Regulation of Blood and Lymphatic Vessels by Immune Cells in Tumors and Metastasis

Literature Cited

1. 1.

   Leite de Oliveira R, Hamm A, Mazzone M 2011. Growing tumor vessels: more than one way to skin a cat—implications for angiogenesis targeted cancer therapies. Mol. Aspects Med. 32:71–87
   [Google Scholar]
2. 2.

   De Palma M, Biziato D, Petrova TV 2017. Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer 17:457–74
   [Google Scholar]
3. 3.

   Black WC, Welch HG 1993. Advances in diagnostic imaging and overestimations of disease prevalence and the benefits of therapy. N. Engl. J. Med. 328:1237–43
   [Google Scholar]
4. 4.

   Bergers G, Benjamin LE 2003. Tumorigenesis and the angiogenic switch. Nat. Rev. Cancer 3:401–10
   [Google Scholar]
5. 5.

   Baeriswyl V, Christofori G 2009. The angiogenic switch in carcinogenesis. Semin. Cancer Biol. 19:329–37
   [Google Scholar]
6. 6.

   Saharinen P, Eklund L, Pulkki K, Bono P, Alitalo K 2011. VEGF and angiopoietin signaling in tumor angiogenesis and metastasis. Trends Mol. Med. 17:347–62
   [Google Scholar]
7. 7.

   Carmeliet P. 2005. Angiogenesis in life, disease and medicine. Nature 438:932–36
   [Google Scholar]
8. 8.

   Baluk P, Hashizume H, McDonald DM 2005. Cellular abnormalities of blood vessels as targets in cancer. Curr. Opin. Genet. Dev. 15:102–11
   [Google Scholar]
9. 9.

   Carmeliet P, Jain RK 2011. Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298–307
   [Google Scholar]
10. 10.

    Jain RK. 2005. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62
    [Google Scholar]
11. 11.

    Jain RK. 2013. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J. Clin. Oncol. 31:2205–18
    [Google Scholar]
12. 12.

    Folkman J. 1974. Proceedings: tumor angiogenesis factor. Cancer Res 34:2109–13
    [Google Scholar]
13. 13.

    Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P et al. 2006. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444:1032–37
    [Google Scholar]
14. 14.

    Ridgway J, Zhang G, Wu Y, Stawicki S, Liang WC et al. 2006. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444:1083–87
    [Google Scholar]
15. 15.

    Yan M, Callahan CA, Beyer JC, Allamneni KP, Zhang G et al. 2010. Chronic DLL4 blockade induces vascular neoplasms. Nature 463:E6–7
    [Google Scholar]
16. 16.

    Liu Z, Turkoz A, Jackson EN, Corbo JC, Engelbach JA et al. 2011. Notch1 loss of heterozygosity causes vascular tumors and lethal hemorrhage in mice. J. Clin. Investig. 121:800–8
    [Google Scholar]
17. 17.

    Leite de Oliveira R, Deschoemaeker S, Henze AT, Debackere K, Finisguerra V et al. 2012. Gene-targeting of Phd2 improves tumor response to chemotherapy and prevents side-toxicity. Cancer Cell 22:263–77
    [Google Scholar]
18. 18.

    Mazzone M, Dettori D, de Oliveira RL, Loges S, Schmidt T et al. 2009. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136:839–51
    [Google Scholar]
19. 19.

    Xian X, Håkansson J, Ståhlberg A, Lindblom P, Betsholtz C et al. 2006. Pericytes limit tumor cell metastasis. J. Clin. Investig. 116:642–51
    [Google Scholar]
20. 20.

    Tolaney SM, Boucher Y, Duda DG, Martin JD, Seano G et al. 2015. Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients. PNAS 112:14325–30
    [Google Scholar]
21. 21.

    Lambrechts D, Claes B, Delmar P, Reumers J, Mazzone M et al. 2012. VEGF pathway genetic variants as biomarkers of treatment outcome with bevacizumab: an analysis of data from the AViTA and AVOREN randomised trials. Lancet Oncol 13:724–33
    [Google Scholar]
22. 22.

    Leu AJ, Berk DA, Lymboussaki A, Alitalo K, Jain RK 2000. Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation. Cancer Res 60:4324–27
    [Google Scholar]
23. 23.

    Mainiero MB. 2010. Regional lymph node staging in breast cancer: the increasing role of imaging and ultrasound-guided axillary lymph node fine needle aspiration. Radiol. Clin. N. Am. 48:989–97
    [Google Scholar]
24. 24.

    Hofmann M, Guschel M, Bernd A, Bereiter-Hahn J, Kaufmann R et al. 2006. Lowering of tumor interstitial fluid pressure reduces tumor cell proliferation in a xenograft tumor model. Neoplasia 8:89–95
    [Google Scholar]
25. 25.

    Murdoch C, Muthana M, Coffelt SB, Lewis CE 2008. The role of myeloid cells in the promotion of tumour angiogenesis. Nat. Rev. Cancer 8:618–31
    [Google Scholar]
26. 26.

