The role of mechanical forces in tumor growth and therapy

Annual Review of Biomedical Engineering

Volumn 16, Issue , 2014, Pages 321-346

  Jain, Rakesh K ^a   Martin, John D ^a,b   Stylianopoulos, Triantafyllos ^c  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

^b Massachusetts Institute of Technology Cambridge   (United States)

^c UNIVERSITY OF CYPRUS   (Cyprus)

Author keywords

solid stress; stress alleviation; tumor microenvironment; tumor perfusion; vascular hyperpermeability; vascular normalization; vessel compression

Indexed keywords

BLOOD; BLOOD VESSELS; DISEASES; ENZYME INHIBITION;

SOLID STRESS; STRESS ALLEVIATION; TUMOR MICROENVIRONMENT; TUMOR PERFUSION; VASCULAR HYPERPERMEABILITY; VASCULAR NORMALIZATION;

TUMORS;

ANGIOGENESIS INHIBITOR; ANGIOTENSIN RECEPTOR ANTAGONIST; BEVACIZUMAB; CEDIRANIB; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; LOSARTAN; MONOCLONAL ANTIBODY DC101; SARIDEGIB; VASCULOTROPIN INHIBITOR; VASCULOTROPIN A;

BLOOD VESSEL OCCLUSION; BLOOD VESSEL PERMEABILITY; CANCER RESISTANCE; CELL INVASION; DRUG MECHANISM; FORCE; GLIOBLASTOMA; HUMAN; HYPOXIA; IMMUNE EVASION; LYMPHATIC SYSTEM; MECHANICAL STRESS; METASTASIS POTENTIAL; NONHUMAN; PANCREAS CANCER; RECTUM CANCER; REVIEW; SHEAR STRESS; TISSUE PERFUSION; TISSUE PRESSURE; TREATMENT FAILURE; TUMOR BLOOD FLOW; TUMOR GROWTH; TUMOR MICROENVIRONMENT; TUMOR VASCULARIZATION; ANIMAL; ANOXIA; CHEMISTRY; DISEASE COURSE; DRUG DELIVERY SYSTEM; EXTRACELLULAR FLUID; IMMUNE SYSTEM; LYMPH; METASTASIS; MICROCIRCULATION; NEOPLASMS; PATHOLOGY; PATHOPHYSIOLOGY; PERFUSION; SHEAR STRENGTH; THEORETICAL MODEL;

ANIMALS; ANOXIA; DISEASE PROGRESSION; DRUG DELIVERY SYSTEMS; EXTRACELLULAR FLUID; HUMANS; IMMUNE SYSTEM; LYMPH; MICROCIRCULATION; MODELS, THEORETICAL; NEOPLASM METASTASIS; NEOPLASMS; PERFUSION; SHEAR STRENGTH; STRESS, MECHANICAL; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

EID: 84904323068     PISSN: 15239829     EISSN: 15454274     Source Type: Book Series    
DOI: 10.1146/annurev-bioeng-071813-105259     Document Type: Review

References (154)

