Extracellular Matrix Remodeling and Stiffening Modulate Tumor Phenotype and Treatment Response

Jennifer L. Leight; Allison P. Drain; Valerie M. Weaver

doi:10.1146/annurev-cancerbio-050216-034431

Annual Review of Cancer Biology

Volume 1, 2017

Review Article

Free

Extracellular Matrix Remodeling and Stiffening Modulate Tumor Phenotype and Treatment Response

Jennifer L. Leight¹, Allison P. Drain², and Valerie M. Weaver³
View Affiliations Hide Affiliations

Affiliations: ¹Department of Biomedical Engineering and The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210; email: [email protected] ²University of California, Berkeley–University of California, San Francisco Graduate Program in Bioengineering, Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, California 94143; email: [email protected] ³Center for Bioengineering and Tissue Regeneration, Department of Surgery, Department of Anatomy, Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, and Helen Diller Comprehensive Cancer Center, University of California, San Francisco, California 94143; email: [email protected]
Vol. 1:313-334 (Volume publication date March 2017) https://doi.org/10.1146/annurev-cancerbio-050216-034431
First published as a Review in Advance on November 09, 2016
© Annual Reviews

Abstract

Solid tumors are characterized by a remodeled and stiffened extracellular matrix. The extracellular matrix is not a passive by-product of the tumor, but actively compromises tissue-specific differentiation, enhances tumor cell proliferation and survival, and fosters tumor cell invasion and migration. The tumor extracellular matrix also influences the behavior of the stromal cells, which through vicious, feedforward-reinforcing pathways promote tumor progression and compromise treatment efficacy. To investigate how the tumor extracellular matrix alters cancer phenotype and treatment, a number of three-dimensional, organotypic culture models have been developed that employ a variety of materials, including natural matrices, collagen, fibrin, and reconstituted basement membrane gels, as well as synthetic hydrogel materials such as polyacrylamide and polyethylene glycol. These models have been used to interrogate how specific microenvironmental features modify tumor and stromal cell function and to identify the molecular mechanisms that regulate tumorigenesis and therapeutic efficacy. To translate these findings into more effective treatment strategies for patients, clinically informed studies are needed that incorporate computational modeling and in vivo validation.

Keyword(s): cancer, extracellular matrix, remodeling, tissue stiffness, tumor microenvironment

Article metrics loading...

/content/journals/10.1146/annurev-cancerbio-050216-034431

2017-03-06

2025-04-28

Full text loading...

/deliver/fulltext/cancerbio/1/1/annurev-cancerbio-050216-034431.html?itemId=/content/journals/10.1146/annurev-cancerbio-050216-034431&mimeType=html&fmt=ahah