    Talmadge JE, Gabrilovich DI 2013. History of myeloid-derived suppressor cells. Nat. Rev. Cancer 13:739–52
    [Google Scholar]
27. 27.

    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 56:4625–29
    [Google Scholar]
28. 28.

    Lewis CE, Harney AS, Pollard JW 2016. The multifaceted role of perivascular macrophages in tumors. Cancer Cell 30:18–25
    [Google Scholar]
29. 29.

    Bingle L, Lewis CE, Corke KP, Reed MW, Brown NJ 2006. Macrophages promote angiogenesis in human breast tumour spheroids in vivo. Br. J. Cancer 94:101–7
    [Google Scholar]
30. 30.

    Coussens LM, Tinkle CL, Hanahan D, Werb Z 2000. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103:481–90
    [Google Scholar]
31. 31.

    Du R, Lu KV, Petritsch C, Liu P, Ganss R et al. 2008. HIF1α induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13:206–20
    [Google Scholar]
32. 32.

    Giraudo E, Inoue M, Hanahan D 2004. An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J. Clin. Investig. 114:623–33
    [Google Scholar]
33. 33.

    Lin EY, Li JF, Gnatovskiy L, Deng Y, Zhu L et al. 2006. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 66:11238–46
    [Google Scholar]
34. 34.

    Shojaei F, Wu X, Zhong C, Yu L, Liang XH et al. 2007. Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450:825–31
    [Google Scholar]
35. 35.

    Mantovani A. 2010. Molecular pathways linking inflammation and cancer. Curr. Mol. Med. 10:369–73
    [Google Scholar]
36. 36.

    Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G et al. 2009. Polarization of tumor-associated neutrophil phenotype by TGF-β: “N1” versus “N2” TAN. Cancer Cell 16:183–94
    [Google Scholar]
37. 37.

    Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR et al. 2011. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331:1612–16
    [Google Scholar]
38. 38.

    Palmieri EM, Menga A, Martin-Pérez R, Quinto A, Riera-Domingo C et al. 2017. Pharmacologic or genetic targeting of glutamine synthetase skews macrophages toward an M1-like phenotype and inhibits tumor metastasis. Cell Rep 20:1654–66
    [Google Scholar]
39. 39.

    Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I et al. 2011. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19:31–44
    [Google Scholar]
40. 40.

    Stockmann C, Doedens A, Weidemann A, Zhang N, Takeda N et al. 2008. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456:814–18
    [Google Scholar]
41. 41.

    Priceman SJ, Sung JL, Shaposhnik Z, Burton JB, Torres-Collado AX et al. 2010. Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy. Blood 115:1461–71
    [Google Scholar]
42. 42.

    Bergers G, Brekken R, McMahon G, Vu TH, Itoh T et al. 2000. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat. Cell Biol. 2:737–44
    [Google Scholar]
43. 43.

    De Palma M, Murdoch C, Venneri MA, Naldini L, Lewis CE 2007. Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications. Trends Immunol 28:519–24
    [Google Scholar]
44. 44.

    Matsubara T, Kanto T, Kuroda S, Yoshio S, Higashitani K et al. 2013. TIE2-expressing monocytes as a diagnostic marker for hepatocellular carcinoma correlates with angiogenesis. Hepatology 57:1416–25
    [Google Scholar]
45. 45.

    De Palma M, Venneri MA, Galli R, Sergi LS, Politi LS et al. 2005. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8:211–26
    [Google Scholar]
46. 46.

    Mazzieri R, Pucci F, Moi D, Zonari E, Ranghetti A 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 19:512–26
    [Google Scholar]
47. 47.

    Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR et al. 1999. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284:1994–8
    [Google Scholar]
48. 48.

    Papapetropoulos A, Garcia-Cardena G, Dengler TJ, Maisonpierre PC, Yancopoulos GD, Sessa WC 1999. Direct actions of angiopoietin-1 on human endothelium: evidence for network stabilization, cell survival, and interaction with other angiogenic growth factors. Lab. Investig. 79:213–23
    [Google Scholar]
49. 49.

    Bird L. 2016. Tumour immunology: neutrophils help tumours spread. Nat. Rev. Immunol. 16:74–75
    [Google Scholar]
50. 50.

    Finisguerra V, Di Conza G, Di Matteo M, Serneels J, Costa S et al. 2015. MET is required for the recruitment of anti-tumoural neutrophils. Nature 522:349–53
    [Google Scholar]
51. 51.

    Liang W, Ferrara N 2016. The complex role of neutrophils in tumor angiogenesis and metastasis. Cancer Immunol. Res. 4:83–91
    [Google Scholar]
52. 52.

    Coffelt SB, de Visser KE 2015. Immune-mediated mechanisms influencing the efficacy of anticancer therapies. Trends Immunol 36:198–216
    [Google Scholar]
53. 53.

