Normalizing Function of Tumor Vessels: Progress, Opportunities, and Challenges

Literature Cited

1. 1.

   Jain RK. 2013. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J. Clin. Oncol. 31:2205–18
   [Google Scholar]
2. 2.

   Jain RK. 2014. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26:605–22
   [Google Scholar]
3. 3.

   Martin JD, Fukumura D, Duda DG, Boucher Y, Jain RK 2016. Reengineering the tumor microenvironment to alleviate hypoxia and overcome cancer heterogeneity. Cold Spring Harb. Perspect. Med. 6:a027094
   [Google Scholar]
4. 4.

   Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK 2018. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat. Rev. Clin. Oncol. 15:325–40Provides a current and comprehensive perspective on using AAT to improve immunotherapy.
   [Google Scholar]
5. 5.

   Carmeliet P, Jain RK 2011. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat. Rev. Drug Discov. 10:417–27
   [Google Scholar]
6. 6.

   Goel S, Duda DG, Xu L, Munn LL, Boucher Y et al. 2011. Normalization of the vasculature for treatment of cancer and other diseases. Physiol. Rev. 91:1071–121Represents the most comprehensive review of studies on tumor vessel normalization until 2011.
   [Google Scholar]
7. 7.

   Jain RK. 2001. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat. Med. 7:987–89Introduces the normalization hypothesis.
   [Google Scholar]
8. 8.

   Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF et al. 2004. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6:553–63
   [Google Scholar]
9. 9.

   Lu-Emerson C, Duda DG, Emblem KE, Taylor JW, Gerstner ER et al. 2015. Lessons from anti-vascular endothelial growth factor and anti-vascular endothelial growth factor receptor trials in patients with glioblastoma. J. Clin. Oncol. 33:1197–213
   [Google Scholar]
10. 10.

    Stylianopoulos T, Munn LL, Jain RK 2018. Reengineering the physical microenvironment of tumors to improve drug delivery and efficacy: from mathematical modeling to bench to bedside. Trends Cancer 4:292–319Reviews the mechanical microenvironment of tumors, including solid stress and abnormal vessels.
    [Google Scholar]
11. 11.

    Hagendoorn J, Tong R, Fukumura D, Lin Q, Lobo J et al. 2006. Onset of abnormal blood and lymphatic vessel function and interstitial hypertension in early stages of carcinogenesis. Cancer Res 66:3360–64
    [Google Scholar]
12. 12.

    Carmeliet P, Jain RK 2011. Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298–307
    [Google Scholar]
13. 13.

    Helmlinger G, Netti PA, Lichtenbeld HC, Melder RJ, Jain RK 1997. Solid stress inhibits the growth of multicellular tumor spheroids. Nat. Biotechnol. 15:778–83
    [Google Scholar]
14. 14.

    Motz GT, Santoro SP, Wang L-P, Garrabrant T, Lastra RR et al. 2014. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat. Med. 20:607–15
    [Google Scholar]
15. 15.

    Jain RK, Koenig GC, Dellian M, Fukumura D, Munn LL, Melder RJ 1996. Leukocyte-endothelial adhesion and angiogenesis in tumors. Cancer Metastasis Rev 15:195–204
    [Google Scholar]
16. 16.

    Noman MZ, Hasmim M, Messai Y, Terry S, Kieda C et al. 2015. Hypoxia: a key player in antitumor immune response. A review in the theme: cellular responses to hypoxia. Am. J. Physiol. Cell Physiol. 309:C569–79
    [Google Scholar]
17. 17.

    Palazon A, Tyrakis PA, Macias D, Veliça 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]
18. 18.

    Engblom C, Pfirschke C, Pittet MJ 2016. The role of myeloid cells in cancer therapies. Nat. Rev. Cancer 16:447
    [Google Scholar]
19. 19.

    Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M et al. 2012. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. PNAS 109:17561–66Shows the beneficial effect of tumor vessel normalization on immunotherapy.
    [Google Scholar]
20. 20.

    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]
21. 21.

    Wilson WR, Hay MP 2011. Targeting hypoxia in cancer therapy. Nat. Rev. Cancer 11:393–410
    [Google Scholar]
22. 22.

    Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K et al. 1998. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394:485–90
    [Google Scholar]
23. 23.

