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Mechanical Forces in Tumor Angiogenesis

  • Matthew R. Zanotelli
  • Cynthia A. Reinhart-KingEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1092)

Abstract

A defining hallmark of cancer and cancer development is upregulated angiogenesis. The vasculature formed in tumors is structurally abnormal, not organized in the conventional hierarchical arrangement, and more permeable than normal vasculature. These features contribute to leaky, tortuous, and dilated blood vessels, which act to create heterogeneous blood flow, compression of vessels, and elevated interstitial fluid pressure. As such, abnormalities in the tumor vasculature not only affect the delivery of nutrients and oxygen to the tumor, but also contribute to creating an abnormal tumor microenvironment that further promotes tumorigenesis. The role of chemical signaling events in mediating tumor angiogenesis has been well researched; however, the relative contribution of physical cues and mechanical regulation of tumor angiogenesis is less understood. Growing research indicates that the physical microenvironment plays a significant role in tumor progression and promoting abnormal tumor vasculature. Here, we review how mechanical cues found in the tumor microenvironment promote aberrant tumor angiogenesis. Specifically, we discuss the influence of matrix stiffness and mechanical stresses in tumor tissue on tumor vasculature, as well as the mechanosensory pathways utilized by endothelial cells to respond to the physical cues found in the tumor microenvironment. We also discuss the impact of the resulting aberrant tumor vasculature on tumor progression and therapeutic treatment.

Keywords

VE-cadherin VEGF Matrix stiffness MMP Contractility Fluid shear stress Interstitial pressure Mechanotransduction Mechanosensitivity Barrier function 

Notes

Acknowledgments

The authors gratefully acknowledge support from the National Heart, Lung, and Blood Institute (HL127499) to CAR-K and a National Science Foundation Graduate Research Fellowship under Grant No. DGE-1650441 to MRZ.

References

  1. 1.
    Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switchduring tumorigenesis. Cell 86:353–364PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3(6):401–410PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Less JR et al (1991) Microvascular architecture in a mammary carcinoma: branching patterns and vessel dimensions. Cancer Res 51(265):265–273PubMedPubMedCentralGoogle Scholar
  5. 5.
    Baluk P, Hashizume H, McDonald DM (2005) Cellular abnormalities of blood vessels as targets in cancer. Curr Opin Genet Dev 15(1):102–111PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Dudley AC (2012) Tumor endothelial cells. Cold Spring Harb Perspect Med 2(3):1–18CrossRefGoogle Scholar
  7. 7.
    Aird WC (2012) Endothelial cell heterogeneity. Cold Spring Harb Perspect Med 2(1):a006429–a006429PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Aird WC (2009) Molecular heterogeneity of tumor endothelium. Cell Tissue Res 335(1):271–281PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Hashizume H et al (2000) Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol 156(4):1363–1380PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Hobbs SK et al (1998) Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci 95(8):4607–4612PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Dvorak HF et al (1999) Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis. Curr Top Microbiol Immunol 237:97–132PubMedGoogle Scholar
  12. 12.
    Bordeleau F et al (2017) Matrix stiffening promotes a tumor vasculature phenotype. Proc Natl Acad Sci 114(3):492–497PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Jain RK (2014) Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26(5):605–622PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Lu P, Weaver VM, Werb Z (2012) The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol 196(4):395–406PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Daley WP, Peters SB, Larsen M (2008) Extracellular matrix dynamics in development and regenerative medicine. J Cell Sci 121(3):255–264PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Kim DH et al (2012) Matrix nanotopography as a regulator of cell function. J Cell Biol 197(3):351–360PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Hynes RO (2009) The extracellular matrix: not just pretty fibrils. Science 326(5957):1216–1219PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Mongiat, M et al (2016) Extracellular matrix, a hard player in angiogenesis. Int J Mol Sci 17(11):1822PubMedCentralCrossRefGoogle Scholar
  19. 19.