1. Jain RK. 2013. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J. Clin. Oncol. 31:2205-18
2. Jain RK. 2014. An indirect way to tame cancer. Sci. Am. 310:46-53
3. Chuong CJ, Fung YC. 1986. On residual stresses in arteries. J. Biomech. Eng. 108:189-92
4. Skalak R, Zargaryan S, Jain RK, Netti PA, Hoger A. 1996. Compatibility and the genesis of residual stress by volumetric growth. J. Math. Biol. 34:889-914
5. 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. Proc. Natl. Acad. Sci. USA 109:15101-8
6. Stylianopoulos T, Martin JD, Snuderl M, Mpekris F, Jain SR, Jain RK. 2013. Coevolution of solid stress and interstitial fluid pressure in tumors during progression: implications for vascular collapse. Cancer Res. 73:3833-41
7. 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
8. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. 2002. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell Biol. 3:349-63
9. Paszek MJ, Weaver VM. 2004. The tension mounts: Mechanics meets morphogenesis and malignancy. J. Mammary Gland Biol. Neoplasia 9:325-42
10. Wipff PJ, Hinz B. 2009. Myofibroblasts work best under stress. J. Bodyw. Mov. Ther. 13:121-27
11. Cheng G, Tse J, Jain RK, Munn LL. 2009. Micro-environmental mechanical stress controls tumor spheroid size and morphology by suppressing proliferation and inducing apoptosis in cancer cells. PLoS ONE 4:e4632
12. Demou ZN. 2010. Gene expression profiles in 3D tumor analogs indicate compressive strain differentially enhances metastatic potential. Ann. Biomed. Eng. 38:3509-20
13. Tse JM, Cheng G, Tyrrell JA, Wilcox-Adelman SA, Boucher Y, et al. 2012. Mechanical compression drives cancer cells toward invasive phenotype. Proc. Natl. Acad. Sci. USA 109:911-16
14. 2 gradients in solid tumors in vivo: High-resolution measurements reveal a lack of correlation. Nat. Med. 3:177-82
15. Griffon-Etienne G, Boucher Y, Brekken C, Suit HD, Jain RK. 1999. Taxane-induced apoptosis decompresses blood vessels and lowers interstitial fluid pressure in solid tumors: clinical implications. Cancer Res. 59:3776-82
16. Padera TP, Stoll BR, Tooredman JB, Capen D, di Tomaso E, Jain RK. 2004. Pathology: Cancer cells compress intratumour vessels. Nature 427:695
17. Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR. 2012. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21:418-29
18. Stylianopoulos T, Jain RK. 2013. Combining two strategies to improve perfusion and drug delivery in solid tumors. Proc. Natl. Acad. Sci. USA 110:18632-37
19. Koumoutsakos P, Pivkin I, Milde F. 2013. The fluid mechanics of cancer and its therapy. Annu. Rev. Fluid Mech. 45:325-55
20. Jain RK. 1988. Determinants of tumor blood flow: a review. Cancer Res. 48:2641-58
21. Jain RK, Baxter LT. 1988. Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: significance of elevated interstitial pressure. Cancer Res. 48:7022-32
22. Baxter LT, Jain RK. 1989. Transport of fluid and macromolecules in tumors. I. Role of interstitial pressure and convection. Microvasc. Res. 37:77-104
23. Netti PA, Roberge S, Boucher Y, Baxter LT, Jain RK. 1996. Effect of transvascular fluid exchange on pressure-flow relationship in tumors: a proposed mechanism for tumor blood flow heterogeneity. Microvasc. Res. 52:27-46
24. Baish JW, Netti PA, Jain RK. 1997. Transmural coupling of fluid flow in microcirculatory network and interstitium in tumors. Microvasc. Res. 53:128-41
25. Baxter LT, Jain RK. 1990. Transport of fluid and macromolecules in tumors. II. Role of heterogeneous perfusion and lymphatics. Microvasc. Res. 40:246-63
26. Boucher Y, Baxter LT, Jain RK. 1990. Interstitial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy. Cancer Res. 50:4478-84
27. Jain RK, Tong RT, Munn LL. 2007. Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model. Cancer Res. 67:2729-35