    Thienpont B, Steinbacher J, Zhao H, D'Anna F, Kuchnio A et al. 2016. Tumour hypoxia causes DNA hypermethylation by reducing TET activity. Nature 537:63–68
    [Google Scholar]
24. 24.

    Estrella V, Chen T, Lloyd M, Wojtkowiak J, Cornnell HH et al. 2013. Acidity generated by the tumor microenvironment drives local invasion. Cancer Res 73:1524–35
    [Google Scholar]
25. 25.

    Schito L, Semenza GL 2016. Hypoxia-inducible factors: master regulators of cancer progression. Trends Cancer 2:758–70
    [Google Scholar]
26. 26.

    Semenza GL. 2016. Dynamic regulation of stem cell specification and maintenance by hypoxia-inducible factors. Mol. Aspects Med. 47–48:15–23
    [Google Scholar]
27. 27.

    Philip B, Ito K, Moreno-Sánchez R, Ralph SJ 2013. HIF expression and the role of hypoxic microenvironments within primary tumours as protective sites driving cancer stem cell renewal and metastatic progression. Carcinogenesis 34:1699–707
    [Google Scholar]
28. 28.

    Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN et al. 1992. Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. J. Natl. Cancer Inst. 84:1875–87
    [Google Scholar]
29. 29.

    Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG et al. 2007. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95
    [Google Scholar]
30. 30.

    Sorensen AG, Batchelor TT, Zhang WT, Chen PJ, Yeo P et al. 2009. A “vascular normalization index” as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients. Cancer Res 69:5296–300
    [Google Scholar]
31. 31.

    Batchelor TT, Gerstner ER, Emblem KE, Duda DG, Kalpathy-Cramer J et al. 2013. Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. PNAS 110:19059–64Demonstrates that improved oxygenation relates to outcome in glioblastoma patients treated with AAT.
    [Google Scholar]
32. 32.

    Emblem KE, Mouridsen K, Bjornerud A, Farrar CT, Jennings D et al. 2013. Vessel architectural imaging identifies cancer patient responders to anti-angiogenic therapy. Nat. Med. 19:1178–83
    [Google Scholar]
33. 33.

    Sorensen AG, Emblem KE, Polaskova P, Jennings D, Kim H et al. 2012. Increased survival of glioblastoma patients who respond to antiangiogenic therapy with elevated blood perfusion. Cancer Res 72:402–7
    [Google Scholar]
34. 34.

    Quintela-Fandino M, Lluch A, Manso LM, Calvo I, Cortes J et al. 2016. ¹⁸F-fluoromisonidazole PET and activity of neoadjuvant nintedanib in early HER2-negative breast cancer: a window-of-opportunity randomized trial. Am. Assoc. Cancer Res. 23:1432–41
    [Google Scholar]
35. 35.

    Ueda S, Saeki T, Takeuchi H, Shigekawa T, Yamane T et al. 2016. In vivo imaging of eribulin-induced reoxygenation in advanced breast cancer patients: a comparison to bevacizumab. Br. J. Cancer 114:1212–18
    [Google Scholar]
36. 36.

    Garcia-Foncillas J, Martinez P, Lahuerta A, Cussac AL, Gonzalez MG et al. 2012. Dynamic contrast-enhanced MRI versus ¹⁸F-misonidazol-PET/CT to predict pathologic response in bevacizumab-based neoadjuvant therapy in breast cancer. J. Clin. Oncol. 30:10512 Abstr. )
    [Google Scholar]
37. 37.

    Ueda S, Kuji I, Shigekawa T, Takeuchi H, Sano H et al. 2014. Optical imaging for monitoring tumor oxygenation response after initiation of single-agent bevacizumab followed by cytotoxic chemotherapy in breast cancer patients. PLOS ONE 9:e98715
    [Google Scholar]
38. 38.

    Ueda S, Saeki T, Osaki A, Yamane T, Kuji I 2017. Bevacizumab induces acute hypoxia and cancer progression in patients with refractory breast cancer: multimodal functional imaging and multiplex cytokine analysis. Clin. Cancer Res. 23:5769–78
    [Google Scholar]
39. 39.

    Heist RS, Duda DG, Sahani DV, Ancukiewicz M, Fidias P et al. 2015. Improved tumor vascularization after anti-VEGF therapy with carboplatin and nab-paclitaxel associates with survival in lung cancer. PNAS 112:1547–52
    [Google Scholar]
40. 40.