    Bonnans C, Chou J, Werb Z (2014) Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol 15(12):786–801PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Mammoto T, Ingber DE (2010) Mechanical control of tissue and organ development. Development 137(9):1407–1420PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Provenzano PP et al (2006) Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med 4(1):38–38PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Wiseman BS (2002) Stromal effects on mammary gland development and breast cancer. Science 296(5570):1046–1049PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Butcher DT, Alliston T, Weaver VM (2009) A tense situation: forcing tumour progression. Nat Rev Cancer 9(2):108–122PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Grassian AR, Coloff JL, Brugge JS (2011) Extracellular matrix regulation of metabolism and implications for tumorigenesis. Cold Spring Harb Symp Quant Biol 76:313–324PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Morris BA et al (2016) Collagen matrix density drives the metabolic shift in breast cancer cells. EBioMedicine 13:146–156PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Paszek MJ et al (2005) Tensional homeostasis and the malignant phenotype. Cancer Cell 8(3):241–254PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Wozniak MA et al (2003) ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix. J Cell Biol 163(3):583–595PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Provenzano PP et al (2009) Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK-ERK linkage. Oncogene 28(49):4326–4343PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Samani A et al (2003) Measuring the elastic modulus of ex vivo small tissue samples. Phys Med Biol 48(14):2183–2198PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Gefen A, Dilmoney B (2007) Mechanics of the normal woman’s breast. Technol Health Care 15(4):259–271PubMedPubMedCentralGoogle Scholar
  31. 31.
    Jain RK (1994) Barriers to drug delivery in solid tumors. Sci Am 271(1):58–65PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Less JR et al (1992) Interstitial hypertension in human breast and colorectal tumors. Cancer Res 52(22):6371–6374PubMedPubMedCentralGoogle Scholar
  33. 33.
    Nathanson SD, Nelson L (1994) Interstitial fluid pressure in breast cancer, benign breast conditions, and breast parenchyma. Ann Surg Oncol 1(4):333–338PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Stylianopoulos T et al (2012) Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors. Proc Natl Acad Sci 109(38):15101–15108PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    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(6):2729–2735PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Ebihara T et al (2000) Changes in extracellular matrix and tissue viscoelasticity in bleomycin-induced lung fibrosis. Temporal aspects. Am J Respir Crit Care Med 162(4):1569–1576PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Aukland K, Reed RK (1993) Interstitial-lymphatic mechanisms in the control of extracellular fluid volume. Physiol Rev 73(1):1–78PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Mori T et al (2015) Interstitial fluid pressure correlates clinicopathological factors of lung cancer. Ann Thorac Cardiovasc Surg 21(3):201–208PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Kumar S, Weaver VM (2009) Mechanics, malignancy, and metastasis: the force journey of a tumor cell. Cancer Metastasis Rev 28(1–2):113–127PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Boucher Y et al (1997) Interstitial fluid pressure in intracranial tumours in patients and in rodents. Br J Cancer 75(6):829–836PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Arbit E, Lee J, Diresta G (1994) Interstitial hypertension in human brain tumors: possible role in peritumoral edema formation. In: Nagai H, Kamlya K (eds) Intracranial pressure, 9th edn. Springer, TokyoGoogle Scholar
  42. 42.
    Goel S et al (2011) Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev 91(3):1071–1121PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Navalitloha Y et al (2006) Therapeutic implications of tumor interstitial fluid pressure in subcutaneous RG-2 tumors. Neuro-Oncology 8(3):227–233PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Nia HT et al (2016) Solid stress and elastic energy as measures of tumour mechanopathology. Nat Biomed Eng 1.  https://doi.org/10.1038/s41551-016-0004 PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Guyton AC, Hall JE (2006) Textbook of medical physiology, Guyton physiology series. Elsevier Saunders, AmsterdamGoogle Scholar
  46. 46.
    Wells RG (2008) The role of matrix stiffness in regulating cell behavior. Hepatology 47(4):1394–1400PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Yeh WC et al (2002) Elastic modulus measurements of human liver and correlation with pathology. Ultrasound Med Biol 28(4):467–474PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Hori K et al (1986) Increased tumor tissue pressure in association with the growth of rat tumors. Jpn J Cancer Res 77(1):65–73PubMedPubMedCentralGoogle Scholar
  49. 49.
    Kawano S et al (2015) Assessment of elasticity of colorectal cancer tissue, clinical utility, pathological and phenotypical relevance. Cancer Sci 106(9):1232–1239PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Johnson LA et al (2013) Matrix stiffness corresponding to strictured bowel induces a fibrogenic response in human colonic fibroblasts. Inflamm Bowel Dis 19(5):891–903PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Nebuloni M et al (2016) Insight on colorectal carcinoma infiltration by studying perilesional extracellular matrix. Sci Rep 6:22522PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Netti PA et al (2000) Role of extracellular matrix assembly in interstitial transport in solid tumors role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res 60:2497–2503PubMedPubMedCentralGoogle Scholar
  53. 53.
