Research Papers

The Solid Mechanics of Cancer and Strategies for Improved Therapy

[+] Author and Article Information
Triantafyllos Stylianopoulos

Cancer Biophysics Laboratory,
Department of Mechanical and
Manufacturing Engineering,
University of Cyprus,
Nicosia, 1678, Cyprus
e-mail: tstylian@ucy.ac.cy

Manuscript received June 1, 2016; final manuscript received October 6, 2016; published online January 19, 2017. Assoc. Editor: Carlijn V.C Bouten.

J Biomech Eng 139(2), 021004 (Jan 19, 2017) (10 pages) Paper No: BIO-16-1230; doi: 10.1115/1.4034991 History: Received June 01, 2016; Revised October 06, 2016

Tumor progression and response to treatment is determined in large part by the generation of mechanical stresses that stem from both the solid and the fluid phase of the tumor. Furthermore, elevated solid stress levels can regulate fluid stresses by compressing intratumoral blood and lymphatic vessels. Blood vessel compression reduces tumor perfusion, while compression of lymphatic vessels hinders the ability of the tumor to drain excessive fluid from its interstitial space contributing to the uniform elevation of the interstitial fluid pressure. Hypoperfusion and interstitial hypertension pose major barriers to the systemic administration of chemotherapeutic agents and nanomedicines to tumors, reducing treatment efficacies. Hypoperfusion can also create a hypoxic and acidic tumor microenvironment that promotes tumor progression and metastasis. Hence, alleviation of intratumoral solid stress levels can decompress tumor vessels and restore perfusion and interstitial fluid pressure. In this review, three major types of tissue level solid stresses involved in tumor growth, namely stress exerted externally on the tumor by the host tissue, swelling stress, and residual stress, are discussed separately and details are provided regarding their causes, magnitudes, and remedies. Subsequently, evidence of how stress-alleviating drugs could be used in combination with chemotherapy to improve treatment efficacy is presented, highlighting the potential of stress-alleviation strategies to enhance cancer therapy. Finally, a continuum-level, mathematical framework to incorporate these types of solid stress is outlined.