    Bais C, Mueller B, Brady MF, Mannel RS, Burger RA et al. 2017. Tumor microvessel density as a potential predictive marker for bevacizumab benefit: GOG-0218 biomarker analyses. J. Natl. Cancer Inst. 109:djx066
    [Google Scholar]
41. 41.

    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]
42. 42.

    Jayson GC, Kerbel R, Ellis LM, Harris AL 2016. Antiangiogenic therapy in oncology: current status and future directions. Lancet 388:518–29
    [Google Scholar]
43. 43.

    Nowosielski M, Gorlia T, Bromberg J, Sahm F, Harting I et al. 2017. Nimg-75. Necrosis during treatment is associated with worse survival in recurrent glioblastoma patients—post hoc image analysis of EORTC 26101. Neuro-Oncology 19:vi159
    [Google Scholar]
44. 44.

    Fang L, He Y, Tong Y, Hu L, Xin W et al. 2017. Flattened microvessel independently predicts poor prognosis of patients with non-small cell lung cancer. Oncotarget 8:30092–99
    [Google Scholar]
45. 45.

    Emblem KE, Gerstner ER, Sorensen G, Rosen BR, Wen PY et al. 2016. Matrix-depleting anti-hypertensives decompress tumor blood vessels and improve perfusion in patients with glioblastomas receiving anti-angiogenic therapy. Cancer Res 76:3975
    [Google Scholar]
46. 46.

    Levin VA, Chan J, Datta M, Yee JL, Jain RK 2017. Effect of angiotensin system inhibitors on survival in newly diagnosed glioma patients and recurrent glioblastoma patients receiving chemotherapy and/or bevacizumab. J. Neuro-Oncol. 134:325–30Demonstrates the potential of ASIs in combination with bevacizumab through a retrospective analysis of glioblastoma patients.
    [Google Scholar]
47. 47.

    Stylianopoulos T, Jain RK 2013. Combining two strategies to improve perfusion and drug delivery in solid tumors. PNAS 110:18632–37
    [Google Scholar]
48. 48.

    Stylianopoulos T, Martin JD, Chauhan VP, Jain SR, Diop-Frimpong B et al. 2012. Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors. PNAS 109:15101–8
    [Google Scholar]
49. 49.

    Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF et al. 2014. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25:735–47
    [Google Scholar]
50. 50.

    Jain RK. 1987. Transport of molecules across tumor vasculature. Cancer Metastasis Rev 6:559–93
    [Google Scholar]
51. 51.

    Chauhan VP, Stylianopoulos T, Martin JD, Popovic Z, Chen O et al. 2012. Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nat. Nanotechnol. 7:383–88
    [Google Scholar]
52. 52.

    Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR et al. 2013. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat. Commun. 4:2516Illustrates the potential of ASIs in reprogramming CAFs to improve perfusion and drug delivery.
    [Google Scholar]
53. 53.

    Jain RK. 1988. Determinants of tumor blood flow: a review. Cancer Res 48:2641–58
    [Google Scholar]
54. 54.

    Jain RK. 2005. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62
    [Google Scholar]
55. 55.

    Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M et al. 2015. VEGF-A modulates expression of inhibitory checkpoints on CD8⁺ T cells in tumors. J. Exp. Med. 212:139–48
    [Google Scholar]
56. 56.

    Wallin JJ, Bendell JC, Funke R, Sznol M, Korski K et al. 2016. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat. Commun. 7:12624
    [Google Scholar]
57. 57.

    Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V et al. 1998. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 92:4150–66
    [Google Scholar]
58. 58.

    Maenhout SK, Thielemans K, Aerts JL 2014. Location, location, location: functional and phenotypic heterogeneity between tumor-infiltrating and non-infiltrating myeloid-derived suppressor cells. Oncoimmunology 3:e956579
    [Google Scholar]
59. 59.

    Tian L, Goldstein A, Wang H, Lo HC, Kim IS et al. 2017. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 544:250–54
    [Google Scholar]
60. 60.

    De Palma M, Jain RK 2017. CD4⁺ T cell activation and vascular normalization: Two sides of the same coin?. Immunity 46:773–75
    [Google Scholar]
61. 61.