    Stanczyk M et al (2010) Lack of functioning lymphatics and accumulation of tissue fluid/lymph in interstitial “lakes” in colon cancer tissue. Lymphology 43(4):158–167PubMedPubMedCentralGoogle Scholar
  54. 54.
    Levental I, Georges PC, Janmey PA (2007) Soft biological materials and their impact on cell function. Soft Matter 3:2990306CrossRefGoogle Scholar
  55. 55.
    Lee JW et al (2011) Palpation device for the identification of kidney and bladder cancer: a pilot study. Yonsei Med J 52(5):768–772PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Wortman T, Hsu F, Slocum A (2016) A novel phantom tissue model for skin elasticity quantification. ASME J Med Devices 10(2):020961CrossRefGoogle Scholar
  57. 57.
    Boucher Y et al (1991) Interstitial hypertension in superficial metastatic melanomas in humans. Cancer Res 51(24):6691–6694PubMedPubMedCentralGoogle Scholar
  58. 58.
    Rice AJ et al (2017) Matrix stiffness induces epithelial-mesenchymal transition and promotes chemoresistance in pancreatic cancer cells. Oncogene 6(7):e352CrossRefGoogle Scholar
  59. 59.
    Provenzano PP et al (2012) Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21(3):418–429PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Zysset PK et al (1999) Elastic modulus and hardness of cortical and trabecular bone lamellae measured by nanoindentation in the human femur. J Biomech 32(10):1005–1012PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Odgaard A, Linde F (1991) The underestimation of Young’s modulus in compressive testing of cancellous bone specimens. J Biomech 24(8):691–698PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Nathan SS et al (2008) Tumor interstitial fluid pressure may regulate angiogenic factors in osteosarcoma. J Orthop Res 26(11):1520–1525PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Davis GE, Senger DR (2005) Endothelial extracellular matrix: biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization. Circ Res 97(11):1093–1107PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Ingber DE, Folkman J (1989) Mechanochemical switching between growth and differentiation during fibroblast growth factor-stimulated angiogenesis in vitro: role of extracellular matrix. J Cell Biol 109(1):317–330PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Vailhé B et al (1997) In vitro angiogenesis is modulated by the mechanical properties of fibrin gels and is related to alpha(v)beta3 integrin localization. In Vitro Cell Dev Biol Anim 33(10):763–773PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Ghajar CM et al (2008) The effect of matrix density on the regulation of 3-D capillary morphogenesis. Biophys J 94(5):1930–1941PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Rao RR et al (2012) Matrix composition regulates three-dimensional network formation by endothelial cells and mesenchymal stem cells in collagen fibrin materials. Angiogenesis 15(2):253–264PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Kniazeva E, Putnam AJ (2009) Endothelial cell traction and ECM density influence both capillary morphogenesis and maintenance in 3-D. Am J Physiol Cell Physiol 297(1):C179–C187PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Mason BN et al (2013) Tuning three-dimensional collagen matrix stiffness independently of collagen concentration modulates endothelial cell behavior. Acta Biomater 9(1):4635–4644PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Sieminski AL, Hebbel RP, Gooch KJ (2004) The relative magnitudes of endothelial force generation and matrix stiffness modulate capillary morphogenesis in vitro. Exp Cell Res 297(2):574–584PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    LaValley DJ, Reinhart-King CA (2014) Matrix stiffening in the formation of blood vessel. Adv Regen Biol 1:1–18Google Scholar
  72. 72.
    Wu Y, Al-Ameen MA, Ghosh G (2014) Integrated effects of matrix mechanics and vascular endothelial growth factor (VEGF) on capillary sprouting. Ann Biomed Eng 42(5):1024–1036PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Cox TR, Erler JT (2011) Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. Dis Model Mech 4(2):165–178PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Bershadsky AD, Balaban NQ, Geiger B (2003) Adhesion-dependent cell mechanosensitivity. Annu Rev Cell Dev Biol 19(1):677–695PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Ingber DE (1991) Integrins as mechanochemical transducers. Curr Opin Cell Biol 3(5):841–848PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Polet F, Feron O (2013) Endothelial cell metabolism and tumour angiogenesis: glucose and glutamine as essential fuels and lactate as the driving force. J Intern Med 273(2):156–165PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Liu Z et al (2010) Mechanical tugging force regulates the size of cell-cell junctions. Proc Natl Acad Sci 107(22):9944–9949PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Croix BS et al (2000) Genes expressed in human tumor endothelium. Science 289(5482):1197–1202CrossRefGoogle Scholar
  79. 79.
