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Biomechanical Forces Shape the Tumor Microenvironment

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Abstract

The importance of the tumor microenvironment in cancer progression is indisputable, yet a key component of the microenvironment—biomechanical forces—remains poorly understood. Tumor growth and progression is paralleled by a host of physical changes in the tumor microenvironment, such as growth-induced solid stresses, increased matrix stiffness, high fluid pressure, and increased interstitial flow. These changes to the biomechanical microenvironment promote tumorigenesis and tumor cell invasion and induce stromal cells—such as fibroblasts, immune cells, and endothelial cells—to change behavior and support cancer progression. This review highlights what we currently know about the biomechanical forces generated in the tumor microenvironment, how they arise, and how these forces can dramatically influence cell behavior, drawing not only upon studies directly related to cancer and tumor cells, but also work in other fields that have shown the effects of these types of mechanical forces vis-à-vis cell behaviors relevant to the tumor microenvironment. By understanding how all of these biomechanical forces can affect tumor cells, stromal cells, and tumor–stromal crosstalk, as well as alter how tumor and stromal cells perceive other extracellular signals in the tumor microenvironment, we can develop new approaches for diagnosis, prognosis, and ultimately treatment of cancer.

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References

  1. Adams, M., J. L. Jones, R. A. Walker, J. H. Pringle, and S. C. Bell. Changes in tenascin-C isoform expression in invasive and preinvasive breast disease. Cancer Res. 62:3289–3297, 2002.

    PubMed  CAS  Google Scholar 

  2. Avvisato, C. L., X. Yang, S. Shah, B. Hoxter, W. Li, R. Gaynor, R. Pestell, A. Tozeren, and S. W. Byers. Mechanical force modulates global gene expression and beta-catenin signaling in colon cancer cells. J. Cell Sci. 120:2672–2682, 2007.

    Article  PubMed  CAS  Google Scholar 

  3. Baker, E. L., R. T. Bonnecaze, and M. H. Zaman. Extracellular matrix stiffness and architecture govern intracellular rheology in cancer. Biophys. J. 97:1013–1021, 2009.

    Article  PubMed  CAS  Google Scholar 

  4. Baker, E. L., J. Lu, D. Yu, R. T. Bonnecaze, and M. H. Zaman. Cancer cell stiffness: integrated roles of three-dimensional matrix stiffness and transforming potential. Biophys. J. 99:2048–2057, 2010.

    Article  PubMed  CAS  Google Scholar 

  5. Barry-Hamilton, V., R. Spangler, D. Marshall, S. McCauley, H. M. Rodriguez, M. Oyasu, A. Mikels, M. Vaysberg, H. Ghermazien, C. Wai, C. A. Garcia, A. C. Velayo, B. Jorgensen, D. Biermann, D. Tsai, J. Green, S. Zaffryar-Eilot, A. Holzer, S. Ogg, D. Thai, G. Neufeld, P. Van Vlasselaer, and V. Smith. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat. Med. 16:1009–1017, 2010.

    Article  PubMed  CAS  Google Scholar 

  6. Baxter, L. T., and R. K. Jain. Transport of fluid and macromolecules in tumors I. Role of interstitial pressure and convection. Microvasc. Res. 37:77–104, 1989.

    Article  PubMed  CAS  Google Scholar 

  7. Boardman, K. C., and M. A. Swartz. Interstitial flow as a guide for lymphangiogenesis. Circ. Res. 92:801–808, 2003.

    Article  PubMed  CAS  Google Scholar 

  8. Boucher, Y., and R. K. Jain. Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse. Cancer Res. 52:5110–5114, 1992.

    PubMed  CAS  Google Scholar 

  9. Boucher, Y., M. Leunig, and R. K. Jain. Tumor angiogenesis and interstitial hypertension. Cancer Res. 56:4264–4266, 1996.

    PubMed  CAS  Google Scholar 

  10. Boyd, N. F., G. A. Lockwood, J. W. Byng, D. L. Tritchler, and M. J. Yaffe. Mammographic densities and breast cancer risk. Cancer Epidemiol. Biomark. Prev. 7:1133–1144, 1998.

    CAS  Google Scholar 

  11. Brown, L. F., A. J. Guidi, S. J. Schnitt, L. Van De Water, M. L. Iruela-Arispe, T. K. Yeo, K. Tognazzi, and H. F. Dvorak. Vascular stroma formation in carcinoma in situ, invasive carcinoma, and metastatic carcinoma of the breast. Clin. Cancer Res. 5:1041–1056, 1999.