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Hanahan, D. , and Coussens, L. M. , 2012, “ Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment,” Cancer Cell, 21(3), pp. 309–322. [CrossRef] [PubMed]
Gkretsi, V. , Stylianou, A. , Papageorgis, P. , Polydorou, C. , and Stylianopoulos, T. , 2015, “ Remodeling Components of the Tumor Microenvironment to Enhance Cancer Therapy,” Front. Oncol., 5, p. 214. [CrossRef] [PubMed]
Jain, R. K. , Martin, J. D. , and Stylianopoulos, T. , 2014, “ The Role of Mechanical Forces in Tumor Growth and Therapy,” Annu. Rev. Biomed. Eng., 16(1), pp. 321–346. [CrossRef] [PubMed]
Koumoutsakos, P. , Pivkin, I. , and Milde, F. , 2013, “ The Fluid Mechanics of Cancer and Its Therapy,” Annu. Rev. Fluid Mech., 45(1), pp. 325–355. [CrossRef]
Voutouri, C. , Mpekris, F. , Papageorgis, P. , Odysseos, A. D. , and Stylianopoulos, T. , 2014, “ Role of Constitutive Behavior and Tumor-Host Mechanical Interactions in the State of Stress and Growth of Solid Tumors,” PLoS One, 9(8), p. e104717. [CrossRef] [PubMed]
Stylianopoulos, T. , Martin, J. D. , Snuderl, M. , Mpekris, F. , Jain, S. R. , and Jain, R. K. , 2013, “ Coevolution of Solid Stress and Interstitial Fluid Pressure in Tumors During Progression: Implications for Vascular Collapse,” Cancer Res., 73(13), pp. 3833–3841. [CrossRef] [PubMed]
McGrail, D. J. , McAndrews, K. M. , Brandenburg, C. P. , Ravikumar, N. , Kieu, Q. M. , and Dawson, M. R. , 2015, “ Osmotic Regulation Is Required for Cancer Cell Survival Under Solid Stress,” Biophys. J., 109(7), pp. 1334–1337. [CrossRef] [PubMed]
Voutouri, C. , Polydorou, C. , Papageorgis, P. , Gkretsi, V. , and Stylianopoulos, T. , 2016, “ Hyaluronan-Derived Swelling of Solid Tumors, the Contribution of Collagean and Cancer Cells and Implications for Cancer Therapy,” Neoplasia, (to appear).
Stylianopoulos, T. , Martin, J. D. , Chauhan, V. P. , Jain, S. R. , Diop-Frimpong, B. , Bardeesy, N. , Smith, B. L. , Ferrone, C. R. , Hornicek, F. J. , Boucher, Y. , Munn, L. L. , and Jain, R. K. , 2012, “ Causes, Consequences, and Remedies for Growth-Induced Solid Stress in Murine and Human Tumors,” Proc. Natl. Acad. Sci. U. S. Am., 109(38), pp. 15101–15108. [CrossRef]
Helmlinger, G. , Netti, P. A. , Lichtenbeld, H. C. , Melder, R. J. , and Jain, R. K. , 1997, “ Solid Stress Inhibits the Growth of Multicellular Tumor Spheroids,” Nat. Biotechnol., 15(8), pp. 778–783. [CrossRef] [PubMed]
Kaufman, L. J. , Brangwynne, C. P. , Kasza, K. E. , Filippidi, E. , Gordon, V. D. , Deisboeck, T. S. , and Weitz, D. A. , 2005, “ Glioma Expansion in Collagen I Matrices: Analyzing Collagen Concentration-Dependent Growth and Motility Patterns,” Biophys. J., 89(1), pp. 635–650. [CrossRef] [PubMed]
Cheng, G. , Tse, J. , Jain, R. K. , and Munn, L. L. , 2009, “ Micro-Environmental Mechanical Stress Controls Tumor Spheroid Size and Morphology by Suppressing Proliferation and Inducing Apoptosis in Cancer Cells,” PLoS One, 4(2), p. e4632. [CrossRef] [PubMed]
Demou, Z. N. , 2010, “ Gene Expression Profiles in 3D Tumor Analogs Indicate Compressive Strain Differentially Enhances Metastatic Potential,” Ann. Biomed. Eng., 38(11), pp. 3509–3520. [CrossRef] [PubMed]
Tse, J. M. , Cheng, G. , Tyrrell, J. A. , Wilcox-Adelman, S. A. , Boucher, Y. , Jain, R. K. , and Munn, L. L. , 2012, “ Mechanical Compression Drives Cancer Cells Toward Invasive Phenotype,” Proc. Natl. Acad. Sci., 109(3), pp. 911–916. [CrossRef]
Jain, R. K. , Tong, R. T. , and Munn, L. L. , 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), pp. 2729–2735. [CrossRef] [PubMed]
Jain, R. K. , 2014, “ Antiangiogenesis Strategies Revisited: From Starving Tumors to Alleviating Hypoxia,” Cancer Cell, 26(5), pp. 605–622. [CrossRef] [PubMed]