    Bussolati B et al (2003) Altered angiogenesis and survival in human tumor-derived endothelial cells. FASEB J 17(9):1159–1161PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Ghosh K et al (2008) Tumor-derived endothelial cells exhibit aberrant Rho-mediated mechanosensing and abnormal angiogenesis in vitro. Proc Natl Acad Sci 105(32):11305–11310PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Francis-Sedlak ME et al (2010) Collagen glycation alters neovascularization in vitro and in vivo. Microvasc Res 80(1):3–9PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Lee PF et al (2013) Angiogenic responses are enhanced in mechanically and microscopically characterized, microbial transglutaminase crosslinked collagen matrices with increased stiffness. Acta Biomater 9(7):7178–7190PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Whittington CF, Yoder MC, Voytik-Harbin SL (2013) Collagen-polymer guidance of vessel network formation and stabilization by endothelial colony forming cells in vitro. Macromol Biosci 13(9):1135–1149PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Yao C et al (2008) The effect of cross-linking of collagen matrices on their angiogenic capability. Biomaterials 29(1):66–74PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Yamamura N et al (2007) Effects of the mechanical properties of collagen gel on the in vitro formation of microvessel networks by endothelial cells. Tissue Eng 13(7):1443–1453PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Fantozzi A, Christofori G (2006) Mouse models of breast cancer metastasis. Breast Cancer Res 8(4):212PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Sternlicht MD, Werb Z (2001) How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 17(1):463–516PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Haage A, Schneider IC (2014) Cellular contractility and extracellular matrix stiffness regulate matrix metalloproteinase activity in pancreatic cancer cells. FASEB J 28(8):3589–3599PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Jain RK, Martin JD, Stylianopoulos T (2014) The role of mechanical forces in tumor growth and therapy. Annu Rev Biomed Eng 16(1):321–346PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Stylianopoulos T et al (2013) Coevolution of solid stress and interstitial fluid pressure in tumors during progression: implications for vascular collapse. Cancer Res 73(13):3833–3841PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Harris AK, Stopak D, Wild P (1981) Fibroblast traction as a mechanism for collagen morphogenesis. Nature 290(5803):249–251PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Miron-Mendoza M, Seemann J, Grinnell F (2008) Collagen fibril flow and tissue translocation coupled to fibroblast migration in 3D collagen matrices. Mol Biol Cell 19(5):2051–2058PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Shi Q et al (2014) Rapid disorganization of mechanically interacting systems of mammary acini. Proc Natl Acad Sci 111(2):658–663PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Wang H et al (2014) Long-range force transmission in fibrous matrices enabled by tension-driven alignment of fibers. Biophys J 107(11):2592–2603PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Kilarski WW et al (2009) Biomechanical regulation of blood vessel growth during tissue vascularization. Nat Med 15(6):657–664PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Korff T, Augustin HG (1999) Tensional forces in fibrillar extracellular matrices control directional capillary sprouting. J Cell Sci 112(19):3249–3258PubMedPubMedCentralGoogle Scholar
  97. 97.
    Kenyon BM et al (1996) A model of angiogenesis in the mouse cornea. Invest Ophthalmol Vis Sci 37(8):1625–1632PubMedPubMedCentralGoogle Scholar
  98. 98.
    Lockhart AC et al (2003) A clinical model of dermal wound angiogenesis. Wound Repair Regen 11(4):306–313PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Padera TP et al (2004) Pathology: cancer cells compress intratumour vessels. Nature 427(6976):695PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    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(18):5110–5114PubMedPubMedCentralGoogle Scholar
  101. 101.
    Potente M, Mäkinen T (2017) Vascular heterogeneity and specialization in development and disease. Nat Rev Mol Cell Biol 18(8):477Google Scholar
  102. 102.
    Helmlinger G et al (1991) Effects of pulsatile flow on cultured vascular endothelial cell morphology. J Biomech Eng 113(2):123–131PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Wang Y et al (2007) Selective adapter recruitment and differential signaling networks by VEGF vs. shear stress. Proc Natl Acad Sci 104(21):8875–8879PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Kappas NC et al (2008) The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching. J Cell Biol 181(5):847–858PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Price GM et al (2010) Effect of mechanical factors on the function of engineered human blood microvessels in microfluidic collagen gels. Biomaterials 31(24):6182–6189PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Song JW, Munn LL (2011) Fluid forces control endothelial sprouting. Proc Natl Acad Sci 108(37):15342–15347PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Galie Pa et al (2014) Fluid shear stress threshold regulates angiogenic sprouting. Proc Natl Acad Sci 111(22):7968–7973PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Vickerman V, Kamm RD (2012) Mechanism of a flow-gated angiogenesis switch: early signaling events at cell–matrix and cell–cell junctions. Integr Biol 4(8):863–874CrossRefGoogle Scholar
  109. 109.