    PubMed  CAS  Google Scholar 

  12. Butler, T. P., F. H. Grantham, and P. M. Gullino. Bulk transfer of fluid in the interstitial compartment of mammary tumors. Cancer Res. 35:3084–3088, 1975.

    PubMed  CAS  Google Scholar 

  13. Cabioglu, N., M. S. Yazici, B. Arun, K. R. Broglio, G. N. Hortobagyi, J. E. Price, and A. Sahin. CCR7 and CXCR4 as novel biomarkers predicting axillary lymph node metastasis in T1 breast cancer. Clin. Cancer Res. 11:5686–5693, 2005.

    Article  PubMed  CAS  Google Scholar 

  14. Califano, J., and C. Reinhart-King. A balance of substrate mechanics and matrix chemistry regulates endothelial cell network assembly. Cell Mol. Bioeng. 1:122–132, 2008.

    Article  Google Scholar 

  15. Chan, M. W., B. Hinz, and C. A. McCulloch. Mechanical induction of gene expression in connective tissue cells. Methods Cell Biol. 98:178–205, 2010.

    Article  PubMed  CAS  Google Scholar 

  16. Chen, C. Y., H. M. Byrne, and J. R. King. The influence of growth-induced stress from the surrounding medium on the development of multicell spheroids. J. Math. Biol. 43:191–220, 2001.

    Article  PubMed  CAS  Google Scholar 

  17. Cheng, G., J. Tse, R. K. Jain, and L. L. Munn. Micro-environmental mechanical stress controls tumor spheroid size and morphology by suppressing proliferation and inducing apoptosis in cancer cells. PLoS One 4:e4632, 2009.

    Article  PubMed  CAS  Google Scholar 

  18. Cho, E. S., K. S. Lee, Y. O. Son, Y. S. Jang, S. Y. Lee, S. Y. Kwak, Y. M. Yang, S. M. Park, and J. C. Lee. Compressive mechanical force augments osteoclastogenesis by bone marrow macrophages through activation of c-Fms-mediated signaling. J. Cell. Biochem. 111(5):1260–1269, 2010.

    Article  PubMed  CAS  Google Scholar 

  19. Choe, M. M., P. H. Sporn, and M. A. Swartz. Extracellular matrix remodeling by dynamic strain in a 3D tissue engineered human airway wall model. Am. J. Respir. Cell Mol. Biol. 35(3):306–313, 2006.

    Article  PubMed  CAS  Google Scholar 

  20. Dafni, H., B. Cohen, K. Ziv, T. Israely, O. Goldshmidt, N. Nevo, A. Harmelin, I. Vlodavsky, and M. Neeman. The role of heparanase in lymph node metastatic dissemination: dynamic contrast-enhanced MRI of Eb lymphoma in mice. Neoplasia 7:224–233, 2005.

    Article  PubMed  CAS  Google Scholar 

  21. Dafni, H., T. Israely, Z. M. Bhujwalla, L. E. Benjamin, and M. Neeman. Overexpression of vascular endothelial growth factor 165 drives peritumor interstitial convection and induces lymphatic drain: magnetic resonance imaging, confocal microscopy, and histological tracking of triple-labeled albumin. Cancer Res. 62:6731–6739, 2002.

    PubMed  CAS  Google Scholar 

  22. Davies, P. F. Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat. Clin. Pract. Cardiovasc. Med. 6:16–26, 2009.

    Article  PubMed  CAS  Google Scholar 

  23. De Wever, O., Q. D. Nguyen, L. Van Hoorde, M. Bracke, E. Bruyneel, C. Gespach, and M. Mareel. Tenascin-C and SF/HGF produced by myofibroblasts in vitro provide convergent pro-invasive signals to human colon cancer cells through RhoA and Rac. FASEB J. 18:1016–1018, 2004.

    PubMed  Google Scholar 

  24. Demou, Z. N. Gene expression profiles in 3D tumor analogs indicate compressive strain differentially enhances metastatic potential. Ann. Biomed. Eng. 38:3509–3520, 2010.

    Article  PubMed  Google Scholar 

  25. Diresta, G. R., S. S. Nathan, M. W. Manoso, J. Casas-Ganem, C. Wyatt, T. Kubo, P. J. Boland, E. A. Athanasian, J. Miodownik, R. Gorlick, and J. H. Healey. Cell proliferation of cultured human cancer cells are affected by the elevated tumor pressures that exist in vivo. Ann. Biomed. Eng. 33:1270–1280, 2005.