    Qin L, Li X, Stroiney A, Qu J, Helgager J et al. 2017. Advanced MRI assessment to predict benefit of anti-programmed cell death 1 protein immunotherapy response in patients with recurrent glioblastoma. Neuroradiology 59:135–45
    [Google Scholar]
62. 62.

    Eguchi D, Ikenaga N, Ohuchida K, Kozono S, Cui L et al. 2013. Hypoxia enhances the interaction between pancreatic stellate cells and cancer cells via increased secretion of connective tissue growth factor. J. Surg. Res. 181:225–33
    [Google Scholar]
63. 63.

    Spivak-Kroizman TR, Hostetter G, Posner R, Aziz M, Hu C et al. 2013. Hypoxia triggers hedgehog-mediated tumor–stromal interactions in pancreatic cancer. Cancer Res 73:3235–47
    [Google Scholar]
64. 64.

    Tse JM, Cheng G, Tyrrell JA, Wilcox-Adelman SA, Boucher Y et al. 2012. Mechanical compression drives cancer cells toward invasive phenotype. PNAS 109:911–16
    [Google Scholar]
65. 65.

    Fernández-Sánchez ME, Barbier S, Whitehead J, Béalle G, Michel A et al. 2015. Mechanical induction of the tumorigenic β-catenin pathway by tumour growth pressure. Nature 523:92–95
    [Google Scholar]
66. 66.

    Fukumura D, Xavier R, Sugiura T, Chen Y, Park EC et al. 1998. Tumor induction of VEGF promoter activity in stromal cells. Cell 94:715–25
    [Google Scholar]
67. 67.

    Öhlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS et al. 2017. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 214:579–96
    [Google Scholar]
68. 68.

    Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A et al. 2013. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti–PD-L1 immunotherapy in pancreatic cancer. PNAS 110:20212–17
    [Google Scholar]
69. 69.

    Öhlund D, Elyada E, Tuveson D 2014. Fibroblast heterogeneity in the cancer wound. J. Exp. Med. 211:1503–23
    [Google Scholar]
70. 70.

    Pinter M, Jain RK 2017. Targeting the renin-angiotensin system to improve cancer treatment: implications for immunotherapy. Sci. Transl. Med. 9:eaan5616Reviews ASIs’ clinical potential, with an emphasis on immunotherapy.
    [Google Scholar]
71. 71.

    Salmon H, Franciszkiewicz K, Damotte D, Dieu-Nosjean M-C, Validire P et al. 2012. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J. Clin. Investig. 122:899
    [Google Scholar]
72. 72.

    Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K et al. 2018. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554:544–48
    [Google Scholar]
73. 73.

    Eroglu Z, Zaretsky JM, Hu-Lieskovan S, Kim DW, Algazi A et al. 2018. High response rate to PD-1 blockade in desmoplastic melanomas. Nature 553:347–50
    [Google Scholar]
74. 74.

    Chen Y, Huang Y, Reiberger T, Duyverman AM, Huang P et al. 2014. Differential effects of sorafenib on liver versus tumor fibrosis mediated by stromal-derived factor 1 alpha/C-X-C receptor type 4 axis and myeloid differentiation antigen-positive myeloid cell infiltration in mice. Hepatology 59:1435–47
    [Google Scholar]
75. 75.

    Bordeleau F, Mason BN, Lollis EM, Mazzola M, Zanotelli MR et al. 2017. Matrix stiffening promotes a tumor vasculature phenotype. PNAS 114:492–97
    [Google Scholar]
76. 76.

    Mouw JK, Yui Y, Damiano L, Bainer RO, Lakins JN et al. 2014. Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Nat. Med. 20:360
    [Google Scholar]
77. 77.

    Lorgis V, Maura G, Coppa G, Hassani K, Taillandier L et al. 2012. Relation between bevacizumab dose intensity and high-grade glioma survival: a retrospective study in two large cohorts. J. Neuro-Oncol. 107:351–58
    [Google Scholar]
78. 78.

    Kreisl TN, Smith P, Sul J, Salgado C, Iwamoto FM et al. 2013. Continuous daily sunitinib for recurrent glioblastoma. J. Neuro-Oncol. 111:41–48
    [Google Scholar]
79. 79.

    Goel S, Gupta N, Walcott BP, Snuderl M, Kesler CT et al. 2013. Effects of vascular-endothelial protein tyrosine phosphatase inhibition on breast cancer vasculature and metastatic progression. J. Natl. Cancer Inst. 105:1188–201
    [Google Scholar]
80. 80.

