of renal cell carcinoma. Discov Med 2012; 13: 461–471.

    PubMed  Google Scholar 

  47. Cascone T, Heymach JV . Targeting the angiopoietin/Tie2 pathway: cutting tumor vessels with a double-edged sword? J Clin Oncol 2012; 30: 441–444.

    CAS  PubMed  Google Scholar 

  48. Orimo A, Weinberg RA . Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle 2006; 5: 1597–1601.

    CAS  PubMed  Google Scholar 

  49. Scott AM, Wiseman G, Welt S, Adjei A, Lee FT, Hopkins W et al. A Phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin Cancer Res 2003; 9: 1639–1647.

    CAS  PubMed  Google Scholar 

  50. 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 

  51. Sotgia F, Martinez-Outschoorn UE, Howell A, Pestell RG, Pavlides S, Lisanti MP . Caveolin-1 and cancer metabolism in the tumor microenvironment: markers, models, and mechanisms. Annual Rev Pathol 2012; 7: 423–467.

    CAS  Google Scholar 

  52. Mishra PJ, Humeniuk R, Medina DJ, Alexe G, Mesirov JP, Ganesan S et al. Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer Res 2008; 68: 4331–4339.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Mueller L, Goumas FA, Affeldt M, Sandtner S, Gehling UM, Brilloff S et al. Stromal fibroblasts in colorectal liver metastases originate from resident fibroblasts and generate an inflammatory microenvironment. Am J Pathol 2007; 171: 1608–1618.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Petersen OW, Nielsen HL, Gudjonsson T, Villadsen R, Rank F, Niebuhr E et al. Epithelial to mesenchymal transition in human breast cancer can provide a nonmalignant stroma. Am J Pathol 2003; 162: 391–402.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Zeisberg EM, Potenta S, Xie L, Zeisberg M, Kalluri R . Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res 2007; 67: 10123–10128.

    CAS  PubMed  Google Scholar 

  56. Martinez-Outschoorn UE, Trimmer C, Lin Z, Whitaker-Menezes D, Chiavarina B, Zhou J et al. Autophagy in cancer associated fibroblasts promotes tumor cell survival: role of hypoxia, HIF1 induction and NFkappaB activation in the tumor stromal microenvironment. Cell Cycle 2010; 9: 3515–3533.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Chiavarina B, Whitaker-Menezes D, Migneco G, Martinez-Outschoorn UE, Pavlides S, Howell A et al. HIF1-alpha functions as a tumor promoter in cancer associated fibroblasts, and as a tumor suppressor in breast cancer cells: autophagy drives compartment-specific oncogenesis. Cell Cycle 2010; 9: 3534–3551.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Mercier I, Casimiro MC, Wang C, Rosenberg AL, Quong J, Minkeu A et al. Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation and RB tumor suppressor functional inactivation: implications for the response to hormonal therapy. Cancer Biol Ther 2008; 7: 1212–1225.

    CAS  PubMed  Google Scholar 

  59. Goetz JG, Minguet S, Navarro-Lerida I, Lazcano JJ, Samaniego R, Calvo E et al. Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell 2011; 146: 148–163.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kim JW, Evans C, Weidemann A, Takeda N, Lee YS, Stockmann C et al. Loss of fibroblast HIF-1alpha accelerates tumorigenesis. Cancer Res 2012; 72: 3187–3195.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Toullec A, Gerald D, Despouy G, Bourachot B, Cardon M, Lefort S et al. Oxidative stress promotes myofibroblast differentiation and tumour spreading. EMBO Mol Med 2010; 2: 211–230.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Suzuki A, Kusakai G, Shimojo Y, Chen J, Ogura T, Kobayashi M et al. Involvement of transforming growth factor-beta 1 signaling in hypoxia-induced tolerance to glucose starvation. J Biol Chem 2005; 280: 31557–31563.