    Article  PubMed  Google Scholar 

  26. Discher, D. E., P. Janmey, and Y. L. Wang. Tissue cells feel and respond to the stiffness of their substrate. Science 310:1139–1143, 2005.

    Article  PubMed  CAS  Google Scholar 

  27. Engler, A. J., S. Sen, H. L. Sweeney, and D. E. Discher. Matrix elasticity directs stem cell lineage specification. Cell 126:677–689, 2006.

    Article  PubMed  CAS  Google Scholar 

  28. Fleury, M. E., K. C. Boardman, and M. A. Swartz. Autologous morphogen gradients by subtle interstitial flow and matrix interactions. Biophys. J. 91:113–121, 2006.

    Article  PubMed  CAS  Google Scholar 

  29. Fukumura, D., D. G. Duda, L. L. Munn, and R. K. Jain. Tumor microvasculature and microenvironment: novel insights through intravital imaging in pre-clinical models. Microcirculation 17:206–225, 2010.

    Article  PubMed  CAS  Google Scholar 

  30. Fukumura, D., and R. K. Jain. Tumor microenvironment abnormalities: causes, consequences, and strategies to normalize. J. Cell. Biochem. 101:937–949, 2007.

    Article  PubMed  CAS  Google Scholar 

  31. Fukumura, D., and R. K. Jain. Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization. Microvasc. Res. 74:72–84, 2007.

    Article  PubMed  CAS  Google Scholar 

  32. Gaggioli, C., S. Hooper, C. Hidalgo-Carcedo, R. Grosse, J. F. Marshall, K. Harrington, and E. Sahai. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat. Cell Biol. 9:1392–1400, 2007.

    Article  PubMed  CAS  Google Scholar 

  33. Gang, Z., Q. Qi, C. Jing, and C. Wang. Measuring microenvironment mechanical stress of rat liver during diethylnitrosamine induced hepatocarcinogenesis by atomic force microscope. Microsc. Res. Tech. 72:672–678, 2009.

    Article  PubMed  CAS  Google Scholar 

  34. Ghosh, K., C. K. Thodeti, A. C. Dudley, A. Mammoto, M. Klagsbrun, and D. E. Ingber. Tumor-derived endothelial cells exhibit aberrant Rho-mediated mechanosensing and abnormal angiogenesis in vitro. Proc. Natl. Acad. Sci. USA 105:11305–11310, 2008.

    Article  PubMed  CAS  Google Scholar 

  35. Gjorevski, N., and C. M. Nelson. Endogenous patterns of mechanical stress are required for branching morphogenesis. Integr. Biol. (Camb) 2:424–434, 2010.

    Article  CAS  Google Scholar 

  36. Gomez, E. W., Q. K. Chen, N. Gjorevski, and C. M. Nelson. Tissue geometry patterns epithelial-mesenchymal transition via intercellular mechanotransduction. J. Cell. Biochem. 110:44–51, 2010.

    PubMed  CAS  Google Scholar 

  37. Hadjipanayi, E., V. Mudera, and R. A. Brown. Guiding cell migration in 3D: a collagen matrix with graded directional stiffness. Cell Motil. Cytoskelet. 66:121–128, 2009.

    Article  CAS  Google Scholar 

  38. Hagendoorn, J., R. Tong, D. Fukumura, Q. Lin, J. Lobo, T. P. Padera, L. Xu, R. Kucherlapati, and R. K. Jain. Onset of abnormal blood and lymphatic vessel function and interstitial hypertension in early stages of carcinogenesis. Cancer Res. 66:3360–3364, 2006.

    Article  PubMed  CAS  Google Scholar 

  39. Harrell, M. I., B. M. Iritani, and A. Ruddell. Tumor-induced sentinel lymph node lymphangiogenesis and increased lymph flow precede melanoma metastasis. Am. J. Pathol. 170:774–786, 2007.

    Article  PubMed  Google Scholar 

  40. Helm, C. L., M. E. Fleury, A. H. Zisch, F. Boschetti, and M. A. Swartz. Synergy between interstitial flow and VEGF directs capillary morphogenesis in vitro through a gradient amplification mechanism. Proc. Natl. Acad. Sci. USA 102:15779–15784, 2005.

    Article  PubMed  CAS  Google Scholar 

  41. Helmlinger, G., P. A. Netti, H. C. Lichtenbeld, R. J. Melder, and R. K. Jain. Solid stress inhibits the growth of multicellular tumor spheroids. Nat. Biotechnol. 15:778–783, 1997.