28. 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
29. 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
30. Kaufman LJ, Brangwynne CP, Kasza KE, Filippidi E, Gordon VD, et al. 2005. Glioma expansion in collagen I matrices: analyzing collagen concentration-dependent growth and motility patterns. Biophys. J. 89:635-50
31. Koike C, McKee TD, Pluen A, Ramanujan S, Burton K, et al. 2002. Solid stress facilitates spheroid formation: potential involvement of hyaluronan. Br. J. Cancer 86:947-53
32. Rivron NC, Vrij EJ, Rouwkema J, Le Gac S, Van den Berg A, et al. 2012. Tissue deformation spatially modulates VEGF signaling and angiogenesis. Proc. Natl. Acad. Sci. USA 109:6886-91
33. Roose T, Netti PA, Munn LL, Boucher Y, Jain RK. 2003. Solid stress generated by spheroid growth estimated using a linear poroelasticity model. Microvasc. Res. 66:204-12
34. Sarntinoranont M, Rooney F, Ferrari M. 2003. Interstitial stress and fluid pressure within a growing tumor. Ann. Biomed. Eng. 31:327-35
35. Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, et al. 2013. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumor blood vessels. Nat. Commun. 4:2516
36. Branton MH, Kopp JB. 1999. TGF-β and fibrosis. Microbes Infect. 1:1349-65
37. Butcher DT, Alliston T, Weaver VM. 2009. A tense situation: forcing tumour progression. Nat. Rev. Cancer 9:108-22
38. Egeblad M, Rasch MG, Weaver VM. 2010. Dynamic interplay between the collagen scaffold and tumor evolution. Curr. Opin. Cell Biol. 22:697-706
39. Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, et al. 2005. Tensional homeostasis and the malignant phenotype. Cancer Cell 8:241-54
40. Samuel MS, Lopez JI, McGhee EJ, Croft DR, Strachan D, et al. 2011. Actomyosin-mediated cellular tension drives increased tissue stiffness and beta-catenin activation to induce epidermal hyperplasia and tumor growth. Cancer Cell 19:776-91
41. 1 function. Science 323:642-44
42. Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, et al. 2009. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139:891-906
43. Wipff PJ, Rifkin DB, Meister JJ, Hinz B. 2007. Myofibroblast contraction activates latent TGF-β1 from the extracellular matrix. J. Cell Biol. 179:1311-23
44. Karagiannis GS, Poutahidis T, Erdman SE, Kirsch R, Riddell RH, Diamandis EP. 2012. Cancer-associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue. Mol. Cancer Res. 10:1403-18
45. Potenta S, Zeisberg E, Kalluri R. 2008. The role of endothelial-to- mesenchymal transition in cancer progression. Br. J. Cancer 99:1375-79
46. Kalluri R, Weinberg RA. 2009. The basics of epithelial-mesenchymal transition. J. Clin. Investig. 119:1420-28
47. Huang Y, Goel S, Duda DG, Fukumura D, Jain RK. 2013. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res. 73:2943-48
48. reg cells. Nature 475:226-30
49. 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. 91:1071-121
50. Wilson WR, Hay MP. 2011. Targeting hypoxia in cancer therapy. Nat. Rev. Cancer 11:393-410
51. Carmeliet P, Jain RK. 2011. Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298-307
52. Pries AR, Hopfner M, Le Noble F, Dewhirst MW, Secomb TW. 2010. The shunt problem: control of functional shunting in normal and tumour vasculature. Nat. Rev. Cancer 10:587-93
53. Kamoun WS, Chae SS, Lacorre DA, Tyrrell JA, Mitre M, et al. 2010. Simultaneous measurement of RBC velocity, flux, hematocrit and shear rate in vascular networks. Nat. Methods 7:655-60
54. Baish JW, Stylianopoulos T, Lanning RM, Kamoun WS, Fukumura D, et al. 2011. Scaling rules for diffusive drug delivery in tumor and normal tissues. Proc. Natl. Acad. Sci. USA 108:1799-803
55. Boucher Y, Kirkwood JM, Opacic D, Desantis M, Jain RK. 1991. Interstitial hypertension in superficial metastatic melanomas in humans. Cancer Res. 51:6691-94