Facciabene, A. , Peng, X. , Hagemann, I. S. , Balint, K. , Barchetti, A. , Wang, L. P. , Gimotty, P. A. , Gilks, C. B. , Lal, P. , Zhang, L. , and Coukos, G. , 2011, “ Tumour Hypoxia Promotes Tolerance and Angiogenesis Via CCL28 and T(reg) Cells,” Nature, 475(7355), pp. 226–230. [CrossRef] [PubMed]
Barsoum, I. B. , Koti, M. , Siemens, D. R. , and Graham, C. H. , 2014, “ Mechanisms of Hypoxia-Mediated Immune Escape in Cancer,” Cancer Res., 74(24), pp. 7185–7190. [CrossRef] [PubMed]
Lee, K. E. , and Simon, M. C. , 2012, “ From Stem Cells to Cancer Stem Cells: HIF Takes the Stage,” Curr. Opin. Cell Biol., 24(2), pp. 232–235. [CrossRef] [PubMed]
Samanta, D. , Gilkes, D. M. , Chaturvedi, P. , Xiang, L. , and Semenza, G. L. , 2014, “ Hypoxia-Inducible Factors are Required for Chemotherapy Resistance of Breast Cancer Stem Cells,” Proc. Natl. Acad. Sci. U. S. A., 111(50), p. E5429-5438. [CrossRef]
Finger, E. C. , and Giaccia, A. J. , 2010, “ Hypoxia, Inflammation, and the Tumor Microenvironment in Metastatic Disease,” Cancer Metastasis Rev., 29(2), pp. 285–293. [CrossRef] [PubMed]
Carmeliet, P. , and Jain, R. K. , 2011, “ Molecular Mechanisms and Clinical Applications of Angiogenesis,” Nature, 473(7347), pp. 298–307. [CrossRef] [PubMed]
Batchelor, T. T. , Gerstner, E. R. , Emblem, K. E. , Duda, D. G. , Kalpathy-Cramer, J. , Snuderl, M. , Ancukiewicz, M. , Polaskova, P. , Pinho, M. C. , Jennings, D. , Plotkin, S. R. , Chi, A. S. , Eichler, A. F. , Dietrich, J. , Hochberg, F. H. , Lu-Emerson, C. , Iafrate, A. J. , Rosen, B. , Loeffler, J. S. , Wen, P. Y. , Sorensen, A. G. , and Jain, R. K. , 2013, “ Improved Tumor Oxygenation and Survival in Glioblastoma Patients Who Show Increased Blood Perfusion After Cediranib and Chemoradiation,” Proc. Natl. Acad. Sci. U. S. A., 110(47), pp. 19059–19064. [CrossRef] [PubMed]
Jain, R. K. , and Stylianopoulos, T. , 2010, “ Delivering Nanomedicine to Solid Tumors,” Nat. Rev. Clin. Oncol., 7(11), pp. 653–664. [CrossRef] [PubMed]
Chauhan, V. P. , Stylianopoulos, T. , Boucher, Y. , and Jain, R. K. , 2011, “ Delivery of Molecular and Nanomedicine to Tumors: Transport Barriers and Strategies,” Ann. Rev. Chem. Biomol. Eng., 2(1), pp. 281–298. [CrossRef]
Samani, A. , Zubovits, J. , and Plewes, D. , 2007, “ Elastic Moduli of Normal and Pathological Human Breast Tissues: An Inversion-Technique-Based Investigation of 169 Samples,” Phys. Med. Biol., 52(6), pp. 1565–1576. [CrossRef] [PubMed]
Angeli, S. , and Stylianopoulos, T. , 2016, “ Biphasic Modeling of Brain Tumor Biomechanics and Response to Radiation Treatment,” J. Biomech., 49(9), pp. 1524–1531. [CrossRef] [PubMed]
Roose, T. , Netti, P. A. , Munn, L. L. , Boucher, Y. , and Jain, R. K. , 2003, “ Solid Stress Generated by Spheroid Growth Estimated Using a Linear Poroelasticity Model,” Microvasc. Res., 66(3), pp. 204–212. [CrossRef] [PubMed]
Sarntinoranont, M. , Rooney, F. , and Ferrari, M. , 2003, “ Interstitial Stress and Fluid Pressure Within a Growing Tumor,” Ann. Biomed. Eng., 31(3), pp. 327–335. [CrossRef] [PubMed]
Kim, Y. , Stolarska, M. A. , and Othmer, H. G. , 2011, “ The Role of the Microenvironment in Tumor Growth and Invasion,” Progr. Biophys. Mol. Biol., 106(2), pp. 353–379. [CrossRef]
Griffon-Etienne, G. , Boucher, Y. , Brekken, C. , Suit, H. D. , and Jain, R. K. , 1999, “ Taxane-Induced Apoptosis Decompresses Blood Vessels and Lowers Interstitial Fluid Pressure in Solid Tumors: Clinical Implications,” Cancer Res., 59(15), pp. 3776–3782. http://cancerres.aacrjournals.org/content/59/15/3776.long [PubMed]