    Article  PubMed  CAS  Google Scholar 

  42. Hinz, B., V. Dugina, C. Ballestrem, B. Wehrle-Haller, and C. Chaponnier. Alpha-smooth muscle actin is crucial for focal adhesion maturation in myofibroblasts. Mol. Biol. Cell 14:2508–2519, 2003.

    Article  PubMed  CAS  Google Scholar 

  43. Hinz, B., and G. Gabbiani. Mechanisms of force generation and transmission by myofibroblasts. Curr. Opin. Biotechnol. 14:538–546, 2003.

    Article  PubMed  CAS  Google Scholar 

  44. Hinz, B., G. Gabbiani, and C. Chaponnier. The NH2-terminal peptide of alpha-smooth muscle actin inhibits force generation by the myofibroblast in vitro and in vivo. J. Cell Biol. 157:657–663, 2002.

    Article  PubMed  CAS  Google Scholar 

  45. Hofmann, M., M. Guschel, A. Bernd, J. Bereiter-Hahn, R. Kaufmann, C. Tandi, H. Wiig, and S. Kippenberger. Lowering of tumor interstitial fluid pressure reduces tumor cell proliferation in a xenograft tumor model. Neoplasia 8:89–95, 2006.

    Article  PubMed  Google Scholar 

  46. Hofmann, M., E. McCormack, M. Mujic, M. Rossberg, A. Bernd, J. Bereiter-Hahn, B. T. Gjertsen, H. Wiig, and S. Kippenberger. Increased plasma colloid osmotic pressure facilitates the uptake of therapeutic macromolecules in a xenograft tumor model. Neoplasia 11:812–822, 2009.

    PubMed  CAS  Google Scholar 

  47. Hofmann, M., M. Schultz, A. Bernd, J. Bereiter-Hahn, R. Kaufmann, and S. Kippenberger. Long-term lowering of tumour interstitial fluid pressure reduces Ki-67 expression. J. Biomech. 40:2324–2329, 2007.

    Article  PubMed  Google Scholar 

  48. Hoyt, K., B. Castaneda, M. Zhang, P. Nigwekar, P. A. di Sant’agnese, J. V. Joseph, J. Strang, D. J. Rubens, and K. J. Parker. Tissue elasticity properties as biomarkers for prostate cancer. Cancer Biomark. 4:213–225, 2008.

    PubMed  Google Scholar 

  49. Iglesias-Garcia, J., J. Larino-Noia, I. Abdulkader, J. Forteza, and J. E. Dominguez-Munoz. Quantitative endoscopic ultrasound elastography: an accurate method for the differentiation of solid pancreatic masses. Gastroenterology 139:1172–1180, 2010.

    Article  PubMed  Google Scholar 

  50. Jaalouk, D. E., and J. Lammerding. Mechanotransduction gone awry. Nat. Rev. Mol. Cell Biol. 10:63–73, 2009.

    Article  PubMed  CAS  Google Scholar 

  51. Jain, R. K., R. T. Tong, and L. L. Munn. Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model. Cancer Res. 67:2729–2735, 2007.

    Article  PubMed  CAS  Google Scholar 

  52. Ji, R. C. Lymphatic endothelial cells, tumor lymphangiogenesis and metastasis: new insights into intratumoral and peritumoral lymphatics. Cancer Metastasis Rev. 25:677–694, 2006.

    Article  PubMed  Google Scholar 

  53. Joyce, J. A., and J. W. Pollard. Microenvironmental regulation of metastasis. Nat. Rev. Cancer 9:239–252, 2009.

    Article  PubMed  CAS  Google Scholar 

  54. Kalluri, R., and M. Zeisberg. Fibroblasts in cancer. Nat. Rev. Cancer 6:392–401, 2006.

    Article  PubMed  CAS  Google Scholar 

  55. Kilarski, W. W., B. Samolov, L. Petersson, A. Kvanta, and P. Gerwins. Biomechanical regulation of blood vessel growth during tissue vascularization. Nat. Med. 15:657–664, 2009.

    Article  PubMed  CAS  Google Scholar 

  56. Klein, E. A., L. Yin, D. Kothapalli, P. Castagnino, F. J. Byfield, T. Xu, I. Levental, E. Hawthorne, P. A. Janmey, and R. K. Assoian. Cell-cycle control by physiological matrix elasticity and in vivo tissue stiffening. Curr. Biol. 19:1511–1518, 2009.

    Article  PubMed  CAS  Google Scholar 

  57. Kniazeva, E., and A. J. Putnam. Endothelial cell traction and ECM density influence both capillary morphogenesis and maintenance in 3-D. Am. J. Physiol. Cell Physiol. 297:C179–C187, 2009.