    Ausprunk DH, Folkman J (1977) Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis. Microvasc Res 14(1):53–65PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Chauhan VP et al (2014) Compression of pancreatic tumor blood vessels by hyaluronan is caused by solid stress and not interstitial fluid pressure. Cancer Cell 26(1):14–15PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Li S, Huang NF, Hsu S (2005) Mechanotransduction in endothelial cell migration. J Cell Biochem 96(6):1110–1126PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Li YSJ, Haga JH, Chien S (2005) Molecular basis of the effects of shear stress on vascular endothelial cells. J Biomech 38(10):1949–1971PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Kutys ML, Chen CS (2016) Forces and mechanotransduction in 3D vascular biology. Curr Opin Cell Biol 42:73–79PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Conway DE et al (2013) Fluid shear stress on endothelial cells modulates mechanical tension across VE-cadherin and PECAM-1. Curr Biol 23(11):1024–1030PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Maniotis AJ, Chen CS, Ingber DE (1997) Demonstration of mechanical connections between integrins, cytoskeletal filaments, and nucleoplasm that stabilize nuclear structure. Proc Natl Acad Sci 94(3):849–854PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Stevenson RP, Veltman D, Machesky LM (2012) Actin-bundling proteins in cancer progression at a glance. J Cell Sci 125:1073–1079PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Alenghat FJ, Ingber DE (2002) Mechanotransduction: all signals point to cytoskeleton, matrix, and integrins. Sci Signal 2002(119):pe6CrossRefGoogle Scholar
  118. 118.
    Schwarz US, Gardel ML (2012) United we stand – integrating the actin cytoskeleton and cell–matrix adhesions in cellular mechanotransduction. J Cell Sci 125(13):3051–3060PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Katsumi A et al (2004) Integrins in mechanotransduction. J Biol Chem 279(13):12001–12004PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Giancotti FG, Ruoslahti E (1999) Integrin signaling. Science 285(5430):1028–1033PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Miranti CK, Brugge JS (2002) Sensing the environment: a historical perspective on integrin signal transduction. Nat Cell Biol 4(4):E83–E90PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Matthews BD et al (2006) Cellular adaptation to mechanical stress: role of integrins, Rho, cytoskeletal tension and mechanosensitive ion channels. J Cell Sci 119(3):508–518PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Reinhart-King CA, Dembo M, Hammer DA (2005) The dynamics and mechanics of endothelial cell spreading. Biophys J 89(1):676–689PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Zanotelli MR, Bordeleau F, Reinhart-King CA (2017) Subcellular regulation of cancer cell mechanics. Curr Opin Biomed Eng 1:8–14CrossRefGoogle Scholar
  125. 125.
    Kraning-Rush CM, Califano JP, Reinhart-King CA (2012) Cellular traction stresses increase with increasing metastatic potential. PLoS One 7(2):e32572–e32572PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Weis SM, Cheresh DA (2011) αV integrins in angiogenesis and cancer. Cold Spring Harb Perspect Med 1(1):1–14CrossRefGoogle Scholar
  127. 127.
    Paszek MJ, Weaver VM (2004) The tension mounts: mechanics meets morphogenesis and malignancy. J Mammary Gland Biol Neoplasia 9(4):325–342PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Tzima E et al (2001) Activation of integrins in endothelial cells by fluid shear stress mediates Rho-dependent cytoskeletal alignment. EMBO J 20(17):4639–4647PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Nikolopoulos SN et al (2004) Integrin β4 signaling promotes tumor angiogenesis. Cancer Cell 6(5):471–483PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Ruoslahti E (2000) Targeting tumor vasculature with homing peptides from phage display. Semin Cancer Biol 10(6):435–442PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Ruoslahti E (2002) Specialization of tumour vasculature. Nat Rev Cancer 2(2):83–90PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Senger DR et al (1997) Angiogenesis promoted by vascular endothelial growth factor: regulation through α1β1 and α2β1 integrins. Proc Natl Acad Sci 94(25):13612–13617PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Senger D et al (2002) The α1β1 and α2β1 integrins provide critical support for vascular endothelial growth factor signaling, endothelial cell migration, and tumor angiogenesis. Am J Pathol 160(1):195–204PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Kim S et al (2000) Regulation of angiogenesis in vivo by ligation of integrin α5β1 with the central cell-binding domain of fibronectin. Am J Pathol 156(4):1345–1362PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Brooks PC et al (1994) Integrin αvβ3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79(7):1157–1164PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Friedlander M et al (1995) Definition of two angiogenic pathways by distinct αv integrins. Science 270(5241):1500–1502PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Hood JD et al (2003) Differential alphav integrin-mediated Ras-ERK signaling during two pathways of angiogenesis. J Cell Biol 162(5):933–943PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Brooks PC, Clark RAF, Cheresh DA (1994) Requirement of vascular integrin αvβ3 for angiogenesis. Science 264(5158):569–571CrossRefPubMedGoogle Scholar
  139. 139.