Padera, T. P. , Stoll, B. R. , Tooredman, J. B. , Capen, D. , di Tomaso, E. , and Jain, R. K. , 2004, “ Pathology: Cancer Cells Compress Intratumour Vessels,” Nature, 427(6976), p. 695. [CrossRef] [PubMed]
Nia, H. T. , Liu, H. , Seano, G. , Datta, M. , Jones, D. , Rahbari, N. , Incio, J. , Chauhan, V. P. , Jung, K. , Martin, J. D. , Askoxylakis, V. , Padera, T. P. , Fukumura, D. , Boucher, Y. , Hornicek, F. J. , Grodzinsky, A. J. , Baish, J. W. , Munn, L. L. , and Jain, R. K. , 2017, “ Solid Stress and Elastic Energy: new Measures of Tumor Mechanopathology,” Nat. Biomed. Eng., (to appear).
Netti, P. A. , Berk, D. A. , Swartz, M. A. , Grodzinsky, A. J. , and Jain, R. K. , 2000, “ Role of Extracellular Matrix Assembly in Interstitial Transport in Solid Tumors,” Cancer Res., 60(9), pp. 2497–2503. http://cancerres.aacrjournals.org/content/60/9/2497 [PubMed]
Fung, Y. C. , 1993, Biomechanics: Mechanical Properties of Living Tissues, Spinger-Verlag, New York.
Ferguson, S. J. , Ito, K. , and Nolte, L. P. , 2004, “ Fluid Flow and Convective Transport of Solutes Within the Intervertebral Disc,” J. Biomech., 37(2), pp. 213–221. [CrossRef] [PubMed]
Ambrosi, D. , and Mollica, F. , 2002, “ On the Mechanics of a Growing Tumor,” Int. J. Eng. Sci., 40(12), pp. 1297–1316. [CrossRef]
MacLaurin, J. , Chapman, J. , Jones, G. W. , and Roose, T. , 2012, “ The Buckling of Capillaries in Solid Tumours,” Proc. R. Soc. A, 468(2148), pp. 4123–4145. [CrossRef]
Ciarletta, P. , 2013, “ Buckling Instability in Growing Tumor Spheroids,” Phys. Rev. Lett., 110(15), p. 158102. [CrossRef] [PubMed]
Delarue, M. , Montel, F. , Vignjevic, D. , Prost, J. , Joanny, J. F. , and Cappello, G. , 2014, “ Compressive Stress Inhibits Proliferation in Tumor Spheroids Through a Volume Limitation,” Biophys. J., 107(8), pp. 1821–1828. [CrossRef] [PubMed]
Desmaison, A. , Frongia, C. , Grenier, K. , Ducommun, B. , and Lobjois, V. , 2013, “ Mechanical Stress Impairs Mitosis Progression in Multi-Cellular Tumor Spheroids,” PLoS One, 8(12), p. e80447. [CrossRef] [PubMed]
Wiig, H. , and Swartz, M. A. , 2012, “ Interstitial Fluid and Lymph Formation and Transport: Physiological Regulation and Roles in Inflammation and Cancer,” Physiol. Rev., 92(3), pp. 1005–1060. [CrossRef] [PubMed]
Eisenberg, S. R. , and Grodzinsky, A. J. , 1985, “ Swelling of Articular Cartilage and Other Connective Tissues: Electromechanochemical Forces,” J. Orthop. Res. Off. Publ. Orthop. Res. Soc., 3(2), pp. 148–159. [CrossRef]
Lai, V. K. , Nedrelow, D. S. , Lake, S. P. , Kim, B. , Weiss, E. M. , Tranquillo, R. T. , and Barocas, V. H. , 2016, “ Swelling of Collagen-Hyaluronic Acid Co-Gels: An In Vitro Residual Stress Model,” Ann. Biomed. Eng., 44(1), pp. 2984–2993. [CrossRef] [PubMed]
Choung, C. J. , and Fung, Y. C. , 1986, “ Residual Stress in Arteries,” Frontiers in Biomechanics, G. W. Schmid-Schoenbein , S. L. Woo , and B. W. Zweifach , eds., Springer, New York, pp. 117–129.
Liu, S. Q. , and Fung, Y. C. , 1988, “ Zero-Stress States of Arteries,” ASME J. Biomech. Eng., 110(1), pp. 82–84. [CrossRef]
Omens, J. H. , and Fung, Y. C. , 1990, “ Residual Strain in Rat Left Ventricle,” Circ. Res., 66(1), pp. 37–45. [CrossRef] [PubMed]
Taber, L. A. , and Humphrey, J. D. , 2001, “ Stress-Modulated Growth, Residual Stress, and Vascular Heterogeneity,” ASME J. Biomech. Eng., 123(6), pp. 528–535. [CrossRef]
Omens, J. H. , Vaplon, S. M. , Fazeli, B. , and McCulloch, A. D. , 1998, “ Left Ventricular Geometric Remodeling and Residual Stress in the Rat Heart,” ASME J. Biomech. Eng., 120(6), pp. 715–719. [CrossRef]
Xu, G. , Bayly, P. V. , and Taber, L. A. , 2009, “ Residual Stress in the Adult Mouse Brain,” Biomech. Model. Mechanobiol., 8(4), pp. 253–262. [CrossRef] [PubMed]