Literature Cited

Acerbi I, Cassereau L, Dean I, Shi Q, Au A. et al. 2015. Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr. Biol. 7:101120–34 [Google Scholar]
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. 2003. Prospective identification of tumorigenic breast cancer cells. PNAS 100:73983–88 [Google Scholar]
Aragona M, Panciera T, Manfrin A, Giulitti S, Michielin F. et al. 2013. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell 154:51047–59 [Google Scholar]
Aung A, Seo YN, Lu S, Wang Y, Jamora C, Juan CA. 2014. 3D traction stresses activate protease-dependent invasion of cancer. Biophys. J. 107:2528–37 [Google Scholar]
Bergers G, Benjamin LE. 2003. Tumorigenesis and the angiogenic switch. Nat. Rev. Cancer 3:6401–10 [Google Scholar]
Bhat KPL, Salazar KL, Balasubramaniyan V, Wani K, Heathcock L. et al. 2011. The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma. Genes Dev 25:242594–609 [Google Scholar]
Birukova AA, Tian X, Cokic I, Beckham Y, Gardel ML, Birukov KG. 2013. Endothelial barrier disruption and recovery is controlled by substrate stiffness. Microvasc. Res. 87:50–57 [Google Scholar]
Blakney AK, Swartzlander MD, Bryant SJ. 2013. The effects of substrate stiffness on the in vitro activation of macrophages and in vivo host response to poly(ethylene glycol)-based hydrogels. J. Biomed. Mater. Res. A 100:61375–86 [Google Scholar]
Blomback B, Bark N. 2004. Fibrinopeptides and fibrin gel structure. Biophys. Chem. 112:2–3147–51 [Google Scholar]
Bollyky PL, Wu RP, Falk BA, Lord JD, Long SA. et al. 2011. ECM components guide IL-10 producing regulatory T-cell (TR1) induction from effector memory T-cell precursors. PNAS 108:197938–43 [Google Scholar]
Bonnans C, Chou J, Werb Z. 2014. Remodelling the extracellular matrix in development and disease. Nat. Rev. Mol. Cell Biol. 15:12786–801 [Google Scholar]
Bravo-Cordero JJ, Hodgson L, Condeelis J. 2012. Directed cell invasion and migration during metastasis. Curr. Opin. Cell Biol. 24:2277–83 [Google Scholar]
Burdett E, Kasper FK, Mikos AG, Ludwig JA. 2010. Engineering tumors: a tissue engineering perspective in cancer biology. Tissue Eng. B Rev. 16:3351–59 [Google Scholar]
Buxboim A, Rajagopal K, Brown AEX, Discher DE. 2010. How deeply cells feel: methods for thin gels. J. Phys. Condens. Matter 22:19194116 [Google Scholar]
Califano JP, Reinhart-King CA. 2008. A balance of substrate mechanics and matrix chemistry regulates endothelial cell network assembly. Cell. Mol. Bioeng. 1:2–3122–32 [Google Scholar]
Calvo F, Ege N, Grande-Garcia A, Hooper S, Jenkins RP. et al. 2013. Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat. Cell Biol. 15:6637–46 [Google Scholar]
Cassereau L, Miroshnikova YA, Ou G, Lakins J, Weaver VM. 2015. A 3D tension bioreactor platform to study the interplay between ECM stiffness and tumor phenotype. J. Biotechnol. 193:66–69 [Google Scholar]
Castelló-Cros R, Khan DR, Simons J, Valianou M, Cukierman E. 2009. Staged stromal extracellular 3D matrices differentially regulate breast cancer cell responses through PI3K and β1-integrins. BMC Cancer 9:94 [Google Scholar]
Chambard JC, Lefloch R, Pouysségur J, Lenormand P. 2007. ERK implication in cell cycle regulation. Biochim. Biophys. Acta 1773:81299–310 [Google Scholar]
Chang C, Goel HL, Gao H, Pursell B, Shultz LD. et al. 2015. A laminin 511 matrix is regulated by Taz and functions as the ligand for the α6β1 integrin to sustain breast cancer stem cells. Genes Dev 29:11–6 [Google Scholar]
Chen C, Chen K, Yang S-T. 2003. Effects of three-dimensional culturing on osteosarcoma cells grown in a fibrous matrix: analyses of cell morphology, cell cycle, and apoptosis. Biotechnol. Prog. 19:51574–82 [Google Scholar]
Chen J, Li Y, Yu T-S, McKay RM, Burns DK. et al. 2012. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488:7412522–26 [Google Scholar]
Cheung KJ, Gabrielson E, Werb Z, Ewald AJ. 2013. Collective invasion in breast cancer requires a conserved basal epithelial program. Cell 155:71639–51 [Google Scholar]
Clavería C, Giovinazzo G, Sierra R, Torres M. 2013. Myc-driven endogenous cell competition in the early mammalian embryo. Nature 500:746039–44 [Google Scholar]
Culver JC, Hoffmann JC, Poché RA, Slater JH, West JL, Dickinson ME. 2012. Three-dimensional biomimetic patterning in hydrogels to guide cellular organization. Adv. Mater. 24:172344–48 [Google Scholar]
Davalos AR, Coppe JP, Campisi J, Desprez PY. 2010. Senescent cells as a source of inflammatory factors for tumor progression. Cancer Metastasis Rev. 29:2273–83 [Google Scholar]
De La Cova C, Abril M, Bellosta P, Gallant P, Johnston LA. 2004. Drosophila myc regulates organ size by inducing cell competition. Cell 117:1107–16 [Google Scholar]