    Article  PubMed  CAS  Google Scholar 

  58. Koike, C., T. D. McKee, A. Pluen, S. Ramanujan, K. Burton, L. L. Munn, Y. Boucher, and R. K. Jain. Solid stress facilitates spheroid formation: potential involvement of hyaluronan. Br. J. Cancer 86:947–953, 2002.

    Article  PubMed  CAS  Google Scholar 

  59. Kostic, A., C. D. Lynch, and M. P. Sheetz. Differential matrix rigidity response in breast cancer cell lines correlates with the tissue tropism. PLoS One 4:e6361, 2009.

    Article  PubMed  CAS  Google Scholar 

  60. Lam, W. A., L. Cao, V. Umesh, A. J. Keung, S. Sen, and S. Kumar. Extracellular matrix rigidity modulates neuroblastoma cell differentiation and N-myc expression. Mol. Cancer 9:35, 2010.

    Article  PubMed  CAS  Google Scholar 

  61. Less, J. R., M. C. Posner, Y. Boucher, D. Borochovitz, N. Wolmark, and R. K. Jain. Interstitial hypertension in human breast and colorectal tumors. Cancer Res. 52:6371–6374, 1992.

    PubMed  CAS  Google Scholar 

  62. Levental, K. R., H. Yu, L. Kass, J. N. Lakins, M. Egeblad, J. T. Erler, S. F. Fong, K. Csiszar, A. Giaccia, W. Weninger, M. Yamauchi, D. L. Gasser, and V. M. Weaver. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139:891–906, 2009.

    Article  PubMed  CAS  Google Scholar 

  63. Li, G. N., L. L. Livi, C. M. Gourd, E. S. Deweerd, and D. Hoffman-Kim. Genomic and morphological changes of neuroblastoma cells in response to three-dimensional matrices. Tissue Eng. 13:1035–1047, 2007.

    Article  PubMed  CAS  Google Scholar 

  64. Lo, C. M., H. B. Wang, M. Dembo, and Y. L. Wang. Cell movement is guided by the rigidity of the substrate. Biophys. J. 79:144–152, 2000.

    Article  PubMed  CAS  Google Scholar 

  65. Meng, Y., X. Han, L. Huang, D. Bai, H. Yu, Y. He, and Y. Jing. Orthodontic mechanical tension effects on the myofibroblast expression of alpha-smooth muscle actin. Angle Orthod. 80:912–918, 2010.

    Article  PubMed  Google Scholar 

  66. Micke, P., and A. Ostman. Tumour-stroma interaction: cancer-associated fibroblasts as novel targets in anti-cancer therapy? Lung Cancer 45(Suppl. 2):S163–S175, 2004.

    Article  PubMed  Google Scholar 

  67. Miteva, D. O., J. M. Rutkowski, J. B. Dixon, W. Kilarski, J. D. Shields, and M. A. Swartz. Transmural flow modulates cell and fluid transport functions of lymphatic endothelium. Circ. Res. 106:920–931, 2010.

    Article  PubMed  CAS  Google Scholar 

  68. Muller, A., B. Homey, H. Soto, N. Ge, D. Catron, M. E. Buchanan, T. McClanahan, E. Murphy, W. Yuan, S. N. Wagner, J. L. Barrera, A. Mohar, E. Verastegui, and A. Zlotnik. Involvement of chemokine receptors in breast cancer metastasis. Nature 410:50–56, 2001.

    Article  PubMed  CAS  Google Scholar 

  69. Nahon, P., A. Kettaneh, M. Lemoine, O. Seror, N. Barget, J. C. Trinchet, M. Beaugrand, and N. Ganne-Carrie. Liver stiffness measurement in patients with cirrhosis and hepatocellular carcinoma: a case–control study. Eur. J. Gastroenterol. Hepatol. 21:214–219, 2009.

    Article  PubMed  CAS  Google Scholar 

  70. Nathan, S. S., G. R. DiResta, J. E. Casas-Ganem, B. H. Hoang, R. Sowers, R. Yang, A. G. Huvos, R. Gorlick, and J. H. Healey. Elevated physiologic tumor pressure promotes proliferation and chemosensitivity in human osteosarcoma. Clin. Cancer Res. 11:2389–2397, 2005.

    Article  PubMed  CAS  Google Scholar 

  71. Nathan, S. S., A. G. Huvos, J. E. Casas-Ganem, R. Yang, I. Linkov, R. Sowers, G. R. DiResta, R. Gorlick, and J. H. Healey. Tumor interstitial fluid pressure may regulate angiogenic factors in osteosarcoma. J. Orthop. Res. 26:1520–1525, 2008.