    CAS  PubMed  Google Scholar 

  63. Kojima Y, Acar A, Eaton EN, Mellody KT, Scheel C, Ben-Porath I et al. Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc Natl Acad Sci USA 2010; 107: 20009–20014.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Arnold F, West D, Kumar S . Wound healing: the effect of macrophage and tumour derived angiogenesis factors on skin graft vascularization. Br J Exp Pathol 1987; 68: 569–574.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Denko NC, Giaccia AJ . Tumor hypoxia, the physiological link between Trousseau's syndrome (carcinoma-induced coagulopathy) and metastasis. Cancer Res 2001; 61: 795–798.

    CAS  PubMed  Google Scholar 

  66. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nature Med 2004; 10: 858–864.

    CAS  PubMed  Google Scholar 

  67. Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegue E et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 2008; 13: 206–220.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W . Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 2003; 425: 307–311.

    CAS  PubMed  Google Scholar 

  69. De Falco E, Porcelli D, Torella AR, Straino S, Iachininoto MG, Orlandi A et al. SDF-1 involvement in endothelial phenotype and ischemia-induced recruitment of bone marrow progenitor cells. Blood 2004; 104: 3472–3482.

    CAS  PubMed  Google Scholar 

  70. Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Jung S et al. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 2006; 124: 175–189.

    CAS  PubMed  Google Scholar 

  71. Kunz M, Hartmann A, Flory E, Toksoy A, Koczan D, Thiesen HJ et al. Anoxia-induced up-regulation of interleukin-8 in human malignant melanoma. A potential mechanism for high tumor aggressiveness. Am J Pathol 1999; 155: 753–763.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Shi Q, Abbruzzese JL, Huang S, Fidler IJ, Xiong Q, Xie K . Constitutive and inducible interleukin 8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic. Clin Cancer Res 1999; 5: 3711–3721.

    CAS  PubMed  Google Scholar 

  73. Morote-Garcia JC, Napiwotzky D, Kohler D, Rosenberger P . Endothelial Semaphorin 7A promotes neutrophil migration during hypoxia. Proc Natl Acad Sci USA 2012; 109: 14146–14151.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Walmsley SR, Print C, Farahi N, Peyssonnaux C, Johnson RS, Cramer T et al. Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J Exp Med 2005; 201: 105–115.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Walmsley SR, Cowburn AS, Clatworthy MR, Morrell NW, Roper EC, Singleton V et al. Neutrophils from patients with heterozygous germline mutations in the von Hippel Lindau protein (pVHL) display delayed apoptosis and enhanced bacterial phagocytosis. Blood 2006; 108: 3176–3178.

    CAS  PubMed  Google Scholar 

  76. Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N et al. HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 2003; 112: 645–657.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Kempner W . The nature of leukemic blood cells as determined by their metabolism. J Clin Invest 1939; 18: 291–300.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Hannah S, Mecklenburgh K, Rahman I, Bellingan GJ, Greening A, Haslett C et al. Hypoxia prolongs neutrophil survival in vitro. FEBS Lett 1995; 372: 233–237.

    CAS  PubMed  Google Scholar 

  79. Walmsley SR, Chilvers ER, Thompson AA, Vaughan K, Marriott HM, Parker LC et al. Prolyl hydroxylase 3 (PHD3) is essential for hypoxic regulation of neutrophilic inflammation in humans and mice. J Clin Invest 2011; 121: 1053–1063.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. McGovern NN, Cowburn AS, Porter L, Walmsley SR, Summers C, Thompson AA et al. Hypoxia selectively inhibits respiratory burst activity and killing of Staphylococcus aureus in human neutrophils. J Immunol 2011; 186: 453–463.

    CAS  PubMed  Google Scholar 

  81. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: ‘N1’ versus ‘N2’ TAN. Cancer Cell 2009; 16: 183–194.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Gerrard TL, Cohen DJ, Kaplan AM . Human neutrophil-mediated cytotoxicity to tumor cells. J Natl Cancer Inst 1981; 66: 483–488.

    CAS  PubMed  Google Scholar 

  83. Granot Z, Henke E, Comen EA, King TA, Norton L, Benezra R . Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 2011; 20: 300–314.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. di Carlo E, Iezzi M, Pannellini T, Zaccardi F, Modesti A, Forni G et al. Neutrophils in anti-cancer immunological strategies: old players in new games. J Hematother Stem Cell Res 2001; 10: 739–748.