    Soldi R et al (1999) Role of αvβ3 integrin in the activation of vascular endothelial growth factor receptor-2. EMBO J 18(4):882–892PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Borges E, Jan Y, Ruoslahti E (2000) Platelet-derived growth factor receptor beta and vascular endothelial growth factor receptor 2 bind to the beta 3 integrin through its extracellular domain. J Biol Chem 275(51):39867–39873PubMedCrossRefPubMedCentralGoogle Scholar
  141. 141.
    Brooks PC et al (1995) Antiintegrin αvβ3 blocks human breast cancer growth and angiogenesis in human skin. J Clin Investig 96(4):1815–1822PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Erdreich-Epstein A et al (2000) Integrins alpha(v)beta3 and alpha(v)beta5 are expressed by endothelium of high-risk neuroblastoma and their inhibition is associated with increased endogenous ceramide. Cancer Res 60(3):712–721PubMedPubMedCentralGoogle Scholar
  143. 143.
    Eliceiri BP, Cheresh Da (1999) The role of αv integrins during angiogenesis: insights into potential mechanisms of action and clinical development. J Clin Dev 103(9):1227–12330Google Scholar
  144. 144.
    Kumar CC et al (2001) Inhibition of angiogenesis and tumor growth by SCH221153, a dual alpha(v)beta3 and alpha(v)beta5 integrin receptor antagonist. Cancer Res 61(5):2232–2238PubMedPubMedCentralGoogle Scholar
  145. 145.
    Bazzoni G, Dejana E (2004) Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol Rev 84(3):869–901PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Dorland YL, Huveneers S (2017) Cell–cell junctional mechanotransduction in endothelial remodeling. Cell Mol Life Sci 74(2):279–292PubMedCrossRefPubMedCentralGoogle Scholar
  147. 147.
    Hahn C, Schwartz MA (2009) Mechanotransduction in vascular physiology and atherogenesis. Nat Rev Mol Cell Biol 10(1):53–62PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Lakshmikanthan S et al (2015) Rap1 promotes endothelial mechanosensing complex formation, NO release and normal endothelial function. EMBO Rep 16(5):628–637PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Coon BG et al (2015) Intramembrane binding of VE-cadherin to VEGFR2 and VEGFR3 assembles the endothelial mechanosensory complex. J Cell Biol 208(7):975–986PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Conway D, Schwartz MA (2012) Lessons from the endothelial junctional mechanosensory complex. F1000 Biol Rep 4(1):2–7Google Scholar
  151. 151.
    Collins C et al (2012) Localized tensional forces on PECAM-1 elicit a global mechanotransduction response via the integrin-RhoA pathway. Curr Biol 22(22):2087–2094PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Murakami M, Simons M (2009) Regulation of vascular integrity. J Mol Med 87(6):571–582PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Fraccaroli A et al (2015) Endothelial alpha-parvin controls integrity of developing vasculature and is required for maintenance of cell–cell junctions. Circ Res 117(1):19–40CrossRefGoogle Scholar
  154. 154.
    Huynh J et al (2011) Age-related intimal stiffening enhances endothelial permeability and leukocyte transmigration. Sci Transl Med 3(112):112ra122PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Mazzone M et al (2009) Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136(5):839–851PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Giannotta M, Trani M, Dejana E (2013) VE-cadherin and endothelial adherens junctions: active guardians of vascular integrity. Dev Cell 26(5):441–454PubMedCrossRefPubMedCentralGoogle Scholar
  157. 157.
    van Nieuw Amerongen GP et al (2003) Involvement of RhoA/Rho kinase signaling in VEGF-induced endothelial cell migration and angiogenesis in vitro. Arterioscler Thromb Vasc Biol 23(2):211–217PubMedCrossRefPubMedCentralGoogle Scholar
  158. 158.