    Article  PubMed  Google Scholar 

  72. Nelson, C. M., J. L. Inman, and M. J. Bissell. Three-dimensional lithographically defined organotypic tissue arrays for quantitative analysis of morphogenesis and neoplastic progression. Nat. Protoc. 3:674–678, 2008.

    Article  PubMed  CAS  Google Scholar 

  73. Orimo, A., P. B. Gupta, D. C. Sgroi, F. Arenzana-Seisdedos, T. Delaunay, R. Naeem, V. J. Carey, A. L. Richardson, and R. A. Weinberg. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121:335–348, 2005.

    Article  PubMed  CAS  Google Scholar 

  74. Padera, T. P., A. Kadambi, E. di Tomaso, C. M. Carreira, E. B. Brown, Y. Boucher, N. C. Choi, D. Mathisen, J. Wain, E. J. Mark, L. L. Munn, and R. K. Jain. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296:1883–1886, 2002.

    Article  PubMed  CAS  Google Scholar 

  75. Paszek, M. J., N. Zahir, K. R. Johnson, J. N. Lakins, G. I. Rozenberg, A. Gefen, C. A. Reinhart-King, S. S. Margulies, M. Dembo, D. Boettiger, D. A. Hammer, and V. M. Weaver. Tensional homeostasis and the malignant phenotype. Cancer Cell 8:241–254, 2005.

    Article  PubMed  CAS  Google Scholar 

  76. Pedersen, J. A., F. Boschetti, and M. A. Swartz. Effects of extracellular fiber architecture on cell membrane shear stress in a 3D fibrous matrix. J. Biomech. 40:1484–1492, 2007.

    Article  PubMed  Google Scholar 

  77. Pedersen, J. A., S. Lichter, and M. A. Swartz. Cells in 3D matrices under interstitial flow: effects of extracellular matrix alignment on cell shear stress and drag forces. J. Biomech. 43:900–905, 2010.

    Article  PubMed  Google Scholar 

  78. Provenzano, P. P., K. W. Eliceiri, J. M. Campbell, D. R. Inman, J. G. White, and P. J. Keely. Collagen reorganization at the tumor–stromal interface facilitates local invasion. BMC Med. 4:38, 2006.

    Article  PubMed  CAS  Google Scholar 

  79. Provenzano, P. P., D. R. Inman, K. W. Eliceiri, and P. J. Keely. Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK-ERK linkage. Oncogene 28:4326–4343, 2009.

    Article  PubMed  CAS  Google Scholar 

  80. Provenzano, P. P., D. R. Inman, K. W. Eliceiri, J. G. Knittel, L. Yan, C. T. Rueden, J. G. White, and P. J. Keely. Collagen density promotes mammary tumor initiation and progression. BMC Med. 6:11, 2008.

    Article  PubMed  CAS  Google Scholar 

  81. Provenzano, P. P., D. R. Inman, K. W. Eliceiri, S. M. Trier, and P. J. Keely. Contact guidance mediated three-dimensional cell migration is regulated by Rho/ROCK-dependent matrix reorganization. Biophys. J. 95:5374–5384, 2008.

    Article  PubMed  CAS  Google Scholar 

  82. Roelofsen, J., J. Klein-Nulend, and E. H. Burger. Mechanical stimulation by intermittent hydrostatic compression promotes bone-specific gene expression in vitro. J. Biomech. 28:1493–1503, 1995.

    Article  PubMed  CAS  Google Scholar 

  83. Roskelley, C. D., and M. J. Bissell. Dynamic reciprocity revisited: a continuous, bidirectional flow of information between cells and the extracellular matrix regulates mammary epithelial cell function. Biochem. Cell Biol. 73:391–397, 1995.

    Article  PubMed  CAS  Google Scholar 

  84. Ruddell, A., M. I. Harrell, S. Minoshima, K. R. Maravilla, B. M. Iritani, S. W. White, and S. C. Partridge. Dynamic contrast-enhanced magnetic resonance imaging of tumor-induced lymph flow. Neoplasia 10:706–713, 701 p following 713, 2008.

    PubMed  Google Scholar 

  85. Sarntinoranont, M., F. Rooney, and M. Ferrari. Interstitial stress and fluid pressure within a growing tumor. Ann. Biomed. Eng. 31:327–335, 2003.