    CAS  PubMed  Google Scholar 

  85. Piccard H, Muschel RJ, Opdenakker G . On the dual roles and polarized phenotypes of neutrophils in tumor development and progression. Crit Rev Oncol Hematol 2012; 82: 296–309.

    CAS  PubMed  Google Scholar 

  86. Houghton AM, Rzymkiewicz DM, Ji H, Gregory AD, Egea EE, Metz HE et al. Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nat Med 2010; 16: 219–223.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Movahedi K, Schoonooghe S, Laoui D, Houbracken I, Waelput W, Breckpot K et al. Nanobody-based targeting of the macrophage mannose receptor for effective in vivo imaging of tumor-associated macrophages. Cancer Res 2012; 72: 4165–4177.

    CAS  PubMed  Google Scholar 

  88. Imtiyaz HZ, Williams EP, Hickey MM, Patel SA, Durham AC, Yuan LJ et al. Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest 2010; 120: 2699–2714.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Movahedi K, Laoui D, Gysemans C, Baeten M, Stange G, Van den Bossche J et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res 2010; 70: 5728–5739.

    CAS  PubMed  Google Scholar 

  90. Mantovani A, Allavena P, Sica A, Balkwill F . Cancer-related inflammation. Nature 2008; 454: 436–444.

    CAS  PubMed  Google Scholar 

  91. Murdoch C, Muthana M, Lewis CE . Hypoxia regulates macrophage functions in inflammation. J Immunol 2005; 175: 6257–6263.

    CAS  PubMed  Google Scholar 

  92. Eltzschig HK, Carmeliet P . Hypoxia and inflammation. N Engl J Med 2011; 364: 656–665.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Nibbering PH, Leijh PC, van Furth R . Quantitative immunocytochemical characterization of mononuclear phagocytes. II. Monocytes and tissue macrophages. Immunology 1987; 62: 171–176.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Biswas SK, Mantovani A . Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 2010; 11: 889–896.

    CAS  PubMed  Google Scholar 

  95. Andreu P, Johansson M, Affara NI, Pucci F, Tan T, Junankar S et al. FcRgamma activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 2010; 17: 121–134.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Saccani A, Schioppa T, Porta C, Biswas SK, Nebuloni M, Vago L et al. p50 nuclear factor-kappaB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance. Cancer Res 2006; 66: 11432–11440.

    CAS  PubMed  Google Scholar 

  97. Fang HY, Hughes R, Murdoch C, Coffelt SB, Biswas SK, Harris AL et al. Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia. Blood 2009; 114: 844–859.

    CAS  PubMed  Google Scholar 

  98. Schioppa T, Uranchimeg B, Saccani A, Biswas SK, Doni A, Rapisarda A et al. Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med 2003; 198: 1391–1402.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Stockmann C, Doedens A, Weidemann A, Zhang N, Takeda N, Greenberg JI et al. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 2008; 456: 814–818.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Doedens AL, Stockmann C, Rubinstein MP, Liao D, Zhang N, DeNardo DG et al. Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. Cancer Res 2010; 70: 7465–7475.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Takeda N, O'Dea EL, Doedens A, Kim JW, Weidemann A, Stockmann C et al. Differential activation and antagonistic function of HIF-{alpha} isoforms in macrophages are essential for NO homeostasis. Genes Dev 2010; 24: 491–501.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Acosta-Iborra B, Elorza A, Olazabal IM, Martin-Cofreces NB, Martin-Puig S, Miro M et al. Macrophage oxygen sensing modulates antigen presentation and phagocytic functions involving IFN-gamma production through the HIF-1 alpha transcription factor. J Immunol 2009; 182: 3155–3164.

    CAS  PubMed  Google Scholar 

  103. Werno C, Menrad H, Weigert A, Dehne N, Goerdt S, Schledzewski K et al. Knockout of HIF-1alpha in tumor-associated macrophages enhances M2 polarization and attenuates their pro-angiogenic responses. Carcinogenesis 2010; 31: 1863–1872.