    Peterson TE, Kirkpatrick ND, Huang Y, Farrar CT, Marijt KA et al. 2016. Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages. PNAS 113:4470–75
    [Google Scholar]
81. 81.

    Kloepper J, Riedemann L, Amoozgar Z, Seano G, Susek K et al. 2016. Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. PNAS 113:4476–81
    [Google Scholar]
82. 82.

    Wu FTH, Man S, Xu P, Chow A, Paez-Ribes M et al. 2016. Efficacy of cotargeting angiopoietin-2 and the VEGF pathway in the adjuvant postsurgical setting for early breast, colorectal, and renal cancers. Cancer Res 76:6988–7000
    [Google Scholar]
83. 83.

    Schmittnaegel M, Rigamonti N, Kadioglu E, Cassará A, Rmili CW 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]
84. 84.

    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]
85. 85.

    De Bock K, Georgiadou M, Schoors S, Kuchnio A, Wong BW et al. 2013. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 154:651–63
    [Google Scholar]
86. 86.

    Schoors S, De Bock K, Cantelmo AR, Georgiadou M, Ghesquière B et al. 2014. Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis. Cell Metab 19:37–48
    [Google Scholar]
87. 87.

    Cantelmo AR, Conradi L-C, 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]
88. 88.

    Li X, Carmeliet P 2018. Targeting angiogenic metabolism in disease. Science 359:1335–56
    [Google Scholar]
89. 89.

    Kieda C, El Hafny-Rahbi B, Collet G, Lamerant-Fayel N, Grillon C et al. 2013. Stable tumor vessel normalization with pO₂ increase and endothelial PTEN activation by inositol trispyrophosphate brings novel tumor treatment. J. Mol. Med. 91:883–99
    [Google Scholar]
90. 90.

    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]
91. 91.

    Wenes M, Shang M, Di Matteo M, Goveia J, Martín-Pérez R et al. 2016. Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metab 24:701–15
    [Google Scholar]
92. 92.

    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]
93. 93.

    Magrini E, Villa A, Angiolini F, Doni A, Mazzarol G et al. 2014. Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization. J. Clin. Investig. 124:4335–50
    [Google Scholar]
94. 94.

    Maione F, Molla F, Meda C, Latini R, Zentilin L et al. 2009. Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models. J. Clin. Investig. 119:3356–72
    [Google Scholar]
95. 95.

    Maione F, Capano S, Regano D, Zentilin L, Giacca M et al. 2012. Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic treatment in mice. J. Clin. Investig. 122:1832–48
    [Google Scholar]
96. 96.

    Gioelli N, Maione F, Camillo C, Ghitti M, Valdembri D et al. 2018. A rationally-designed NRP1-independent superagonist SEMA3A mutant is an effective anticancer agent. Sci. Transl. Med. 10:eaah4807
    [Google Scholar]
97. 97.

    Sawada J, Urakami T, Li F, Urakami A, Zhu W et al. 2012. Small GTPase R-Ras regulates integrity and functionality of tumor blood vessels. Cancer Cell 22:235–49
    [Google Scholar]
98. 98.

    Takara K, Eino D, Ando K, Yasuda D, Naito H et al. 2017. Lysophosphatidic acid receptor 4 activation augments drug delivery in tumors by tightening endothelial cell-cell contact. Cell Rep 20:2072–86
    [Google Scholar]
99. 99.

    Maes H, Kuchnio A, Peric A, Moens S, Nys K et al. 2014. Tumor vessel normalization by chloroquine independent of autophagy. Cancer Cell 26:190–206
    [Google Scholar]
100. 100.

     Adapala RK, Thoppil RJ, Ghosh K, Cappelli H, Dudley AC et al. 2016. Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy. Oncogene 35:314–22
     [Google Scholar]
101. 101.

     Primo L, Seano G, Roca C, Maione F, Gagliardi PA et al. 2010. Increased expression of α6 integrin in endothelial cells unveils a proangiogenic role for basement membrane. Cancer Res 70:5759–69
     [Google Scholar]
102. 102.