    Gaudry M, Bregerie O, Andrieu V, El Benna J, Pocidalo MA, Hakim J 1997. Intracellular pool of vascular endothelial growth factor in human neutrophils. Blood 90:4153–61
    [Google Scholar]
54. 54.

    Nozawa H, Chiu C, Hanahan D 2006. Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. PNAS 103:12493–98
    [Google Scholar]
55. 55.

    Movahedi K, Guilliams M, Van den Bossche J, Van den Bergh R, Gysemans C et al. 2008. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 111:4233–44
    [Google Scholar]
56. 56.

    Kujawski M, Kortylewski M, Lee H, Herrmann A, Kay H, Yu H 2008. Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. J. Clin. Investig. 118:3367–77
    [Google Scholar]
57. 57.

    Yang L, Huang J, Ren X, Gorska AE, Chytil A et al. 2008. Abrogation of TGFβ signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 13:23–35
    [Google Scholar]
58. 58.

    Pan PY, Wang GX, Yin B, Ozao J, Ku T et al. 2008. Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function. Blood 111:219–28
    [Google Scholar]
59. 59.

    Adams RH, Alitalo K 2007. Molecular regulation of angiogenesis and lymphangiogenesis. Nat. Rev. Mol. Cell Biol. 8:464–78
    [Google Scholar]
60. 60.

    de Palma M, Coussens LM 2008. Immune cells and inflammatory mediators as regulators of tumor angiogenesis. Angiogenesis: An Integrative Approach from Science to Medicine WD Figg, J Folkman 225–37 New York: Springer Sci. Bus. Media
    [Google Scholar]
61. 61.

    Betsholtz C, Lindblom P, Bjarnegard M, Enge M, Gerhardt H, Lindahl P 2004. Role of platelet-derived growth factor in mesangium development and vasculopathies: lessons from platelet-derived growth factor and platelet-derived growth factor receptor mutations in mice. Curr. Opin. Nephrol. Hypertens. 13:45–52
    [Google Scholar]
62. 62.

    De Falco E, Porcelli D, Torella AR, Straino S, Iachininoto MG et al. 2004. SDF-1 involvement in endothelial phenotype and ischemia-induced recruitment of bone marrow progenitor cells. Blood 104:3472–82
    [Google Scholar]
63. 63.

    Compagni A, Wilgenbus P, Impagnatiello MA, Cotten M, Christofori G 2000. Fibroblast growth factors are required for efficient tumor angiogenesis. Cancer Res 60:7163–69
    [Google Scholar]
64. 64.

    Joyce JA, Hanahan D 2004. Multiple roles for cysteine cathepsins in cancer. Cell Cycle 3:1516–19
    [Google Scholar]
65. 65.

    Potente M, Gerhardt H, Carmeliet P 2011. Basic and therapeutic aspects of angiogenesis. Cell 146:873–87
    [Google Scholar]
66. 66.

    Wang M, Wang T, Liu S, Yoshida D, Teramoto A 2003. The expression of matrix metalloproteinase-2 and -9 in human gliomas of different pathological grades. Brain Tumor Pathol 20:65–72
    [Google Scholar]
67. 67.

    Pahler JC, Tazzyman S, Erez N, Chen YY, Murdoch C et al. 2008. Plasticity in tumor-promoting inflammation: impairment of macrophage recruitment evokes a compensatory neutrophil response. Neoplasia 10:329–40
    [Google Scholar]
68. 68.

    Rivera LB, Meyronet D, Hervieu V, Frederick MJ, Bergsland E, Bergers G 2015. Intratumoral myeloid cells regulate responsiveness and resistance to antiangiogenic therapy. Cell Rep 11:577–91
    [Google Scholar]
69. 69.

    Yang C, Lee H, Pal S, Jove V, Deng J et al. 2013. B cells promote tumor progression via STAT3 regulated-angiogenesis. PLOS ONE 8:e64159
    [Google Scholar]
70. 70.

    Andreu P, Johansson M, Affara NI, Pucci F, Tan T et al. 2010. FcRγ activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 17:121–34
    [Google Scholar]
71. 71.

    DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D et al. 2009. CD4⁺ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16:91–102
    [Google Scholar]
72. 72.

    Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A et al. 2011. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 475:226–30
    [Google Scholar]
73. 73.

    Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S et al. 2007. Anti-PIGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131:463–75
    [Google Scholar]
74. 74.

    Zumsteg A, Christofori G 2012. Myeloid cells and lymphangiogenesis. Cold Spring Harb. Perspect. Med. 2:a006494
    [Google Scholar]
75. 75.

    Schoppmann SF, Birner P, Stöckl J, Kalt R, Ullrich R et al. 2002. Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am. J. Pathol. 161:947–56
    [Google Scholar]
76. 76.

    Tammela T, Petrova TV, Alitalo K 2005. Molecular lymphangiogenesis: new players. Trends Cell Biol 15:434–41
    [Google Scholar]
77. 77.