Debnath J, Brugge JS. 2005. Modelling glandular epithelial cancers in three-dimensional cultures. Nat. Rev. Cancer 5:9675–88 [Google Scholar]
DeForest CA, Polizzotti BD, Anseth KS. 2009. Sequential click reactions for synthesizing and patterning three-dimensional cell microenvironments. Nat. Mater. 8:8659–64 [Google Scholar]
Denais CM, Gilbert RM, Isermann P, McGregor AL. Lindert M. , te et al. 2016. Nuclear envelope rupture and repair during cancer cell migration. Science 352:6283353–58 [Google Scholar]
Denisin AK, Pruitt BL. 2016. Tuning the range of polyacrylamide gel stiffness for mechanobiology applications. ACS Appl. Mater. Interfaces. In press [Google Scholar]
Desgrosellier JS, Lesperance J, Seguin L, Gozo M, Kato S. et al. 2014. Integrin αvβ3 drives slug activation and stemness in the pregnant and neoplastic mammary gland. Dev. Cell 30:3295–308 [Google Scholar]
Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S. et al. 2011. Role of YAP/TAZ in mechanotransduction. Nature 474:7350179–83 [Google Scholar]
Ebihara T, Venkatesan N, Tanaka R, Ludwig MS. 2000. Changes in extracellular matrix and tissue viscoelasticity in bleomycin-induced lung fibrosis: temporal aspects. Am. J. Respir. Crit. Care Med. 162:41569–76 [Google Scholar]
Eke I, Deuse Y, Hehlgans S, Gurtner K, Krause M. et al. 2012. 1 Integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy. J. Clin. Investig. 122:41529–40 [Google Scholar]
Ellem SJ, De-Juan-Pardo EM, Risbridger GP. 2014. In vitro modeling of the prostate cancer microenvironment. Adv. Drug Deliv. Rev. 79–80:214–21 [Google Scholar]
Enemchukwu NO, Cruz-Acuña R, Bongiorno T, Johnson CT, García JR. et al. 2016. Synthetic matrices reveal contributions of ECM biophysical and biochemical properties to epithelial morphogenesis. J. Cell Biol. 212:1113–24 [Google Scholar]
Erler JT, Bennewith KL, Cox TR, Lang G, Bird D. et al. 2009. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15:135–44 [Google Scholar]
Erler JT, Bennewith KL, Nicolau M, Dornhöfer N, Kong C. et al. 2006. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440:70881222–26 [Google Scholar]
Esbona K, Inman D, Saha S, Jeffery J, Schedin P. et al. 2016. COX-2 modulates mammary tumor progression in response to collagen density. Breast Cancer Res. 18:135 [Google Scholar]
Fischbach C, Chen R, Matsumoto T, Schmelzle T, Brugge JS. et al. 2007. Engineering tumors with 3D scaffolds. Nat. Methods 4:10855–60 [Google Scholar]
Fischbach C, Kong HJ, Hsiong SX, Evangelista MB, Yuen W, Mooney DJ. 2009. Cancer cell angiogenic capability is regulated by 3D culture and integrin engagement. PNAS 106:2399–404 [Google Scholar]
Fong ELS, Lamhamedi-Cherradi S-E, Burdett E, Ramamoorthy V, Lazar AJ. et al. 2013. Modeling Ewing sarcoma tumors in vitro with 3D scaffolds. PNAS 110:166500–5 [Google Scholar]
Fraley SI, Wu P-H, He L, Feng Y, Krisnamurthy R. et al. 2015. Three-dimensional matrix fiber alignment modulates cell migration and MT1–MMP utility by spatially and temporally directing protrusions. Sci. Rep. 5:14580 [Google Scholar]
Frantz C, Stewart KM, Weaver VM. 2010. The extracellular matrix at a glance. J. Cell Sci. 123:4195–200 [Google Scholar]
Friedl P, Gilmour D. 2009. Collective cell migration in morphogenesis, regeneration and cancer. Nat. Rev. Mol. Cell Biol. 10:7445–57 [Google Scholar]
Friedl P, Wolf K. 2010. Plasticity of cell migration: a multiscale tuning model. J. Cell Biol. 188:111–19 [Google Scholar]
Fuller ES, Howell VM. 2014. Culture models to define key mediators of cancer matrix remodeling. Front. Oncol. 4:57 [Google Scholar]
Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. 2012. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12:4253–68 [Google Scholar]
Gaggioli C, Hooper S, Hidalgo-Carcedo C, Grosse R, Marshall JF. et al. 2007. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat. Cell Biol. 9:121392–400 [Google Scholar]
Garcion E, Halilagic A, Faissner A, ffrench-Constant C. 2004. Generation of an environmental niche for neural stem cell development by the extracellular matrix molecule tenascin C. Development 131:143423–32 [Google Scholar]
Georges PC, Hui J-J, Gombos Z, McCormick ME, Wang AY. et al. 2007. Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 293:6G1147–54 [Google Scholar]
Ghosh K, Thodeti CK, Dudley AC, Mammoto A, Klagsbrun M, Ingber DE. 2008. Tumor-derived endothelial cells exhibit aberrant Rho-mediated mechanosensing and abnormal angiogenesis in vitro. PNAS 105:3211305–10 [Google Scholar]
Gilkes DM, Bajpai S, Chaturvedi P, Wirtz D, Semenza GL. 2013. Hypoxia-inducible factor 1 (HIF-1) promotes extracellular matrix remodeling under hypoxic conditions by inducing P4HA1, P4HA2, and PLOD2 expression in fibroblasts. J. Biol. Chem. 288:1510819–29 [Google Scholar]