     Ager EI, Kozin SV, Kirkpatrick ND, Seano G, Kodack DP et al. 2015. Blockade of MMP14 activity in murine breast carcinomas: implications for macrophages, vessels, and radiotherapy. J. Natl. Cancer Inst. 107:djv017
     [Google Scholar]
103. 103.

     Adams JC, Lawler J 2004. The thrombospondins. Int. J. Biochem. Cell Biol. 36:961–68
     [Google Scholar]
104. 104.

     Campbell NE, Greenaway J, Henkin J, Moorehead RA, Petrik J 2010. The thrombospondin-1 mimetic ABT-510 increases the uptake and effectiveness of cisplatin and paclitaxel in a mouse model of epithelial ovarian cancer. Neoplasia 12:275–83
     [Google Scholar]
105. 105.

     Izumi Y, Xu L, di Tomaso E, Fukumura D, Jain RK 2002. Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature 416:279–80
     [Google Scholar]
106. 106.

     Mpekris F, Baish JW, Stylianopoulos T, Jain RK 2017. Role of vascular normalization in benefit from metronomic chemotherapy. PNAS 114:1994–99
     [Google Scholar]
107. 107.

     Bocci G, Francia G, Man S, Lawler J, Kerbel RS 2003. Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. PNAS 100:12917–22
     [Google Scholar]
108. 108.

     Jain RK, Safabakhsh N, Sckell A, Chen Y, Jiang P et al. 1998. Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor. PNAS 95:10820–25
     [Google Scholar]
109. 109.

     Funahashi Y, Okamoto K, Adachi Y, Semba T, Uesugi M et al. 2014. Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models. Cancer Sci 105:1334–42
     [Google Scholar]
110. 110.

     Ruiz-Casado A, Martín-Ruiz A, Pérez LM, Provencio M, Fiuza-Luces C, Lucia A 2017. Exercise and the hallmarks of cancer. Trends Cancer 3:423–41
     [Google Scholar]
111. 111.

     Schadler KL, Thomas NJ, Galie PA, Bhang DH, Roby KC et al. 2016. Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy. Oncotarget 7:65429
     [Google Scholar]
112. 112.

     Betof AS, Lascola CD, Weitzel D, Landon C, Scarbrough PM et al. 2015. Modulation of murine breast tumor vascularity, hypoxia, and chemotherapeutic response by exercise. J. Natl. Cancer Inst. 107:djv040
     [Google Scholar]
113. 113.

     McCullough DJ, Stabley JN, Siemann DW, Behnke BJ 2014. Modulation of blood flow, hypoxia, and vascular function in orthotopic prostate tumors during exercise. J. Natl. Cancer Inst. 106:dju036
     [Google Scholar]
114. 114.

     Whatcott CJ, Han H, Von Hoff DD 2015. Orchestrating the tumor microenvironment to improve survival for patients with pancreatic cancer: normalization, not destruction. Cancer J 21:299–306
     [Google Scholar]
115. 115.

     Sherman MH, Yu RT, Engle DD, Ding N, Atkins AR et al. 2014. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 159:80–93
     [Google Scholar]
116. 116.

     Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N et al. 2013. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62:112–20
     [Google Scholar]
117. 117.

     Chauhan VP, Boucher Y, Ferrone CR, Roberge S, Martin JD et al. 2014. Compression of pancreatic tumor blood vessels by hyaluronan is caused by solid stress and not interstitial fluid pressure. Cancer Cell 26:14–15
     [Google Scholar]
118. 118.

     Mpekris F, Papageorgis P, Polydorou C, Voutouri C, Kalli M et al. 2017. Sonic-hedgehog pathway inhibition normalizes desmoplastic tumor microenvironment to improve chemo- and nanotherapy. J. Control. Release 261:105–12
     [Google Scholar]
119. 119.

     Pinter M, Weinmann A, Wörns M-A, Hucke F, Bota S et al. 2017. Use of inhibitors of the renin–angiotensin system is associated with longer survival in patients with hepatocellular carcinoma. United Eur. Gastroenterol. J. 5:987–96
     [Google Scholar]
120. 120.

     Liu H, Naxerova K, Pinter M, Incio J, Lee H et al. 2017. Use of angiotensin system inhibitors is associated with immune activation and longer survival in nonmetastatic pancreatic ductal adenocarcinoma. Clin. Cancer Res. 23:5959–69
     [Google Scholar]
121. 121.