    Shay-salit A et al (2002) VEGF receptor 2 and the adherens junction as a mechanical transducer in vascular endothelial cells. Proc Natl Acad Sci 99(14):9462–9467PubMedCrossRefPubMedCentralGoogle Scholar
  159. 159.
    Koch S, Claesson-Welsh L (2012) Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med 2(7):a006502Google Scholar
  160. 160.
    Kubo H et al (2000) Involvement of vascular endothelial growth factor receptor-3 in maintenance of integrity of endothelial cell lining during tumor angiogenesis. Blood 96(2):546–553PubMedPubMedCentralGoogle Scholar
  161. 161.
    Laakkonen P et al (2007) Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. Cancer Res 67(2):593–599PubMedCrossRefGoogle Scholar
  162. 162.
    Mammoto A et al (2009) A mechanosensitive transcriptional mechanism that controls angiogenesis. Nature 457(7233):1103–1108PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Sack KD, Teran M, Nugent MA (2016) Extracellular matrix stiffness controls vegf signaling and processing in endothelial cells. J Cell Physiol 231(9):2026–2039PubMedCrossRefGoogle Scholar
  164. 164.
    Yang MT, Reich DH, Chen CS (2011) Measurement and analysis of traction force dynamics in response to vasoactive agonists. Integr Biol 3(6):663–674CrossRefGoogle Scholar
  165. 165.
    Goel HL, Mercurio AM (2013) VEGF targets the tumour cell. Nat Rev Cancer 13(12):871–882PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Ogawa K et al (2000) The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization. Oncogene 19(52):6043–6052PubMedCrossRefPubMedCentralGoogle Scholar
  167. 167.
    Shin D et al (2001) Expression of EphrinB2 identifies a stable genetic difference between arterial and venous vascular smooth muscle as well as endothelial cells, and marks subsets of microvessels at sites of adult neovascularization. Dev Biol 230(2):139–150PubMedCrossRefPubMedCentralGoogle Scholar
  168. 168.
    Gale NW et al (2001) Ephrin-B2 selectively marks arterial vessels and neovascularization sites in the adult, with expression in both endothelial and smooth-muscle cells. Dev Biol 230(2):151–160PubMedCrossRefPubMedCentralGoogle Scholar
  169. 169.
    Martial S (2016) Involvement of ion channels and transporters in carcinoma angiogenesis and metastasis. Am J Physiol Cell Physiol 310(9):C710–C727PubMedCrossRefPubMedCentralGoogle Scholar
  170. 170.
    Liberati S et al (2013) Oncogenic and anti-oncogenic effects of transient receptor potential channels. Curr Top Med Chem 13(3):344–366PubMedCrossRefPubMedCentralGoogle Scholar
  171. 171.
    Lehen'kyi V, Prevarskaya N (2011) Oncogenic TRP channels. Adv Exp Med Biol 704:929–945PubMedCrossRefPubMedCentralGoogle Scholar
  172. 172.
    Lehen’kyi V, Prevarskaya N (2011) Study of TRP channels in cancer cells. In: Zhu MX (ed) TRP channels. CRC Press/Taylor & Francis. Llc., Boca Raton (FL)Google Scholar
  173. 173.
    Kwan H-Y, Huang Y, Yao X (2007) TRP channels in endothelial function and dysfunction. Biochim Biophys Acta 1772(8):907–914PubMedCrossRefPubMedCentralGoogle Scholar
  174. 174.
    Adapala RK et al (2016) Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy. Oncogene 35(3):314–322PubMedCrossRefPubMedCentralGoogle Scholar
  175. 175.
    Thoppil RJ et al (2016) TRPV4 channels regulate tumor angiogenesis via modulation of Rho/Rho kinase pathway. Oncotarget 7(18): 25849–25861PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Thodeti CK et al (2009) TRPV4 channels mediate cyclic strain-induced endothelial cell reorientation through integrin-to-integrin signaling. Circ Res 104(9):1123–1130PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Chachisvilis M, Zhang YL, Frangos JA (2006) G protein-coupled receptors sense fluid shear stress in endothelial cells. Proc Natl Acad Sci 103(42):15463–15468PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Dorsam RT, Gutkind JS (2007) G-protein-coupled receptors and cancer. Nat Rev Cancer 7(2):79–94PubMedCrossRefPubMedCentralGoogle Scholar
  179. 179.