    Watari K, Shibata T, Kawahara A, Sata K, Nabeshima H et al. 2014. Tumor-derived interleukin-1 promotes lymphangiogenesis and lymph node metastasis through M2-type macrophages. PLOS ONE 9:e99568
    [Google Scholar]
78. 78.

    Moussai D, Mitsui H, Pettersen JS, Pierson KC, Shah KR et al. 2011. The human cutaneous squamous cell carcinoma microenvironment is characterized by increased lymphatic density and enhanced expression of macrophage-derived VEGF-C. J. Investig. Dermatol. 131:229–36
    [Google Scholar]
79. 79.

    Gerszten RE, Garcia-Zepeda EA, Lim YC, Yoshida M, Ding HA et al. 1999. MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature 398:718–23
    [Google Scholar]
80. 80.

    Zhang B, Zhang Y, Yao G, Gao J, Yang B et al. 2012. M2-polarized macrophages promote metastatic behavior of Lewis lung carcinoma cells by inducing vascular endothelial growth factor-C expression. Clinics 67:901–6
    [Google Scholar]
81. 81.

    Ji H, Cao R, Yang Y, Zhang Y, Iwamoto H et al. 2014. TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling. Nat. Commun. 5:4944
    [Google Scholar]
82. 82.

    Casazza A, Finisguerra V, Capparuccia L, Camperi A, Swiercz JM et al. 2010. Sema3E-Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice. J. Clin. Investig. 120:2684–98
    [Google Scholar]
83. 83.

    Du X, Gao Y, Sun P, Chen Y, Chang H, Wei B 2018. CD163⁺/CD68⁺ tumor-associated macrophages in angiosarcoma with lymphedema. Int. J. Clin. Exp. Pathol. 11:2106–11
    [Google Scholar]
84. 84.

    Cursiefen C, Chen L, Borges LP, Jackson D, Cao J et al. 2004. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J. Clin. Investig. 113:1040–50
    [Google Scholar]
85. 85.

    Hong YK, Lange-Asschenfeldt B, Velasco P, Hirakawa S, Kunstfeld R et al. 2004. VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the α1β1 and α2β1 integrins. FASEB J 18:1111–13
    [Google Scholar]
86. 86.

    Björndahl MA, Cao R, Burton JB, Brakenhielm E, Religa P et al. 2005. Vascular endothelial growth factor-a promotes peritumoral lymphangiogenesis and lymphatic metastasis. Cancer Res 65:9261–68
    [Google Scholar]
87. 87.

    Hirakawa S, Kodama S, Kunstfeld R, Kajiya K, Brown LF, Detmar M 2005. VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J. Exp. Med. 201:1089–99
    [Google Scholar]
88. 88.

    Mantovani A, Romero P, Palucka AK, Marincola FM 2008. Tumour immunity: effector response to tumour and role of the microenvironment. Lancet 371:771–83
    [Google Scholar]
89. 89.

    Forget MA, Voorhees JL, Cole SL, Dakhlallah D, Patterson IL et al. 2014. Macrophage colony-stimulating factor augments Tie2-expressing monocyte differentiation, angiogenic function, and recruitment in a mouse model of breast cancer. PLOS ONE 9:e98623
    [Google Scholar]
90. 90.

    Karaman S, Detmar M 2014. Mechanisms of lymphatic metastasis. J. Clin. Investig. 124:922–28
    [Google Scholar]
91. 91.

    Storr SJ, Safuan S, Ahmad N, El-Refaee M, Jackson AM, Martin SG 2017. Macrophage-derived interleukin-1beta promotes human breast cancer cell migration and lymphatic adhesion in vitro. Cancer Immunol. Immunother. 66:1287–94
    [Google Scholar]
92. 92.

    Bron S, Henry L, Faes-Van't Hull E, Turrini R, Vanhecke D et al. 2016. TIE-2-expressing monocytes are lymphangiogenic and associate specifically with lymphatics of human breast cancer. Oncoimmunology 5:e1073882
    [Google Scholar]
93. 93.

    Schindl M, Schoppmann SF, Samonigg H, Hausmaninger H, Kwasny W et al. 2002. Overexpression of hypoxia-inducible factor 1α is associated with an unfavorable prognosis in lymph node-positive breast cancer. Clin. Cancer Res. 8:1831–7
    [Google Scholar]
94. 94.

    Mantovani A. 2010. La mala educacíon of tumor-associated macrophages: diverse pathways and new players. Cancer Cell 17:111–12
    [Google Scholar]
95. 95.

    Mantovani A. 2010. Role of inflammatory cells and mediators in tumor invasion and metastasis. Cancer Metastas. Rev. 29:241
    [Google Scholar]
96. 96.

    Zumsteg A, Baeriswyl V, Imaizumi N, Schwendener R, Ruegg C, Christofori G 2009. Myeloid cells contribute to tumor lymphangiogenesis. PLOS ONE 4:e7067
    [Google Scholar]
97. 97.