Skalak, R. , Zargaryan, S. , Jain, R. K. , Netti, P. A. , and Hoger, A. , 1996, “ Compatibility and the Genesis of Residual Stress by Volumetric Growth,” J. Math. Biol., 34(8), pp. 889–914. [CrossRef] [PubMed]
Omens, J. H. , McCulloch, A. D. , and Criscione, J. C. , 2003, “ Complex Distributions of Residual Stress and Strain in the Mouse Left Ventricle: Experimental and Theoretical Models,” Biomech. Model. Mechanobiol., 1(4), pp. 267–277. [CrossRef] [PubMed]
Ren, J. S. , 2013, “ Growth and Residual Stresses of Arterial Walls,” J. Theor. Biol., 337, pp. 80–88. [CrossRef] [PubMed]
Hagendoorn, J. , Tong, R. , Fukumura, D. , Lin, Q. , Lobo, J. , Padera, T. P. , Xu, L. , Kucherlapati, R. , and Jain, R. K. , 2006, “ Onset of Abnormal Blood and Lymphatic Vessel Function and Interstitial Hypertension in Early Stages of Carcinogenesis,” Cancer Res., 66(7), pp. 3360–3364. [CrossRef] [PubMed]
Boucher, Y. , Baxter, L. T. , and Jain, R. K. , 1990, “ Interstitial Pressure Gradients in Tissue-Isolated and Subcutaneous Tumors: Implications for Therapy,” Cancer Res., 50(15), pp. 4478–4484. http://cancerres.aacrjournals.org/content/50/15/4478 [PubMed]
Boucher, Y. , and Jain, R. K. , 1992, “ Microvascular Pressure Is the Principal Driving Force for Interstitial Hypertension in Solid Tumors: Implications for Vascular Collapse,” Cancer Res., 52(18), pp. 5110–5114. http://cancerres.aacrjournals.org/content/52/18/5110 [PubMed]
Chauhan, V. P. , Stylianopoulos, T. , Martin, J. D. , Popovic, Z. , Chen, O. , Kamoun, W. S. , Bawendi, M. G. , Fukumura, D. , and Jain, R. K. , 2012, “ Normalization of Tumour Blood Vessels Improves the Delivery of Nanomedicines in a Size-Dependent Manner,” Nat. Nanotechnol., 7(6), pp. 383–388. [CrossRef] [PubMed]
Popovic, Z. , Liu, W. , Chauhan, V. P. , Lee, J. , Wong, C. , Greytak, A. B. , Insin, N. , Nocera, D. G. , Fukumura, D. , Jain, R. K. , and Bawendi, M. G. , 2010, “ A Nanoparticle Size Series for In Vivo Fluorescence Imaging,” Angew. Chem. Int. Ed. Engl., 49(46), pp. 8649–8652. [CrossRef] [PubMed]
Stylianopoulos, T. , and Jain, R. K. , 2015, “ Design Considerations for Nanotherapeutics in Oncology,” Nanomed. Nanotechnol., Biol. Med., 11(8), pp. 1893–1907. [CrossRef]
Baxter, L. T. , and Jain, R. K. , 1989, “ Transport of Fluid and Macromolecules in Tumors—I: Role of Interstitial Pressure and Convection,” Microvasc. Res., 37(1), pp. 77–104. [CrossRef] [PubMed]
Baxter, L. T. , and Jain, R. K. , 1990, “ Transport of Fluid and Macromolecules in Tumors—II: Role of Heterogeneous Perfusion and Lymphatics,” Microvasc. Res., 40(2), pp. 246–263. [CrossRef] [PubMed]
Chauhan, V. P. , Martin, J. D. , Liu, H. , Lacorre, D. A. , Jain, S. R. , Kozin, S. V. , Stylianopoulos, T. , Mousa, A. , Han, X. , Adstamongkonkul, P. , Popovic, Z. , Bawendi, M. G. , Boucher, Y. , and Jain, R. K. , 2013, “ Angiotensin Inhibition Enhances Drug Delivery and Potentiates Chemotherapy by Decompressing Tumor Blood Vessels,” Nat. Commun., 4, p. 2516. [CrossRef] [PubMed]
Jain, R. K. , 2014, “ An Indirect Way to Tame Cancer,” Sci. Am., 310(2), pp. 46–53. [CrossRef] [PubMed]
Stylianopoulos, T. , and Jain, R. K. , 2013, “ Combining Two Strategies to Improve Perfusion and Drug Delivery in Solid Tumors,” Proc. Natl. Acad. Sci. U. S. A., 110(46), pp. 18632–18637. [CrossRef] [PubMed]
Perentes, J. Y. , McKee, T. D. , Ley, C. D. , Mathiew, H. , Dawson, M. , Padera, T. P. , Munn, L. L. , Jain, R. K. , and Boucher, Y. , 2009, “ In Vivo Imaging of Extracellular Matrix Remodeling by Tumor-Associated Fibroblasts,” Nat. Methods, 6(2), pp. 143–145. [CrossRef] [PubMed]