     Pinter M, Kwanten WJ, Jain RK 2018. Renin-angiotensin system inhibitors to mitigate cancer treatment-related adverse events. Clin. Cancer Res. 24:3803–12
     [Google Scholar]
122. 122.

     Murphy JE, Wo JY-L, Ryan DP, Jiang W, Yeap BY et al. 2018. Potentially curative combination of TGF-β1 inhibitor losartan and FOLFIRINOX (FFX) for locally advanced pancreatic cancer (LAPC): R0 resection rates and preliminary survival data from a prospective phase II study Paper presented at the Annual Meeting of the American Society of Clinical Oncology Chicago, IL: June 3
123. 123.

     Tauriello DV, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J et al. 2018. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554:538–43
     [Google Scholar]
124. 124.

     Incio J, Suboj P, Chin SM, Vardam-Kaur T, Liu H et al. 2015. Metformin reduces desmoplasia in pancreatic cancer by reprogramming stellate cells and tumor-associated macrophages. PLOS ONE 10:e0141392
     [Google Scholar]
125. 125.

     Ferrer-Mayorga G, Gómez-López G, Barbáchano A, Fernández-Barral A, Peña C et al. 2016. Vitamin D receptor expression and associated gene signature in tumour stromal fibroblasts predict clinical outcome in colorectal cancer. Gut 66:1449–62
     [Google Scholar]
126. 126.

     Frese KK, Neesse A, Cook N, Bapiro TE, Lolkema MP et al. 2012. Nab-paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discov 2:260–69
     [Google Scholar]
127. 127.

     Alvarez R, Musteanu M, Garcia-Garcia E, Lopez-Casas PP, Megias D et al. 2013. Stromal disrupting effects of nab-paclitaxel in pancreatic cancer. Br. J. Cancer 109:926–33
     [Google Scholar]
128. 128.

     Cooke VG, LeBleu VS, Keskin D, Khan Z, O'Connell JT et al. 2012. Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell 21:66–81
     [Google Scholar]
129. 129.

     Rahbari NN, Kedrin D, Incio J, Liu H, Ho WW et al. 2016. Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases. Sci. Transl. Med. 8:360ra135
     [Google Scholar]
130. 130.

     Chen Y, Ramjiawan RR, Reiberger T, Ng MR, Hato T et al. 2015. CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology 61:1591–602
     [Google Scholar]
131. 131.

     Griveau A, Seano G, Shelton SJ, Kupp R, Jahangiri A et al. 2018. A glial signature and Wnt7 signaling regulate glioma-vascular interactions and tumor microenvironment. Cancer Cell 33:874–89
     [Google Scholar]
132. 132.

     Duda DG, Willett CG, Ancukiewicz M, di Tomaso E, Shah M et al. 2010. Plasma soluble VEGFR-1 is a potential dual biomarker of response and toxicity for bevacizumab with chemoradiation in locally advanced rectal cancer. Oncologist 15:577–83
     [Google Scholar]
133. 133.

     Duda DG, Kozin SV, Kirkpatrick ND, Xu L, Fukumura D, Jain RK 2011. CXCL12 (SDF1α)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies?. Clin. Cancer Res. 17:2074–80
     [Google Scholar]
134. 134.

     Jung K, Heishi T, Incio J, Huang Y, Beech EY et al. 2017. Targeting CXCR4-dependent immunosuppressive Ly6Clow monocytes improves antiangiogenic therapy in colorectal cancer. PNAS 114:10455–60
     [Google Scholar]
135. 135.

     Jung K, Heishi T, Khan OF, Kowalski PS, Incio J et al. 2017. Ly6C^lo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy. J. Clin. Investig. 127:3039–51
     [Google Scholar]
136. 136.

     Vasudev NS, Reynolds AR 2014. Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. Angiogenesis 17:471–94
     [Google Scholar]
137. 137.

     Incio J, Liu H, Suboj P, Chin SM, Chen IX et al. 2016. Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy. Cancer Discov 6:852–69Demonstrates the role of obesity in desmoplasia and immunosuppression while highlighting the potential of ASIs.
     [Google Scholar]
138. 138.

     Incio J, Tam J, Rahbari NN, Suboj P, McManus DT et al. 2016. PlGF/VEGFR-1 signaling promotes macrophage polarization and accelerated tumor progression in obesity. Clin. Cancer Res. 22:2993–3004
     [Google Scholar]
139. 139.