    Maruyama K, Ii M, Cursiefen C, Jackson DG, Keino H et al. 2005. Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages. J. Clin. Investig. 115:2363–72
    [Google Scholar]
98. 98.

    Kuwana M, Okazaki Y, Kodama H, Satoh T, Kawakami Y, Ikeda Y 2006. Endothelial differentiation potential of human monocyte-derived multipotential cells. Stem Cells 24:2733–43
    [Google Scholar]
99. 99.

    De Palma M, Venneri MA, Roca C, Naldini L 2003. Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nat. Med. 9:789–95
    [Google Scholar]
100. 100.

     Ran S, Montgomery KE 2012. Macrophage-mediated lymphangiogenesis: the emerging role of macrophages as lymphatic endothelial progenitors. Cancers 4:618–57
     [Google Scholar]
101. 101.

     Kerjaschki D. 2005. The crucial role of macrophages in lymphangiogenesis. J. Clin. Investig. 115:2316–19
     [Google Scholar]
102. 102.

     He Y, Rajantie I, Ilmonen M, Makinen T, Karkkainen MJ et al. 2004. Preexisting lymphatic endothelium but not endothelial progenitor cells are essential for tumor lymphangiogenesis and lymphatic metastasis. Cancer Res 64:3737–40
     [Google Scholar]
103. 103.

     Zumsteg A, Christofori G 2009. Corrupt policemen: inflammatory cells promote tumor angiogenesis. Curr. Opin. Oncol. 21:60–70
     [Google Scholar]
104. 104.

     Fankhauser M, Broggi MAS, Potin L, Bordry N, Jeanbart L et al. 2017. Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma. Sci. Transl. Med. 9:eeal4712
     [Google Scholar]
105. 105.

     Avraham T, Zampell JC, Yan A, Elhadad S, Weitman ES et al. 2013. Th2 differentiation is necessary for soft tissue fibrosis and lymphatic dysfunction resulting from lymphedema. FASEB J 27:1114–26
     [Google Scholar]
106. 106.

     García Nores GD, Ly CL, Cuzzone DA, Kataru RP, Hespe GE, Torrisi JS et al. 2018. CD4⁺ T cells are activated in regional lymph nodes and migrate to skin to initiate lymphedema. Nat. Commun. 9:11970
     [Google Scholar]
107. 107.

     Kataru RP, Kim H, Jang C, Choi DK, Koh BI et al. 2011. T lymphocytes negatively regulate lymph node lymphatic vessel formation. Immunity 34:96–107
     [Google Scholar]
108. 108.

     Alishekevitz D, Gingis-Velitski S, Kaidar-Person O, Gutter-Kapon L, Scherer SD et al. 2016. Macrophage-induced lymphangiogenesis and metastasis following paclitaxel chemotherapy is regulated by VEGFR3. Cell Rep 17:1344–56
     [Google Scholar]
109. 109.

     Xu J, Escamilla J, Mok S, David J, Priceman S et al. 2013. CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res 73:2782–94
     [Google Scholar]
110. 110.

     Lewis CE, Pollard JW 2006. Distinct role of macrophages in different tumor microenvironments. Cancer Res 66:605–12
     [Google Scholar]
111. 111.

     Ruffell B, Coussens LM 2015. Macrophages and therapeutic resistance in cancer. Cancer Cell 27:462–72
     [Google Scholar]
112. 112.

     Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L et al. 2005. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–7
     [Google Scholar]
113. 113.

     Huang X, Gao L, Wang S, Lee CK, Ordentlich P, Liu B 2009. HDAC inhibitor SNDX-275 induces apoptosis in erbB2-overexpressing breast cancer cells via down-regulation of erbB3 expression. Cancer Res 69:8403–11
     [Google Scholar]
114. 114.

     Erler JT, Bennewith KL, Cox TR, Lang G, Bird D et al. 2009. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15:35–44
     [Google Scholar]
115. 115.

     Hiratsuka S, Duda DG, Huang Y, Goel S, Sugiyama T et al. 2011. C-X-C receptor type 4 promotes metastasis by activating p38 mitogen-activated protein kinase in myeloid differentiation antigen (Gr-1)-positive cells. PNAS 108:302–7
     [Google Scholar]
116. 116.

     Qian BZ, Li J, Zhang H, Kitamura T, Zhang J et al. 2011. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475:222–25
     [Google Scholar]
117. 117.

     Kitamura T, Qian BZ, Soong D, Cassetta L, Noy R et al. 2015. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J. Exp. Med. 212:1043–59
     [Google Scholar]
118. 118.

     Celus W, Di Conza G, Oliveira AI, Ehling M, Costa BM et al. 2017. Loss of caveolin-1 in metastasis-associated macrophages drives lung metastatic growth through increased angiogenesis. Cell Rep 21:2842–54
     [Google Scholar]
119. 119.