56. Less JR, Posner MC, Boucher Y, Borochovitz D, Wolmark N, Jain RK. 1992. Interstitial hypertension in human breast and colorectal tumors. Cancer Res. 52:6371-74
57. Ambrosi D, Mollica F. 2002. On the mechanics of a growing tumor. Int. J. Eng. Sci. 40:1297-316
58. Ambrosi D, Preziosi L. 2009. Cell adhesion mechanisms and stress relaxation in the mechanics of tumours. Biomech. Model. Mechanobiol. 8:397-413
59. MacLaurin J, Chapman J, Jones GW, Roose T. 2012. The buckling of capillaries in solid tumours. Proc. R. Soc. A 468:4123-45
60. Ciarletta P. 2013. Buckling instability in growing tumor spheroids. Phys. Rev. Lett. 110:158102
61. Byrne H, Preziosi L. 2003. Modelling solid tumour growth using the theory of mixtures. Math. Med. Biol. 20:341-66
62. Stylianopoulos T, Barocas VH. 2007. Multiscale, structure-based modeling for the elastic mechanical behavior of arterial walls. J. Biomech. Eng. 129:611-18
63. Sander E, Stylianopoulos T, Tranquillo R, Barocas V. 2009. Image-based biomechanics of collagenbased tissue equivalents. IEEE Eng. Med. Biol. Mag. 28:10-18
64. Chauhan VP, Stylianopoulos T, Boucher Y, Jain RK. 2011. Delivery of molecular and nanomedicine to tumors: transport barriers and strategies. Annu. Rev. Chem. Biomol. Eng. 2:281-98
65. Sevick EM, Jain RK. 1989. Geometric resistance to blood flow in solid tumors perfused ex vivo: effects of tumor size and perfusion pressure. Cancer Res. 49:3506-12
66. Sevick EM, Jain RK. 1989. Viscous resistance to blood flow in solid tumors: effect of hematocrit on intratumor blood viscosity. Cancer Res. 49:3513-19
67. Carmeliet P, Jain RK. 2000. Angiogenesis in cancer and other diseases. Nature 407:249-57
68. Jain RK. 2005. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58-62
69. Leunig M, Yuan F, Menger MD, Boucher Y, Goetz AE, et al. 1992. Angiogenesis, microvascular architecture, microhemodynamics, and interstitial fluid pressure during early growth of human adenocarcinoma LS174T in SCID mice. Cancer Res. 52:6553-60
70. Vakoc BJ, Lanning RM, Tyrrell JA, Padera TP, Bartlett LA, et al. 2009. Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging. Nat. Med. 15:1219-23
71. Jain RK. 1987. Transport of molecules across tumor vasculature. Cancer Metastasis Rev. 6:559-93
72. Hobbs SK, Monsky WL, Yuan F, Roberts WG, Griffith L, et al. 1998. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl. Acad. Sci. USA 95:4607-12
73. Hashizume H, Baluk P, Morikawa S, McLean JW, Thurston G, et al. 2000. Openings between defective endothelial cells explain tumor vessel leakiness. Am. J. Pathol. 156:1363-80
74. Less JR, Posner MC, Skalak TC, Wolmark N, Jain RK. 1997. Geometric resistance and microvascular network architecture of human colorectal carcinoma. Microcirculation 4:25-33
75. Sun C, Jain RK, Munn LL. 2007. Non-uniform plasma leakage affects local hematocrit and blood flow: implications for inflammation and tumor perfusion. Ann. Biomed. Eng. 35:2121-29
76. Yuan F, Salehi HA, Boucher Y, Vasthare US, Tuma RF, Jain RK. 1994. Vascular permeability and microcirculation of gliomas and mammary carcinomas transplanted in rat and mouse cranial windows. Cancer Res. 54:4564-68
77. Wirtz D, Konstantopoulos K, Searson PC. 2011. The physics of cancer: the role of physical interactions and mechanical forces in metastasis. Nat. Rev. Cancer 11:512-22
78. Tarbell JM, Weinbaum S, Kamm RD. 2005. Cellular fluid mechanics and mechanotransduction. Ann. Biomed. Eng. 33:1719-23
79. Song JW, Munn LL. 2011. Fluid forces control endothelial sprouting. Proc. Natl. Acad. Sci. USA 108:15342-47
80. Djonov VG, Kurz H, Burri PH. 2002. Optimality in the developing vascular system: branching remodeling by means of intussusception as an efficient adaptation mechanism. Dev. Dyn. 224:391-402