    Article  PubMed  Google Scholar 

  86. Shi, Z. D., G. Abraham, and J. M. Tarbell. Shear stress modulation of smooth muscle cell marker genes in 2-D and 3-D depends on mechanotransduction by heparan sulfate proteoglycans and ERK1/2. PLoS One 5:e12196, 2010.

    Article  PubMed  CAS  Google Scholar 

  87. Shi, Z. D., X. Y. Ji, D. E. Berardi, H. Qazi, and J. M. Tarbell. Interstitial flow induces MMP-1 expression and vascular SMC migration in collagen I gels via an ERK1/2-dependent and c-Jun-mediated mechanism. Am. J. Physiol. Heart Circ. Physiol. 298:H127–H135, 2010.

    Article  PubMed  CAS  Google Scholar 

  88. Shi, Z. D., X. Y. Ji, H. Qazi, and J. M. Tarbell. Interstitial flow promotes vascular fibroblast, myofibroblast, and smooth muscle cell motility in 3-D collagen I via upregulation of MMP-1. Am. J. Physiol. Heart Circ. Physiol. 297:H1225–H1234, 2009.

    Article  PubMed  CAS  Google Scholar 

  89. Shieh, A. C., and K. A. Athanasiou. Biomechanics of single chondrocytes and osteoarthritis. Crit. Rev. Biomed. Eng. 30:307–343, 2002.

    Article  PubMed  Google Scholar 

  90. Shields, J. D., M. S. Emmett, D. B. Dunn, K. D. Joory, L. M. Sage, H. Rigby, P. S. Mortimer, A. Orlando, J. R. Levick, and D. O. Bates. Chemokine-mediated migration of melanoma cells towards lymphatics—a mechanism contributing to metastasis. Oncogene 26:2997–3005, 2007.

    Article  PubMed  CAS  Google Scholar 

  91. Shields, J. D., M. E. Fleury, C. Yong, A. A. Tomei, G. J. Randolph, and M. A. Swartz. Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Cancer Cell 11:526–538, 2007.

    Article  PubMed  CAS  Google Scholar 

  92. Shields, J. D., I. C. Kourtis, A. A. Tomei, J. M. Roberts, and M. A. Swartz. Induction of lymphoid like stroma and immune escape by tumors that express the chemokine CCL21. Science 328:749–752, 2010.

    Article  PubMed  CAS  Google Scholar 

  93. Singer, C. F., N. Kronsteiner, E. Marton, M. Kubista, K. J. Cullen, K. Hirtenlehner, M. Seifert, and E. Kubista. MMP-2 and MMP-9 expression in breast cancer-derived human fibroblasts is differentially regulated by stromal-epithelial interactions. Breast Cancer Res. Treat. 72:69–77, 2002.

    Article  PubMed  CAS  Google Scholar 

  94. Skobe, M., T. Hawighorst, D. G. Jackson, R. Prevo, L. Janes, P. Velasco, L. Riccardi, K. Alitalo, K. Claffey, and M. Detmar. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat. Med. 7:192–198, 2001.

    Article  PubMed  CAS  Google Scholar 

  95. Smith, R. L., S. F. Rusk, B. E. Ellison, P. Wessells, K. Tsuchiya, D. R. Carter, W. E. Caler, L. J. Sandell, and D. J. Schurman. In vitro stimulation of articular chondrocyte mRNA and extracellular matrix synthesis by hydrostatic pressure. J. Orthop. Res. 14:53–60, 1996.

    Article  PubMed  CAS  Google Scholar 

  96. Stohrer, M., Y. Boucher, M. Stangassinger, and R. K. Jain. Oncotic pressure in solid tumors is elevated. Cancer Res. 60:4251–4255, 2000.

    PubMed  CAS  Google Scholar 

  97. Swartz, M. A., and M. Skobe. Lymphatic function, lymphangiogenesis, and cancer metastasis. Microsc. Res. Tech. 55:92–99, 2001.

    Article  PubMed  CAS  Google Scholar 

  98. Tang, X., T. B. Kuhlenschmidt, J. Zhou, P. Bell, F. Wang, M. S. Kuhlenschmidt, and T. A. Saif. Mechanical force affects expression of an in vitro metastasis-like phenotype in HCT-8 cells. Biophys. J. 99:2460–2469, 2010.

    Article  PubMed  CAS  Google Scholar 

  99. Tilghman, R. W., C. R. Cowan, J. D. Mih, Y. Koryakina, D. Gioeli, J. K. Slack-Davis, B. R. Blackman, D. J. Tschumperlin, and J. T. Parsons. Matrix rigidity regulates cancer cell growth and cellular phenotype. PLoS One 5:e12905, 2010.