     Qian BZ, Zhang H, Li J, He T, Yeo EJ et al. 2015. FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis. J. Exp. Med. 212:1433–48
     [Google Scholar]
120. 120.

     Chitu V, Stanley ER 2006. Colony-stimulating factor-1 in immunity and inflammation. Curr. Opin. Immunol. 18:39–48
     [Google Scholar]
121. 121.

     Srivastava K, Hu J, Korn C, Savant S, Teichert M et al. 2014. Postsurgical adjuvant tumor therapy by combining anti-angiopoietin-2 and metronomic chemotherapy limits metastatic growth. Cancer Cell 26:880–95
     [Google Scholar]
122. 122.

     Shojaei F, Wu X, Qu X, Kowanetz M, Yu L et al. 2009. G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. PNAS 106:6742–47
     [Google Scholar]
123. 123.

     Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME et al. 2007. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b⁺Gr1⁺ myeloid cells. Nat. Biotechnol. 25:911–20
     [Google Scholar]
124. 124.

     Eyles J, Puaux AL, Wang X, Toh B, Prakash C et al. 2010. Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J. Clin. Investig. 120:2030–39
     [Google Scholar]
125. 125.

     Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ et al. 2007. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450:903–7
     [Google Scholar]
126. 126.

     Müller-Hermelink N, Braumüller H, Pichler B, Wieder T, Mailhammer R et al. 2008. TNFR1 signaling and IFN-γ signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis. Cancer Cell 13:507–18
     [Google Scholar]
127. 127.

     Casazza A, Di Conza G, Wenes M, Finisguerra V, Deschoemaeker S, Mazzone M 2014. Tumor stroma: a complexity dictated by the hypoxic tumor microenvironment. Oncogene 33:1743–54
     [Google Scholar]
128. 128.

     Mazzone M, Menga A, Castegna A 2018. Metabolism and TAM functions-it takes two to tango. FEBS J 285:700–16
     [Google Scholar]
129. 129.

     Henze AT, Mazzone M 2016. The impact of hypoxia on tumor-associated macrophages. J. Clin. Investig. 126:3672–79
     [Google Scholar]
130. 130.

     Ghesquiere B, Wong BW, Kuchnio A, Carmeliet P 2014. Metabolism of stromal and immune cells in health and disease. Nature 511:167–76
     [Google Scholar]
131. 131.

     Wenes M, Shang M, Di Matteo M, Goveia J, Martin-Pérez R et al. 2016. Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metab 24:701–15
     [Google Scholar]
132. 132.

     Laoui D, Van Overmeire E, Di Conza G, Aldeni C, Keirsse J et al. 2014. Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population. Cancer Res 74:24–30
     [Google Scholar]
133. 133.

     Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N et al. 2004. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat. Med. 10:858–64
     [Google Scholar]
134. 134.

     Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W 2003. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 425:307–11
     [Google Scholar]
135. 135.

     Lewis CE, De Palma M, Naldini L 2007. Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2. Cancer Res 67:8429–32
     [Google Scholar]
136. 136.

     Squadrito ML, Pucci F, Magri L, Moi D, Gilfillan GD et al. 2012. miR-511-3p modulates genetic programs of tumor-associated macrophages. Cell Rep 1:141–54
     [Google Scholar]
137. 137.

     Casazza A, Mazzone M 2014. Altering the intratumoral localization of macrophages to inhibit cancer progression. Oncoimmunology 3:e27872
     [Google Scholar]
138. 138.

     Casazza A, Kigel B, Maione F, Capparuccia L, Kessler O et al. 2012. Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform. EMBO Mol. Med. 4:234–50
     [Google Scholar]
139. 139.

     Miyauchi JT, Caponegro MD, Chen D, Choi MK, Li M, Tsirka SE 2018. Deletion of neuropilin 1 from microglia or bone marrow-derived macrophages slows glioma progression. Cancer Res 78:685–94
     [Google Scholar]
140. 140.

     Marone G, Varricchi G, Loffredo S, Granata F 2016. Mast cells and basophils in inflammatory and tumor angiogenesis and lymphangiogenesis. Eur. J. Pharmacol. 778:146–51
     [Google Scholar]
141. 141.

     Morisada T, Oike Y, Yamada Y, Urano T, Akao M et al. 2005. Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation. Blood 105:4649–56
     [Google Scholar]
142. 142.

     Fiedler U, Augustin HG 2006. Angiopoietins: a link between angiogenesis and inflammation. Trends Immunol 27:552–58
     [Google Scholar]
143. 143.

     Casazza A, Laoui D, Wenes M, Rizzolio S, Bassani N et al. 2013. Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 24:695–709
     [Google Scholar]
144. 144.

     Lewis C, Murdoch C 2005. Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies. Am. J. Pathol. 167:627–35
     [Google Scholar]
145. 145.

     Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R et al. 2003. HIF-1α is essential for myeloid cell-mediated inflammation. Cell 112:645–57
     [Google Scholar]
146. 146.

     Fang HY, Hughes R, Murdoch C, Coffelt SB, Biswas SK et al. 2009. Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia. Blood 114:844–59
     [Google Scholar]
147. 147.

     Doedens AL, Stockmann C, Rubinstein MP, Liao D, Zhang N et al. 2010. Macrophage expression of hypoxia-inducible factor-1α suppresses T-cell function and promotes tumor progression. Cancer Res 70:7465–75
     [Google Scholar]
148. 148.

     Imtiyaz HZ, Williams EP, Hickey MM, Patel SA, Durham AC et al. 2010. Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation. J. Clin. Investig. 120:2699–714
     [Google Scholar]
149. 149.

     Takeda Y, Costa S, Delamarre E, Roncal C, de Oliveira RL et al. 2011. Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis. Nature 479:122–U53
     [Google Scholar]
150. 150.

     Hamm A, Veschini L, Takeda Y, Costa S, Delamarre E et al. 2013. PHD2 regulates arteriogenic macrophages through TIE2 signalling. EMBO Mol. Med. 5:843–57
     [Google Scholar]
151. 151.

     Joshi S, Singh AR, Zulcic M, Durden DL 2014. A macrophage-dominant PI3K isoform controls hypoxia-induced HIF1α and HIF2α stability and tumor growth, angiogenesis, and metastasis. Mol. Cancer Res. 12:1520–31
     [Google Scholar]
152. 152.

     Di Conza G, Trusso Cafarello S, Loroch S, Mennerich D, Deschoemaeker S et al. 2017. The mTOR and PP2A pathways regulate PHD2 phosphorylation to fine-tune HIF1α levels and colorectal cancer cell survival under hypoxia. Cell Rep 18:1699–712
     [Google Scholar]
153. 153.

     Takeda N, O'Dea EL, Doedens A, Kim JW, Weidemann A et al. 2010. Differential activation and antagonistic function of HIF-α isoforms in macrophages are essential for NO homeostasis. Genes Dev 24:491–501
     [Google Scholar]
154. 154.

     De Henau O, Rausch M, Winkler D, Campesato LF, Liu C et al. 2016. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature 539:443–47
     [Google Scholar]
155. 155.

     Kaneda MM, Messer KS, Ralainirina N, Li H, Leem CJ et al. 2016. PI3Kγ is a molecular switch that controls immune suppression. Nature 539:437–42
     [Google Scholar]
156. 156.

     Palazon A, Tyrakis PA, Macias D, Velica P, Rundqvist H et al. 2017. An HIF-1α/VEGF-A axis in cytotoxic T cells regulates tumor progression. Cancer Cell 32:669–83.e5
     [Google Scholar]
157. 157.

     Clever D, Roychoudhuri R, Constantinides MG, Askenase MH, Sukumar M et al. 2016. Oxygen sensing by T cells establishes an immunologically tolerant metastatic niche. Cell 166:1117–31.e14
     [Google Scholar]
158. 158.

     Gropper Y, Feferman T, Shalit T, Salame TM, Porat Z, Shakhar G 2017. Culturing CTLs under hypoxic conditions enhances their cytolysis and improves their anti-tumor function. Cell Rep 20:2547–55
     [Google Scholar]
159. 159.

     Hasan A, Mazzone M 2015. Sixty shades of oxygen—an attractive opportunity for cancer immunotherapy. Ann. Transl. Med. 3:187
     [Google Scholar]
160. 160.

     Hatfield SM, Sitkovsky M 2015. Oxygenation to improve cancer vaccines, adoptive cell transfer and blockade of immunological negative regulators. Oncoimmunology 4:e1052934
     [Google Scholar]
161. 161.

     Tian L, Goldstein A, Wang H, Ching Lo H, Sun Kim I et al. 2017. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 544:250–54
     [Google Scholar]
162. 162.

     Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M et al. 2008. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453:410–14
     [Google Scholar]
163. 163.

     Pearce EJ, Pearce EL 2018. Immunometabolism in 2017: Driving immunity: all roads lead to metabolism. Nat. Rev. Immunol. 18:81–82
     [Google Scholar]
164. 164.

     Laoui D, Van Overmeire E, De Baetselier P, Van Ginderachter JA, Raes G 2014. Functional relationship between tumor-associated macrophages and macrophage colony-stimulating factor as contributors to cancer progression. Front. Immunol. 5:489
     [Google Scholar]
165. 165.

     Cantelmo AR, Conradi LC, Brajic A, Goveia J, Kalucka J et al. 2016. Inhibition of the glycolytic activator PFKFB3 in endothelium induces tumor vessel normalization, impairs metastasis, and improves chemotherapy. Cancer Cell 30:968–85
     [Google Scholar]
166. 166.