81. Kamiya A, Ando J, Shibata M, Masuda H. 1988. Roles of fluid shear stress in physiological regulation of vascular structure and function. Biorheology 25:271-78
82. Nagy JA, Dvorak AM, Dvorak HF. 2012. Vascular hyperpermeability, angiogenesis, and stroma generation. Cold Spring Harb. Perspect. Med. 2:a006544
83. Kalluri R, Zeisberg M. 2006. Fibroblasts in cancer. Nat. Rev. Cancer 6:392-401
84. Chary SR, Jain RK. 1989. Direct measurement of interstitial convection and diffusion of albumin in normal and neoplastic tissues by fluorescence photobleaching. Proc. Natl. Acad. Sci. USA 86:5385-89
85. Pedersen JA, Lichter S, Swartz MA. 2010. Cells in 3D matrices under interstitial flow: effects of extracellular matrix alignment on cell shear stress and drag forces. J. Biomech. 43:900-5
86. Ng CP, Hinz B, Swartz MA. 2005. Interstitial fluid flow induces myofibroblast differentiation and collagen alignment in vitro. J. Cell Sci. 118:4731-39
87. Swartz MA, Lund AW. 2012. Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity. Nat. Rev. Cancer 12:210-19
88. Avvisato CL, Yang X, Shah S, Hoxter B, Li W, et al. 2007. Mechanical force modulates global gene expression and β-catenin signaling in colon cancer cells. J. Cell Sci. 120:2672-82
89. Shieh AC. 2011. Biomechanical forces shape the tumor microenvironment. Ann. Biomed. Eng. 39:1379-89
90. Levick JR. 1987. Flow through interstitium and other fibrous matrices. Q. J. Exp. Physiol. 72:409-37
91. Stylianopoulos T, Yeckel A, Derby JJ, Luo XJ, Shephard MS, et al. 2008. Permeability calculations in three-dimensional isotropic and oriented fiber networks. Phys. Fluids 20:123601
92. Netti PA, Berk DA, Swartz MA, Grodzinsky AJ, Jain RK. 2000. Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res. 60:2497-503
93. Huijbers IJ, Iravani M, Popov S, Robertson D, Al-Sarraj S, et al. 2010. A role for fibrillar collagen deposition and the collagen internalization receptor endo180 in glioma invasion. PLoS ONE 5:e9808
94. Mok W, Boucher Y, Jain RK. 2007. Matrix metalloproteinases-1 and -8 improve the distribution and efficacy of an oncolytic virus. Cancer Res. 67:10664-68
95. Clayes IL, Brady JF. 1993. Suspensions of prolate spheroids in Stokes flow. Part 2. Statistically homogeneous dispersions. J. Fluid Mech. 251:443-77
96. Stylianopoulos T, Diop-Frimpong B, Munn LL, Jain RK. 2010. Diffusion anisotropy in collagen gels and tumors: the effect of fiber network orientation. Biophys. J. 99:3119-28
97. 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
98. Padera TP, Kadambi A, di Tomaso E, Carreira CM, Brown EB, et al. 2002. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296:1883-86
99. Isaka N, Padera TP, Hagendoorn J, Fukumura D, Jain RK. 2004. Peritumor lymphatics induced by vascular endothelial growth factor-C exhibit abnormal function. Cancer Res. 64:4400-4
100. Hoshida T, Isaka N, Hagendoorn J, di Tomaso E, Chen YL, et al. 2006. Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications. Cancer Res. 66:8065-75
101. Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, et al. 1997. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276:1423-25
102. Alitalo K, Tammela T, Petrova TV. 2005. Lymphangiogenesis in development and human disease. Nature 438:946-53
103. Berk DA, Swartz MA, Leu AJ, Jain RK. 1996. Transport in lymphatic capillaries. II. Microscopic velocity measurement with fluorescence photobleaching. Am. J. Physiol. 270:H330-37
104. Fischer M, Franzeck UK, Herrig I, Costanzo U, Wen S, et al. 1996. Flow velocity of single lymphatic capillaries in human skin. Am. J. Physiol. 270:H358-63
105. Swartz MA, Berk DA, Jain RK. 1996. Transport in lymphatic capillaries. I. Macroscopic measurements using residence time distribution theory. Am. J. Physiol. 270:H324-29