     Incio J, Ligibel JA, McManus DT, Suboj P, Jung K et al. 2018. Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2. Sci. Transl. Med. 10:eaag0945
     [Google Scholar]
140. 140.

     Pereira ER, Kedrin D, Seano G, Gautier O, Meijer EF et al. 2018. Lymph node metastases can invade local blood vessels, exit the node, and colonize distant organs in mice. Science 359:1403–7
     [Google Scholar]
141. 141.

     Naxerova K, Reiter JG, Brachtel E, Lennerz JK, Van De Wetering M et al. 2017. Origins of lymphatic and distant metastases in human colorectal cancer. Science 357:55–60
     [Google Scholar]
142. 142.

     Jeong HS, Jones D, Liao S, Wattson DA, Cui CH et al. 2015. Investigation of the lack of angiogenesis in the formation of lymph node metastases. J. Natl. Cancer Inst. 107:djv155
     [Google Scholar]
143. 143.

     Bridgeman VL, Vermeulen PB, Foo S, Bilecz A, Daley F et al. 2016. Vessel co‐option is common in human lung metastases and mediates resistance to anti‐angiogenic therapy in preclinical lung metastasis models. J. Pathol. 241:362–74
     [Google Scholar]
144. 144.

     Frentzas S, Simoneau E, Bridgeman VL, Vermeulen PB, Foo S et al. 2016. Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nat. Med. 22:1294–302
     [Google Scholar]
145. 145.

     Lee H, Shields AF, Siegel BA, Miller KD, Krop I et al. 2017. ⁶⁴Cu-MM-302 positron emission tomography quantifies variability of enhanced permeability and retention of nanoparticles in relation to treatment response in patients with metastatic breast cancer. Clin. Cancer Res. 23:4190–202
     [Google Scholar]
146. 146.

     Emblem KE, Jain RK 2016. Improving treatment of liver metastases by targeting nonangiogenic mechanisms. Nat. Med. 22:1209
     [Google Scholar]
147. 147.

     Nia HT, Liu H, Seano G, Datta M, Jones D et al. 2016. Solid stress and elastic energy as measures of tumour mechanopathology. Nat. Biomed. Eng. 1:0004
     [Google Scholar]
148. 148.

     Duda DG, Duyverman AM, Kohno M, Snuderl M, Steller EJ et al. 2010. Malignant cells facilitate lung metastasis by bringing their own soil. PNAS 107:21677–82
     [Google Scholar]
149. 149.

     Whatcott CJ, Diep CH, Jiang P, Watanabe A, LoBello J et al. 2015. Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. Clin. Cancer Res. 21:3561–68
     [Google Scholar]
150. 150.

     Kodack DP, Chung E, Yamashita H, Incio J, Duyverman AM et al. 2012. Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases. PNAS 109:E3119–27
     [Google Scholar]
151. 151.

     Kodack DP, Askoxylakis V, Ferraro GB, Sheng Q, Badeaux M et al. 2017. The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation. Sci. Transl. Med. 9:eaal4682
     [Google Scholar]
152. 152.

     Datta M, Via LE, Kamoun WS, Liu C, Chen W et al. 2015. Anti-vascular endothelial growth factor treatment normalizes tuberculosis granuloma vasculature and improves small molecule delivery. PNAS 112:1827–32
     [Google Scholar]
153. 153.

     Plotkin SR, Stemmer-Rachamimov AO, Barker FG, Halpin C, Padera TP et al. 2009. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N. Engl. J. Med. 361:358–67
     [Google Scholar]
154. 154.

     Jain RK, Finn AV, Kolodgie FD, Gold HK, Virmani R 2007. Antiangiogenic therapy for normalization of atherosclerotic plaque vasculature: a potential strategy for plaque stabilization. Nat. Rev. Cardiol. 4:491
     [Google Scholar]
155. 155.

     Wang X, Abraham S, McKenzie JAG, Jeffs N, Swire M et al. 2013. LRG1 promotes angiogenesis by modulating endothelial TGFβ signaling. Nature 499:306–11
     [Google Scholar]
156. 156.

     Yuan F, Leunig M, Huang SK, Berk DA, Papahadjopoulos D et al. 1994. Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft. Cancer Res 54:3352–56
     [Google Scholar]