     Wang Q, He Z, Huang M, Liu T, Wang Y et al. 2018. Vascular niche IL-6 induces alternative macrophage activation in glioblastoma through HIF-2α. Nat. Commun. 9:559
     [Google Scholar]
167. 167.

     Fekete K, Gyorei E, Lohner S, Verduci E, Agostoni C, Decsi T 2015. Long-chain polyunsaturated fatty acid status in obesity: a systematic review and meta-analysis. Obes. Rev. 16:488–97
     [Google Scholar]
168. 168.

     Song H, Lim DY, Jung JI, Cho HJ, Park SY et al. 2017. Dietary oleuropein inhibits tumor angiogenesis and lymphangiogenesis in the B16F10 melanoma allograft model: a mechanism for the suppression of high-fat diet-induced solid tumor growth and lymph node metastasis. Oncotarget 8:32027–42
     [Google Scholar]
169. 169.

     Chang CI, Liao JC, Kuo L 2001. Macrophage arginase promotes tumor cell growth and suppresses nitric oxide-mediated tumor cytotoxicity. Cancer Res 61:1100–6
     [Google Scholar]
170. 170.

     Klug F, Prakash H, Huber PE, Seibel T, Bender N et al. 2013. Low-dose irradiation programs macrophage differentiation to an iNOS⁺/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 24:589–602
     [Google Scholar]
171. 171.

     Rivera LB, Bergers G 2013. Location, location, location: macrophage positioning within tumors determines pro- or antitumor activity. Cancer Cell 24:687–89
     [Google Scholar]
172. 172.

     Newsholme P. 2001. Why is l-glutamine metabolism important to cells of the immune system in health, postinjury, surgery or infection?. J. Nutr. 131:2515S–22S
     [Google Scholar]
173. 173.

     Hubert-Buron A, Leblond J, Jacquot A, Ducrotte P, Dechelotte P, Coeffier M 2006. Glutamine pretreatment reduces IL-8 production in human intestinal epithelial cells by limiting IκBα ubiquitination. J. Nutr. 136:1461–65
     [Google Scholar]
174. 174.

     da Silva R, Levillain O, Brosnan JT, Araneda S, Brosnan ME 2013. The effect of portacaval anastomosis on the expression of glutamine synthetase and ornithine aminotransferase in perivenous hepatocytes. Can. J. Physiol. Pharmacol. 91:362–68
     [Google Scholar]
175. 175.

     Clem BF, O'Neal J, Klarer AC, Telang S, Chesney J 2016. Clinical development of cancer therapeutics that target metabolism. QJM 109:367–72
     [Google Scholar]
176. 176.

     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
     [Google Scholar]
177. 177.

     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
     [Google Scholar]
178. 178.

     Shojaei F, Zhong C, Wu X, Yu L, Ferrara N 2008. Role of myeloid cells in tumor angiogenesis and growth. Trends Cell Biol 18:372–78
     [Google Scholar]
179. 179.

     Jung K, Heishi T, Khan OF, Kowalski PS, Incio J et al. 2017. Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy. J. Clin. Investig. 127:3039–51
     [Google Scholar]
180. 180.

     Welford AF, Biziato D, Coffelt SB, Nucera S, Fisher M et al. 2011. TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice. J. Clin. Investig. 121:1969–73
     [Google Scholar]
181. 181.

     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. 23:939–52
     [Google Scholar]
182. 182.

     Allen E, Walters IB, Hanahan D 2011. Brivanib, a dual FGF/VEGF inhibitor, is active both first and second line against mouse pancreatic neuroendocrine tumors developing adaptive/evasive resistance to VEGF inhibition. Clin. Cancer Res. 17:5299–310
     [Google Scholar]
183. 183.

     Allen E, Jabouille A, Rivera LB, Lodewijckx I, Missiaen R et al. 2017. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci. Transl. Med. 9:eaak9679
     [Google Scholar]
184. 184.

     Schmittnaegel M, Rigamonti N, Kadioglu E, Cassara A, Wyser Rmili C et al. 2017. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci. Transl. Med. 9:eaak9670
     [Google Scholar]
185. 185.

     Ager A, May MJ 2015. Understanding high endothelial venules: lessons for cancer immunology. Oncoimmunology 4:e1008791
     [Google Scholar]
186. 186.

     Thienpont B, Lambrechts D 2017. It's T time for normal blood vessels. Dev. Cell 41:125–26
     [Google Scholar]
187. 187.

     Khan KA, Kerbel RS 2018. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat. Rev. Clin. Oncol. 15:310–24
     [Google Scholar]
188. 188.

     Kroemer G, Galluzzi L 2015. Combinatorial immunotherapy with checkpoint blockers solves the problem of metastatic melanoma—an exclamation sign with a question mark. Oncoimmunology 4:e1058037
     [Google Scholar]
189. 189.

     Campesato LF, Merghoub T 2017. Antiangiogenic therapy and immune checkpoint blockade go hand in hand. Ann. Transl. Med. 5:497
     [Google Scholar]