106. Hagendoorn J, Padera TP, Kashiwagi S, Isaka N, Noda F, et al. 2004. Endothelial nitric oxide synthase regulates microlymphatic flow via collecting lymphatics. Circ. Res. 95:204-9
107. Gasheva OY, Zawieja DC, Gashev AA. 2006. Contraction-initiated NO-dependent lymphatic relaxation: a self-regulatory mechanism in rat thoracic duct. J. Physiol. 575:821-32
108. Kajiya K, Huggenberger R, Drinnenberg I, Ma B, Detmar M. 2008. Nitric oxide mediates lymphatic vessel activation via soluble guanylate cyclase α1β1-impact on inflammation. FASEB J. 22:530-37
109. Liao S, Cheng G, Conner DA, Huang Y, Kucherlapati RS, et al. 2011. Impaired lymphatic contraction associated with immunosuppression. Proc. Natl. Acad. Sci. USA 108:18784-89
110. Kesler CT, Liao S, Munn LL, Padera TP. 2013. Lymphatic vessels in health and disease. Wiley Interdiscip. Rev. Syst. Biol. Med. 5:111-24
111. Ng CP, Helm CL, Swartz MA. 2004. Interstitial flow differentially stimulates blood and lymphatic endothelial cell morphogenesis in vitro. Microvasc. Res. 68:258-64
112. Miteva DO, Rutkowski JM, Dixon JB, Kilarski W, Shields JD, Swartz MA. 2010. Transmural flow modulates cell and fluid transport functions of lymphatic endothelium. Circ. Res. 106:920-31
113. Yuan F, Leunig M, Huang SK, Berk DA, Papahadjopoulos D, Jain RK. 1994. Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft. Cancer Res. 54:3352-56
114. Boucher Y, Jain RK. 1992. Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse. Cancer Res. 52:5110-14
115. Nathanson SD, Nelson L. 1994. Interstitial fluid pressure in breast cancer, benign breast conditions, and breast parenchyma. Ann. Surg. Oncol. 1:333-38
116. Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, et al. 2004. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat. Med. 10:145-47
117. Willett CG, Duda DG, di Tomaso E, Boucher Y, Ancukiewicz M, et al. 2009. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidis-ciplinary Phase II study. J. Clin. Oncol. 27:3020-26
118. Young JS, Lumsden CE, Stalker AL. 1950. The significance of the "tissue pressure" of normal testicular and of neoplastic (Brown-Pearce carcinoma) tissue in the rabbit. J. Pathol. Bacteriol. 62:313-33
119. Stylianopoulos T, Soteriou K, Fukumura D, Jain RK. 2013. Cationic nanoparticles have superior transvascular flux into solid tumors: insights from a mathematical model. Ann. Biomed. Eng. 41(1):68-77
120. Pozrikidis C, Farrow DA. 2003. A model of fluid flow in solid tumors. Ann. Biomed. Eng. 31:181-94
121. Pries AR, Secomb TW, Gaehtgens P, Gross JF. 1990. Blood flow in microvascular networks: experiments and simulation. Circ. Res. 67:826-34
122. Welter M, Bartha K, Rieger H. 2008. Emergent vascular network inhomogeneities and resulting blood flow patterns in a growing tumor. J. Theor. Biol. 250:257-80
123. Cai Y, Xu S, Wu J, Long Q. 2011. Coupled modelling of tumour angiogenesis, tumour growth and blood perfusion. J. Theor. Biol. 279:90-101
124. Wu M, Frieboes HB, McDougall SR, Chaplain MA, Cristini V, Lowengrub J. 2012. The effect of interstitial pressure on tumor growth: coupling with blood and lymphatic vascular systems. J. Theor. Biol. 320:131-51
125. Pozrikidis C. 2005. Axisymmetric motion of a file of red blood cells through capillaries. Phys. Fluids 17:1-14
126. Sun C, Munn LL. 2005. Particulate nature of blood determines macroscopic rheology: a 2-D lattice Boltzmann analysis. Biophys. J. 88:1635-45
127. Dupin MM, Halliday I, Care CM, Alboul L, Munn LL. 2007. Modeling the flow of dense suspensions of deformable particles in three dimensions. Phys. Rev. E 75:066707
128. Pivkin IV, Karniadakis GE. 2008. Accurate coarse-grained modeling of red blood cells. Phys. Rev. Lett. 101:118105
129. Li X, Vlahovska PM, Karniadakis GE. 2013. Continuum-and particle-based modeling of shapes and dynamics of red blood cells in health and disease. Soft Matter 9:28-37