    CAS  PubMed  Google Scholar 

  104. Takeda Y, Costa S, Delamarre E, Roncal C, Leite de Oliveira R, Squadrito ML et al. Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis. Nature 2011; 479: 122–126.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Hagemann T, Lawrence T, McNeish I, Charles KA, Kulbe H, Thompson RG et al. ‘Re-educating’ tumor-associated macrophages by targeting NF-kappaB. J Exp Med 2008; 205: 1261–1268.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Munder M . Arginase: an emerging key player in the mammalian immune system. Br J Pharmacol 2009; 158: 638–651.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. De Palma M, Lewis CE . Cancer: macrophages limit chemotherapy. Nature 2011; 472: 303–304.

    CAS  PubMed  Google Scholar 

  108. Griffiths L, Binley K, Iqball S, Kan O, Maxwell P, Ratcliffe P et al. The macrophage - a novel system to deliver gene therapy to pathological hypoxia. Gene Ther 2000; 7: 255–262.

    CAS  PubMed  Google Scholar 

  109. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ et al. Immunobiology of dendritic cells. Annual Rev Immunol 2000; 18: 767–811.

    CAS  Google Scholar 

  110. Fainaru O, Almog N, Yung CW, Nakai K, Montoya-Zavala M, Abdollahi A et al. Tumor growth and angiogenesis are dependent on the presence of immature dendritic cells. FASEB J 2010; 24: 1411–1418.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Jantsch J, Chakravortty D, Turza N, Prechtel AT, Buchholz B, Gerlach RG et al. Hypoxia and hypoxia-inducible factor-1 alpha modulate lipopolysaccharide-induced dendritic cell activation and function. J Immunol 2008; 180: 4697–4705.

    CAS  PubMed  Google Scholar 

  112. Rama I, Bruene B, Torras J, Koehl R, Cruzado JM, Bestard O et al. Hypoxia stimulus: An adaptive immune response during dendritic cell maturation. Kidney Int 2008; 73: 816–825.

    CAS  PubMed  Google Scholar 

  113. Naldini A, Morena E, Pucci A, Miglietta D, Riboldi E, Sozzani S et al. Hypoxia affects dendritic cell survival: role of the hypoxia-inducible factor-1alpha and lipopolysaccharide. J Cell Physiol 2012; 227: 587–595.

    CAS  PubMed  Google Scholar 

  114. Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang LP et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 2011; 475: 226–230.

    CAS  PubMed  Google Scholar 

  115. Zhang H, Lake DF, Barbuto JA, Bernstein RM, Grimes WJ, Hersh EM . A human monoclonal antimelanoma single-chain Fv antibody derived from tumor-infiltrating lymphocytes. Cancer Res 1995; 55: 3584–3591.

    CAS  PubMed  Google Scholar 

  116. Imahayashi S, Ichiyoshi Y, Yoshino I, Eifuku R, Takenoyama M, Yasumoto K . Tumor-infiltrating B-cell-derived IgG recognizes tumor components in human lung cancer. Cancer Invest 2000; 18: 530–536.

    CAS  PubMed  Google Scholar 

  117. Lim KH, Telisinghe PU, Abdullah MS, Ramasamy R . Possible significance of differences in proportions of cytotoxic T cells and B-lineage cells in the tumour-infiltrating lymphocytes of typical and atypical medullary carcinomas of the breast. Cancer Immun 2010; 10: 3.

    PubMed  PubMed Central  Google Scholar 

  118. Milne K, Kobel M, Kalloger SE, Barnes RO, Gao D, Gilks CB et al. Systematic analysis of immune infiltrates in high-grade serous ovarian cancer reveals CD20, FoxP3 and TIA-1 as positive prognostic factors. PLoS One 2009; 4: e6412.

    PubMed  PubMed Central  Google Scholar 

  119. Nelson BH . CD20+ B cells: the other tumor-infiltrating lymphocytes. J Immunol 2010; 185: 4977–4982.

    CAS  PubMed  Google Scholar 

  120. Li Q, Teitz-Tennenbaum S, Donald EJ, Li M, Chang AE . In vivo sensitized and in vitro activated B cells mediate tumor regression in cancer adoptive immunotherapy. J Immunol 2009; 183: 3195–3203.