Olive, K. P. , Jacobetz, M. A. , Davidson, C. J. , Gopinathan, A. , McIntyre, D. , Honess, D. , Madhu, B. , Goldgraben, M. A. , Caldwell, M. E. , Allard, D. , Frese, K. K. , Denicola, G. , Feig, C. , Combs, C. , Winter, S. P. , Ireland-Zecchini, H. , Reichelt, S. , Howat, W. J. , Chang, A. , Dhara, M. , Wang, L. , Ruckert, F. , Grutzmann, R. , Pilarsky, C. , Izeradjene, K. , Hingorani, S. R. , Huang, P. , Davies, S. E. , Plunkett, W. , Egorin, M. , Hruban, R. H. , Whitebread, N. , McGovern, K. , Adams, J. , Iacobuzio-Donahue, C. , Griffiths, J. , and Tuveson, D. A. , 2009, “ Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer,” Science, 324(5933), pp. 1457–1461. [CrossRef] [PubMed]
Hidalgo, M. , and Von Hoff, D. D. , 2012, “ Translational Therapeutic Opportunities in Ductal Adenocarcinoma of the Pancreas,” Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res., 18(16), pp. 4249–4256. [CrossRef]
Diop-Frimpong, B. , Chauhan, V. P. , Krane, S. , Boucher, Y. , and Jain, R. K. , 2011, “ Losartan Inhibits Collagen I Synthesis and Improves the Distribution and Efficacy of Nanotherapeutics in Tumors,” Proc. Natl. Acad. Sci. U. S. A., 108(7), pp. 2909–2914. [CrossRef] [PubMed]
Wilop, S. , von Hobe, S. , Crysandt, M. , Esser, A. , Osieka, R. , and 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(10), pp. 1429–1435. [CrossRef] [PubMed]
Nakai, Y. , Isayama, H. , Ijichi, H. , Sasaki, T. , Sasahira, N. , Hirano, K. , Kogure, H. , Kawakubo, K. , Yagioka, H. , Yashima, Y. , Mizuno, S. , Yamamoto, K. , Arizumi, T. , Togawa, O. , Matsubara, S. , Tsujino, T. , Tateishi, K. , Tada, M. , Omata, M. , and Koike, K. , 2010, “ Inhibition of Renin-Angiotensin System Affects Prognosis of Advanced Pancreatic Cancer Receiving Gemcitabine,” Br. J. Cancer, 103(11), pp. 1644–1648. [CrossRef] [PubMed]
Keizman, D. , Huang, P. , Eisenberger, M. A. , Pili, R. , Kim, J. J. , Antonarakis, E. S. , Hammers, H. , and Carducci, M. A. , 2011, “ Angiotensin System Inhibitors and Outcome of Sunitinib Treatment in Patients With Metastatic Renal Cell Carcinoma: A Retrospective Examination,” Eur. J. Cancer (Oxford, England: 1990), 47(13), pp. 1955–1961. [CrossRef]
Nakai, Y. , Isayama, H. , Ijichi, H. , Sasaki, T. , Kogure, H. , Yagioka, H. , Miyabayashi, K. , Mizuno, S. , Yamamoto, K. , Mouri, D. , Kawakubo, K. , Yamamoto, N. , Hirano, K. , Sasahira, N. , Tateishi, K. , Tada, M. , and Koike, K. , 2012, “ Phase I Trial of Gemcitabine and Candesartan Combination Therapy in Normotensive Patients With Advanced Pancreatic Cancer: GECA1,” Cancer Sci., 103(8), pp. 1489–1492. [CrossRef] [PubMed]
Jacobetz, M. A. , Chan, D. S. , Neesse, A. , Bapiro, T. E. , Cook, N. , Frese, K. K. , Feig, C. , Nakagawa, T. , Caldwell, M. E. , Zecchini, H. I. , Lolkema, M. P. , Jiang, P. , Kultti, A. , Thompson, C. B. , Maneval, D. C. , Jodrell, D. I. , Frost, G. I. , Shepard, H. M. , Skepper, J. N. , and Tuveson, D. A. , 2012, “ Hyaluronan Impairs Vascular Function and Drug Delivery in a Mouse Model of Pancreatic Cancer,” Gut, 62(1), pp. 112–120. [CrossRef] [PubMed]
Provenzano, P. P. , Cuevas, C. , Chang, A. E. , Goel, V. K. , Von Hoff, D. D. , and Hingorani, S. R. , 2012, “ Enzymatic Targeting of the Stroma Ablates Physical Barriers to Treatment of Pancreatic Ductal Adenocarcinoma,” Cancer Cell, 21(3), pp. 418–429. [CrossRef] [PubMed]
Liu, J. , Liao, S. , Diop-Frimpong, B. , Chen, W. , Goel, S. , Naxerova, K. , Ancukiewicz, M. , Boucher, Y. , Jain, R. K. , and Xu, L. , 2012, “ TGF-Beta Blockade Improves the Distribution and Efficacy of Therapeutics in Breast Carcinoma by Normalizing the Tumor Stroma,” Proc. Natl. Acad. Sci. U. S. A., 109(41), pp. 16618–16623. [CrossRef] [PubMed]