130. Pries AR, Cornelissen AJ, Sloot AA, Hinkeldey M, Dreher MR, et al. 2009. Structural adaptation and heterogeneity of normal and tumor microvascular networks. PLoS Comput. Biol. 5:e1000394
131. Jackson GW, James DF. 1986. The permeability of fibrous porous media. Can. J. Chem. Eng. 64:364-74
132. Ethier R. 1994. Flow through mixed fibrous porous materials. AIChE J. 37:1227-36
133. Mattern KJ, Nakornchai C, Deen WM. 2008. Darcy permeability of agarose-glycosaminoglycan gels analyzed using fiber-mixture and Donnan models. Biophys. J. 95:648-56
134. Jain RK. 1987. Transport of molecules in the tumor interstitium: a review. Cancer Res. 47:3039-51
135. Roose T, Swartz MA. 2012. Multiscale modeling of lymphatic drainage from tissues using homogeniza-tion theory. J. Biomech. 45:107-15
136. Kunert C, Padera TP, Munn LL. 2012. Lattice Boltzmann simulations of lymphatic pumping. Presented at Am. Phys. Soc. (APS), Mar. Meet., Feb. 27-Mar. 2 (Abstr. #D42.002)
137. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, et al. 2009. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324:1457-61
138. Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N, et al. 2012. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62:112-20
139. Liu J, Liao S, Diop-Frimpong B, Chen W, Goel S, et al. 2012. TGF-βblockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma. Proc. Natl. Acad. Sci. USA 109:16618-23
140. Diop-Frimpong B, Chauhan VP, Krane S, Boucher Y, Jain RK. 2011. Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc. Natl. Acad. Sci. USA 108:2909-14
141. Nakai Y, Isayama H, Ijichi H, Sasaki T, Sasahira N, et al. 2010. Inhibition of renin-angiotensin system affects prognosis of advanced pancreatic cancer receiving gemcitabine. Br. J. Cancer 103:1644-48
142. Wilop S, Von Hobe S, Crysandt M, Esser A, Osieka R, Jost E. 2009. Impact of angiotensin I converting enzyme inhibitors and angiotensin II type 1 receptor blockers on survival in patients with advanced non-small-cell lung cancer undergoing first-line platinum-based chemotherapy. J. Cancer Res. Clin. Oncol. 135:1429-35
143. Keizman D, Huang P, Eisenberger MA, Pili R, Kim JJ, et al. 2011. Angiotensin system inhibitors and outcome of sunitinib treatment in patients with metastatic renal cell carcinoma: a retrospective examination. Eur. J. Cancer 47:1955-61
144. Jain RK. 2001. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat. Med. 7:987-89
145. Lee CG, Heijn M, di Tomaso E, Griffon-Etienne G, Ancukiewicz M, et al. 2000. Anti-vascular endothe-lial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res. 60:5565-70
146. 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
147. Wildiers H, Guetens G, De Boeck G, Verbeken E, Landuyt B, et al. 2003. Effect of antivascular en-dothelial growth factor treatment on the intratumoral uptake of CPT-11. Br. J. Cancer 88:1979-86
148. Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK. 2004. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 64:3731-36
149. 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. Proc. Natl. Acad. Sci. USA 109:17561-66
150. Emblem KE, Mouridsen K, Bjornerud A, Farrar C, Jennings D, et al. 2013. Vessel architectural imaging identifies cancer patient responders to anti-angiogenic therapy. Nat. Med. 19:1178-83
151. 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. Proc. Natl. Acad. Sci. USA 110:19059-64
152. 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
153. 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
154. Sorensen AG, Emblem KE, Polaskova P, Jennings D, Kim H, et al. 2012. Increased survival of glioblas-toma patients who respondtoanti-angiogenic therapy with elevated blood perfusion.Cancer Res. 72:402-7