    Article  PubMed  CAS  Google Scholar 

  100. Tlsty, T. D., and L. M. Coussens. Tumor stroma and regulation of cancer development. Annu. Rev. Pathol. 1:119–150, 2006.

    Article  PubMed  CAS  Google Scholar 

  101. Tomasek, J. J., G. Gabbiani, B. Hinz, C. Chaponnier, and R. A. Brown. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell. Biol. 3:349–363, 2002.

    Article  PubMed  CAS  Google Scholar 

  102. Ulrich, T. A., E. M. de Juan Pardo, and S. Kumar. The mechanical rigidity of the extracellular matrix regulates the structure, motility, and proliferation of glioma cells. Cancer Res. 69:4167–4174, 2009.

    Article  PubMed  CAS  Google Scholar 

  103. Van Goethem, E., R. Poincloux, F. Gauffre, I. Maridonneau-Parini, and V. Le Cabec. Matrix architecture dictates three-dimensional migration modes of human macrophages: differential involvement of proteases and podosome-like structures. J. Immunol. 184:1049–1061, 2010.

    Article  PubMed  CAS  Google Scholar 

  104. Wang, J., H. Chen, A. Seth, and C. A. McCulloch. Mechanical force regulation of myofibroblast differentiation in cardiac fibroblasts. Am. J. Physiol. Heart Circ. Physiol. 285:H1871–H1881, 2003.

    PubMed  CAS  Google Scholar 

  105. Wang, W., J. B. Wyckoff, V. C. Frohlich, Y. Oleynikov, S. Huttelmaier, J. Zavadil, L. Cermak, E. P. Bottinger, R. H. Singer, J. G. White, J. E. Segall, and J. S. Condeelis. Single cell behavior in metastatic primary mammary tumors correlated with gene expression patterns revealed by molecular profiling. Cancer Res. 62:6278–6288, 2002.

    PubMed  CAS  Google Scholar 

  106. Weidner, N., J. P. Semple, W. R. Welch, and J. Folkman. Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma. N. Engl. J. Med. 324:1–8, 1991.

    Article  PubMed  CAS  Google Scholar 

  107. Winer, J. P., S. Oake, and P. A. Janmey. Non-linear elasticity of extracellular matrices enables contractile cells to communicate local position and orientation. PLoS One 4:e6382, 2009.

    Article  PubMed  CAS  Google Scholar 

  108. Wipff, P. J., and B. Hinz. Myofibroblasts work best under stress. J. Bodyw. Mov. Ther. 13:121–127, 2009.

    Article  PubMed  Google Scholar 

  109. Wipff, P. J., D. B. Rifkin, J. J. Meister, and B. Hinz. Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J. Cell Biol. 179:1311–1323, 2007.

    Article  PubMed  CAS  Google Scholar 

  110. Wrobel, L. K., T. R. Fray, J. E. Molloy, J. J. Adams, M. P. Armitage, and J. C. Sparrow. Contractility of single human dermal myofibroblasts and fibroblasts. Cell Motil. Cytoskelet. 52:82–90, 2002.

    Article  Google Scholar 

  111. Wu, J., Q. Long, S. Xu, and A. R. Padhani. Study of tumor blood perfusion and its variation due to vascular normalization by anti-angiogenic therapy based on 3D angiogenic microvasculature. J. Biomech. 42:712–721, 2009.

    Article  PubMed  Google Scholar 

  112. Zaman, M. H., L. M. Trapani, A. L. Sieminski, D. Mackellar, H. Gong, R. D. Kamm, A. Wells, D. A. Lauffenburger, and P. Matsudaira. Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis. Proc. Natl. Acad. Sci. USA 103:10889–10894, 2006.

    Article  PubMed  CAS  Google Scholar 

  113. Zhao, G., J. Cui, Q. Qin, J. Zhang, L. Liu, S. Deng, C. Wu, M. Yang, S. Li, and C. Wang. Mechanical stiffness of liver tissues in relation to integrin beta1 expression may influence the development of hepatic cirrhosis and hepatocellular carcinoma. J. Surg. Oncol. 102:482–489, 2010.

    Article  PubMed  CAS  Google Scholar 

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  1. School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, PA, 19104-2875, USA

    Adrian C. Shieh

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Associate Editor Cheng Dong oversaw the review of this article.

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Shieh, A.C. Biomechanical Forces Shape the Tumor Microenvironment. Ann Biomed Eng 39, 1379–1389 (2011). https://doi.org/10.1007/s10439-011-0252-2

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