Papageorgis, P. , and Stylianopoulos, T. , 2015, “ Role of TGFbeta in Regulation of the Tumor Microenvironment and Drug Delivery (Review),” Int. J. Oncol., 46(3), pp. 933–943. [PubMed]
Papageorgis, P. , Polydorou, C. , Mpekris, F. , Voutouri, C. , Eliana, C. , Kapnisi, C. , and Stylianopoulos, T. , 2016, “ Tranilast-Induced Stress Alleviation Improves the Efficacy of Anti-Cancer Drugs in a Size-Independent Manner,” (submitted).
Stockmann, C. , Doedens, A. , Weidemann, A. , Zhang, N. , Takeda, N. , Greenberg, J. I. , Cheresh, D. A. , and Johnson, R. S. , 2008, “ Deletion of Vascular Endothelial Growth Factor in Myeloid Cells Accelerates Tumorigenesis,” Nature, 456(7223), pp. 814–818. [CrossRef] [PubMed]
Rhim, A. D. , Mirek, E. T. , Aiello, N. M. , Maitra, A. , Bailey, J. M. , McAllister, F. , Reichert, M. , Beatty, G. L. , Rustgi, A. K. , Vonderheide, R. H. , Leach, S. D. , and Stanger, B. Z. , 2012, “ EMT and Dissemination Precede Pancreatic Tumor Formation,” Cell, 148(1–2), pp. 349–361. [CrossRef] [PubMed]
Rodriguez, E. K. , Hoger, A. , and McCulloch, A. D. , 1994, “ Stress-Dependent Finite Growth in Soft Elastic Tissues,” J. Biomech., 27(4), pp. 455–467. [CrossRef] [PubMed]
Mpekris, F. , Angeli, S. , Pirentis, A. P. , and Stylianopoulos, T. , 2015, “ Stress-Mediated Progression of Solid Tumors: Effect of Mechanical Stress on Tissue Oxygenation, Cancer Cell Proliferation, and Drug Delivery,” Biomech. Model. Mechanobiol., 14(6), pp. 1391–1402. [CrossRef] [PubMed]
Voutouri, C. , and Stylianopoulos, T. , 2014, “ Evolution of Osmotic Pressure in Solid Tumors,” J. Biomech., 47(14), pp. 3441–3447. [CrossRef] [PubMed]
Sun, D. N. , Gu, W. Y. , Guo, X. E. , Lai, W. M. , and Mow, V. C. , 1999, “ A Mixed Finite Element Formulation of Triphasic Mechano-Electrochemical Theory for Charged, Hydrated Biological Soft Tissues,” Int. J. Numer. Methods Eng., 45(10), pp. 1375–1402. [CrossRef]
Lu, X. L. , Wan, L. Q. , Guo, X. E. , and Mow, V. C. , 2010, “ A Linearized Formulation of Triphasic Mixture Theory for Articular Cartilage, and its Application to Indentation Analysis,” J. Biomech., 43(4), pp. 673–679. [CrossRef] [PubMed]
Ambrosi, D. , and Preziosi, L. , 2009, “ Cell Adhesion Mechanisms and Stress Relaxation in the Mechanics of Tumours,” Biomech. Model. Mechanobiol., 8(5), pp. 397–413. [CrossRef] [PubMed]
Taber, L. A. , 2008, “ Theoretical Study of Beloussov's Hyper-Restoration Hypothesis for Mechanical Regulation of Morphogenesis,” Biomech. Model. Mechanobiol., 7(6), pp. 427–441. [CrossRef] [PubMed]
Stylianopoulos, T. , and Barocas, V. H. , 2007, “ Volume Averaging Theory for the Study of the Mechanics of Collagen Networks,” Comput. Methods Appl. Mech. Eng., 196(31–32), pp. 2981–2990. [CrossRef]
Wijeratne, P. A. , Vavourakis, V. , Hipwell, J. H. , Voutouri, C. , Papageorgis, P. , Stylianopoulos, T. , Evans, A. , and Hawkes, D. J. , 2016, “ Multiscale Modelling of Solid Tumour Growth: the Effect of Collagen Micromechanics,” Biomech. Model. Mechanobiol., 15(5), pp. 1079–1090. [CrossRef] [PubMed]
Pirentis, A. P. , Polydorou, C. , Papageorgis, P. , Voutouri, C. , Mpekris, F. , and Stylianopoulos, T. , 2015, “ Remodeling of Extracellular Matrix Due to Solid Stress Accumulation During Tumor Growth,” Connect. Tissue Res., 56(5), pp. 345–354. [CrossRef] [PubMed]
Ramirez-Torres, A. , Rodriguez-Ramos, R. , Merodio, J. , Bravo-Castillero, J. , Guinovart-Diaz, R. , and Alfonso, J. C. L. , 2015, “ Mathematical Modeling of Anisotropic Avascular Tumor Growth,” Mech. Res. Commun., 69, pp. 8–14. [CrossRef]
Giverso, C. , and Preziosi, L. , 2013, “ Behavior of Cell Aggregates Under Force-Controlled Compression,” Int. J. Nonlinear. Mech., 56, pp. 50–55. [CrossRef]