    CAS  PubMed  Google Scholar 

  121. Boes M, Prodeus AP, Schmidt T, Carroll MC, Chen J . A critical role of natural immunoglobulin M in immediate defense against systemic bacterial infection. J Exp Med 1998; 188: 2381–2386.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Kojima H, Gu H, Nomura S, Caldwell CC, Kobata T, Carmeliet P et al. Abnormal B lymphocyte development and autoimmunity in hypoxia-inducible factor 1alpha -deficient chimeric mice. Proc Natl Acad Sci USA 2002; 99: 2170–2174.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Kojima H, Kobayashi A, Sakurai D, Kanno Y, Hase H, Takahashi R et al. Differentiation stage-specific requirement in hypoxia-inducible factor-1alpha-regulated glycolytic pathway during murine B cell development in bone marrow. J Immunol 2010; 184: 154–163.

    CAS  PubMed  Google Scholar 

  124. Zhong X, Gao W, Degauque N, Bai C, Lu Y, Kenny J et al. Reciprocal generation of Th1/Th17 and T(reg) cells by B1 and B2 B cells. Eur J Immunol 2007; 37: 2400–2404.

    CAS  PubMed  Google Scholar 

  125. Rauch PJ, Chudnovskiy A, Robbins CS, Weber GF, Etzrodt M, Hilgendorf I et al. Innate response activator B cells protect against microbial sepsis. Science 2012; 335: 597–601.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Harris DP, Haynes L, Sayles PC, Duso DK, Eaton SM, Lepak NM et al. Reciprocal regulation of polarized cytokine production by effector B and T cells. Nat Immunol 2000; 1: 475–482.

    CAS  PubMed  Google Scholar 

  127. Goda N, Ryan HE, Khadivi B, McNulty W, Rickert RC, Johnson RS . Hypoxia-inducible factor 1alpha is essential for cell cycle arrest during hypoxia. Mol Cell Biol 2003; 23: 359–369.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Harris JW . Effects of tumor-like assay conditions, lonizing radiation, and hyperthermia on immune lysis of tumor cells by cytotoxic T-lymphocytes. Cancer Res 1976; 36: 2733–2739.

    CAS  PubMed  Google Scholar 

  129. Nathan CF, Mercer-Smith JA, Desantis NM, Palladino MA . Role of oxygen in T cell-mediated cytolysis. J Immunol 1982; 129: 2164–2171.

    CAS  PubMed  Google Scholar 

  130. Loeffler DA, Juneau PL, Masserant S . Influence of tumour physico-chemical conditions on interleukin-2-stimulated lymphocyte proliferation. Br J Cancer 1992; 66: 619–622.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Carraro F, Pucci A, Pellegrini M, Pelicci PG, Baldari CT, Naldini A . p66Shc is involved in promoting HIF-1alpha accumulation and cell death in hypoxic T cells. J Cell Physiol 2007; 211: 439–447.

    CAS  PubMed  Google Scholar 

  132. Naldini A, Morena E, Pucci A, Pellegrini M, Baldari CT, Pelicci PG et al. The adaptor protein p66Shc is a positive regulator in the angiogenic response induced by hypoxic T cells. J Leukoc Biol 2010; 87: 365–369.

    CAS  PubMed  Google Scholar 

  133. Ben-Shoshan J, Maysel-Auslender S, Mor A, Keren G, George J . Hypoxia controls CD4+CD25+ regulatory T-cell homeostasis via hypoxia-inducible factor-1alpha. Eur J Immunol 2008; 38: 2412–2418.

    CAS  PubMed  Google Scholar 

  134. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 2011; 146: 772–784.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 2011; 208: 1367–1376.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Pearce EL . Metabolism in T cell activation and differentiation. Curr Opin Immunol 2010; 22: 314–320.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Fox CJ, Hammerman PS, Thompson CB . Fuel feeds function: energy metabolism and the T-cell response. Nat Rev Immunol 2005; 5: 844–852.