    Richard DE, Vouret-Craviari V, Pouysségur J (2001) Angiogenesis and G-protein-coupled receptors: signals that bridge the gap. Oncogene 20(1):1556–1562PubMedCrossRefPubMedCentralGoogle Scholar
  180. 180.
    O'Hayre M, Degese MS, Gutkind JS (2014) Novel insights into G protein and G protein-coupled receptor signaling in cancer. Curr Opin Cell Biol 27:126–135PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Pai R et al (2001) PGE2 stimulates VEGF expression in endothelial cells via ERK2/JNK1 signaling pathways. Biochem Biophys Res Commun 286(5):923–928PubMedCrossRefPubMedCentralGoogle Scholar
  182. 182.
    Visentin B et al (2006) Validation of an anti-sphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor lineages. Cancer Cell 9(3):225–238PubMedCrossRefPubMedCentralGoogle Scholar
  183. 183.
    Vouret-Craviari V, Grall D, Van Obberghen-Schilling E (2003) Modulation of Rho GTPase activity in endothelial cells by selective proteinase-activated receptor (PAR) agonists. J Thromb Haemost 1(5):1103–1111PubMedCrossRefPubMedCentralGoogle Scholar
  184. 184.
    Evan-Ram S et al (1998) Thrombin receptor overexpression in malignant and physiological invasion processes. Nature 4(8):909–914Google Scholar
  185. 185.
    McDonald DM, Baluk P (2002) Significance of blood vessel leakiness in cancer. Cancer Res 62(18):5381–5385Google Scholar
  186. 186.
    Pries AR et al (2010) The shunt problem: control of functional shunting in normal and tumour vasculature. Nat Rev Cancer 10(8):587–593PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Kamoun WS et al (2010) Simultaneous measurement of RBC velocity, flux, hematocrit and shear rate in vascular networks. Nat Methods 7(8):655–660PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Baish JW et al (2011) Scaling rules for diffusive drug delivery in tumor and normal tissues. Proc Natl Acad Sci 108(5):1799–1803PubMedCrossRefPubMedCentralGoogle Scholar
  189. 189.
    Chauhan VP et al (2011) Delivery of molecular and nanoscale medicine to tumors: transport barriers and strategies. Annu Rev Chem Biomol Eng 2(1):281–298PubMedCrossRefPubMedCentralGoogle Scholar
  190. 190.
    Heldin C-H et al (2004) High interstitial fluid pressure — an obstacle in cancer therapy. Nat Rev Cancer 4(10):806–813PubMedCrossRefPubMedCentralGoogle Scholar
  191. 191.
    Jain RK (2013) Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol 31(17):2205–2218PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Hurwitz H (2004) Integrating the anti-VEGF-A humanized monoclonal antibody bevacizumab with chemotherapy in advanced colorectal cancer. Clin Colorectal Cancer 4(Suppl 2):S62–S68PubMedCrossRefPubMedCentralGoogle Scholar
  193. 193.
    Maes H et al (2014) Tumor vessel normalization by chloroquine independent of autophagy. Cancer Cell 26(2):190–206PubMedCrossRefPubMedCentralGoogle Scholar
  194. 194.
    Potente M, Gerhardt H, Carmeliet P (2011) Basic and therapeutic aspects of angiogenesis. Cell 146(6):873–887PubMedCrossRefPubMedCentralGoogle Scholar
  195. 195.
    Welti J et al (2013) Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer. J Clin Investig 123(8):3190–3200PubMedCrossRefPubMedCentralGoogle Scholar
  196. 196.
    Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8(8):592–603PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58–62PubMedCrossRefPubMedCentralGoogle Scholar
  198. 198.
    Nagy JA et al (2009) Why are tumour blood vessels abnormal and why is it important to know? Br J Cancer 100(6):865–869PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Wilson WR, Hay MP (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11(6):393–410PubMedCrossRefPubMedCentralGoogle Scholar
  200. 200.
    Hockel M, Vaupel P (2001) Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93(4):266–276PubMedCrossRefPubMedCentralGoogle Scholar
  201. 201.
    Minchinton AI, Tannock IF (2006) Drug penetration in solid tumours. Nat Rev Cancer 6(8):583–592PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Matthew R. Zanotelli
    • 1
  • Cynthia A. Reinhart-King
    • 2
    • 3
    Email author
  1. 1.Nancy E. and Peter C. Meinig School of Biomedical EngineeringCornell UniversityIthacaUSA
  2. 2.Department of Biomedical EngineeringVanderbilt UniversityNashvilleUSA
  3. 3.Meinig School of Biomedical EngineeringCornell UniversityIthacaUSA

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