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Fig. 1.

Externally applied solid stress: (a) schematic of externally applied stress at the tumor center and periphery, (b) mathematical model predictions of the spatial profile of radial and circumferential components of solid stress in tumors, and (c) histological sections of human tumors show the deformation of tumor blood vessels. Top: salivary duct carcinoma (left), undifferentiated liposarcoma (right), bottom: differentiated pancreatic neuroendocrine tumors. Arrows show tumor location. (scale bar = 100 μm). (Adapted with permission from Ref. [6]).

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Fig. 2.

Swelling solid stress: (a) schematic of the protocol for measuring swelling stress in tumors utilizing the confined compression experiment and modulated the electrolyte concentration of the tumor interstitial space, (b) swelling stress measurements as a function of NaCl concentration in two orthotopic breast tumor models (MCF10CA1a and 4T1), Swelling stress as a function of (c) hyaluronan, (d) collagen, and (e) hyaluronan to collagen content.

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Fig. 3.

Residual solid stress: (a) evidence of growth-induced, residual stress. A cut along the long axis of a tumor results in swelling of the interior and opening of the periphery of the tumor, (b) tumor opening measurements in murine and human tumors. Tumor opening is normalized by division with the diameter of the tumor (reproduced with permission from Ref. [9]), (c) tumor opening increases with the volume of the tumor for three cancer cell lines, human melanoma Mu89, pancreatic adenocarcinoma AK4.4, and mammary adenocarcinoma 4T1 (adapted with permission from Ref. [6]), and (d) selective depletion of cancer cells, human CAFs (hCAFs), collagen, or hyaluronan decreases significantly tumor opening in melanoma (Mu89), breast (4T1, E0771), and pancreatic (AK4.4) tumors, indicative of stress alleviation. (Adapted with permission from Ref.[9].)

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Fig. 4.

Schematic of stress alleviation treatments. Selective depletion of cancer cells, fibroblasts, collagen, or hyaluronan can result in stress alleviation and blood vessel decompression improving vessel functionality. (Reproduced with permission from Ref. [9].)

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Fig. 5.

Stress alleviation strategy improves perfusion in hypovascular orthotopic pancreatic AK4.4 and Capan2 tumors. (a and b) Fluorescence images showing increased number of perfused vessels in saridegib-treated tumors. Cd31 (green color) stains for all tumor vessels, while lectin (red color) stains only perfused vessels. (c–f) Saridegib alleviates solid stress showed by the decrease in the tumor opening, decompresses both blood and lymphatic vessels, improves fraction of perfused vessels, without affected vascular density. +, saridegib; −, vehicle. The asterisks denote a statistically significant difference. (Reproduced with permission from Ref. [9].)



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