    CAS  PubMed  Google Scholar 

  138. Finlay DK, Rosenzweig E, Sinclair LV, Feijoo-Carnero C, Hukelmann JL, Rolf J et al. PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J Exp Med 2012; 209: 2441–2453.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Palazon A, Aragones J, Morales-Kastresana A, de Landazuri MO, Melero I . Molecular pathways: hypoxia response in immune cells fighting or promoting cancer. Clin Cancer Res 2012; 18: 1207–1213.

    CAS  PubMed  Google Scholar 

  140. Vivier E, Ugolini S, Blaise D, Chabannon C, Brossay L . Targeting natural killer cells and natural killer T cells in cancer. Nat Rev Immunol 2012; 12: 239–252.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Loeffler DA, Juneau PL, Heppner GH . Natural killer-cell activity under conditions reflective of tumor micro-environment. Int J Cancer 1991; 48: 895–899.

    CAS  PubMed  Google Scholar 

  142. Fink T, Ebbesen P, Koppelhus U, Zachar V . Natural killer cell-mediated basal and interferon-enhanced cytotoxicity against liver cancer cells is significantly impaired under in vivo oxygen conditions. Scand J Immunol 2003; 58: 607–612.

    CAS  PubMed  Google Scholar 

  143. Liu D, Song L, Wei J, Courtney AN, Gao X, Marinova E et al. IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity. J Clin Invest 2012; 122: 2221–2233.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Gay LJ, Felding-Habermann B . Contribution of platelets to tumour metastasis. Nat Rev Cancer 2011; 11: 123–134.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Verheul HM, Hoekman K, Luykx-de Bakker S, Eekman CA, Folman CC, Broxterman HJ et al. Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res 1997; 3: 2187–2190.

    CAS  PubMed  Google Scholar 

  146. Italiano JE Jr, Richardson JL, Patel-Hett S, Battinelli E, Zaslavsky A, Short S et al. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood 2008; 111: 1227–1233.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Feng W, Madajka M, Kerr BA, Mahabeleshwar GH, Whiteheart SW, Byzova TV . A novel role for platelet secretion in angiogenesis: mediating bone marrow-derived cell mobilization and homing. Blood 2011; 117: 3893–3902.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Zaslavsky A, Baek KH, Lynch RC, Short S, Grillo J, Folkman J et al. Platelet-derived thrombospondin-1 is a critical negative regulator and potential biomarker of angiogenesis. Blood 2010; 115: 4605–4613.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Klement GL, Yip TT, Cassiola F, Kikuchi L, Cervi D, Podust V et al. Platelets actively sequester angiogenesis regulators. Blood 2009; 113: 2835–2842.

    CAS  PubMed  Google Scholar 

  150. Elwood PC, Gallagher AM, Duthie GG, Mur LA, Morgan G . Aspirin, salicylates, and cancer. Lancet 2009; 373: 1301–1309.

    CAS  PubMed  Google Scholar 

  151. Kaiser J . Will an aspirin a day keep cancer away? Science 2012; 337: 1471–1473.

    CAS  PubMed  Google Scholar 

  152. Sitia G, Aiolfi R, Di Lucia P, Mainetti M, Fiocchi A, Mingozzi F et al. Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B. Proc Natl Acad Sci USA 2012; 109: E2165–E2172.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Sierko E, Wojtukiewicz MZ . Inhibition of platelet function: does it offer a chance of better cancer progression control? Semin Thromb Hemost 2007; 33: 712–721.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Sandy Smets for technical assistance. AC is granted by EMBO; GDC and VF are granted by FWO. MM was supported by an ERC starting-Grant and FWO (G083613N; G068612N; G071810N).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M Mazzone.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Casazza, A., Di Conza, G., Wenes, M. et al. Tumor stroma: a complexity dictated by the hypoxic tumor microenvironment. Oncogene 33, 1743–1754 (2014). https://doi.org/10.1038/onc.2013.121

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.121

Keywords

This article is cited by

Search

Quick links