Gill BJ, Gibbons DL, Roudsari LC, Saik JE, Rizvi ZH. et al. 2012. A synthetic matrix with independently tunable biochemistry and mechanical properties to study epithelial morphogenesis and EMT in a lung adenocarcinoma model. Cancer Res 72:226013–23 [Google Scholar]
Gill BJ, West JL. 2014. Modeling the tumor extracellular matrix: tissue engineering tools repurposed towards new frontiers in cancer biology. J. Biomech. 47:91969–78 [Google Scholar]
Gilmore AP, Metcalfe AD, Romer LH, Streuli CH. 2000. Integrin-mediated survival signals regulate the apoptotic function of Bax through its conformation and subcellular localization. J. Cell Biol. 149:2431–45 [Google Scholar]
Gribova V, Crouzier T, Picart C. 2011. A material's point of view on recent developments of polymeric biomaterials: control of mechanical and biochemical properties. J. Mater. Chem. 21:3814354–66 [Google Scholar]
Hanahan D, Weinberg RA. 2011. Hallmarks of cancer: the next generation. Cell 144:5646–74 [Google Scholar]
Hapach LA, VanderBurgh JA, Miller JP, Reinhart-King CA. 2015. Manipulation of in vitro collagen matrix architecture for scaffolds of improved physiological relevance. Phys. Biol. 12:6061002 [Google Scholar]
Haraguchi N, Ishii H, Mimori K, Ohta K, Uemura M. et al. 2013. CD49f-positive cell population efficiently enriches colon cancer-initiating cells. Int. J. Oncol. 43:2425–30 [Google Scholar]
Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW. et al. 2007. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1:3313–23 [Google Scholar]
Herrmann D, Conway JRW, Vennin C, Magenau A, Hughes WE. et al. 2014. Three-dimensional cancer models mimic cell–matrix interactions in the tumour microenvironment. Carcinogenesis 35:81671–79 [Google Scholar]
Hielscher AC, Qiu C, Gerecht S. 2012. Breast cancer cell–derived matrix supports vascular morphogenesis. Am. J. Physiol. Cell Physiol. 302:8C1243–56 [Google Scholar]
Hirata E, Girotti MR, Viros A, Hooper S, Spencer-Dene B. et al. 2015. Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signaling. Cancer Cell 27:4574–88 [Google Scholar]
Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. 2013. Cancer drug resistance: an evolving paradigm. Nat. Rev. Cancer 13:10714–26 [Google Scholar]
Hoogland AM, Verhoef EI, Roobol MJ, Schröder FH, Wildhagen MF. et al. 2014. Validation of stem cell markers in clinical prostate cancer: α6-Integrin is predictive for non-aggressive disease. Prostate 74:5488–96 [Google Scholar]
Hooley RJ, Scoutt LM, Philpotts LE. 2013. Breast ultrasonography: state of the art. Radiology 268:3642–59 [Google Scholar]
Houghton AM, Quintero PA, Perkins DL, Kobayashi DK, Kelley DG. et al. 2006. Elastin fragments drive disease progression in a murine model of emphysema. J. Clin. Investig. 116:3753–59 [Google Scholar]
Hsieh Y Te, Gang EJ, Geng H, Park E, Huantes S. et al. 2013. Integrin α4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy. Blood 121:101814–18 [Google Scholar]
Huang C, Park CC, Hilsenbeck SG, Ward R, Rimawi MF. et al. 2011. β1 integrin mediates an alternative survival pathway in breast cancer cells resistant to lapatinib. Breast Cancer Res. 13:4R84 [Google Scholar]
Hughes CS, Postovit LM, Lajoie GA. 2010. Matrigel: a complex protein mixture required for optimal growth of cell culture. Proteomics 10:91886–90 [Google Scholar]
Hunninghake GW, Davidson JM, Rennard S, Szapiel S, Gadek JE, Crystal RG. 1981. Elastin fragments attract macrophage precursors to diseased sites in pulmonary emphysema. Science 212:4497925–27 [Google Scholar]
Jain RK, Martin JD, Stylianopoulos T. 2014. The role of mechanical forces in tumor growth and therapy. Annu. Rev. Biomed. Eng. 16:321–46 [Google Scholar]
Jo S, Engel P, Mikos A. 2000. Synthesis of poly(ethylene glycol)-tethered poly(propylene fumarate) and its modification with GRGD peptide. Polymer 41:217595–604 [Google Scholar]
Kanda R, Kawahara A, Watari K, Murakami Y, Sonoda K. et al. 2013. Erlotinib resistance in lung cancer cells mediated by integrin β1/Src/Akt-driven bypass signaling. Cancer Res 73:206243–53 [Google Scholar]
Kandoth C, McLellan MD, Vandin F, Ye K, Niu B. et al. 2013. Mutational landscape and significance across 12 major cancer types. Nature 502:7471333–39 [Google Scholar]
Kessenbrock K, Plaks V, Werb Z. 2010. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141:152–67 [Google Scholar]
Klein EA, Yin L, Kothapalli D, Castagnino P, Byfield FJ. et al. 2009. Cell-cycle control by physiological matrix elasticity and in vivo tissue stiffening. Curr. Biol. 19:181511–18 [Google Scholar]
Klingberg F, Chow ML, Koehler A, Boo S, Buscemi L. et al. 2014. Prestress in the extracellular matrix sensitizes latent TGF-β1 for activation. J. Cell Biol. 207:2283–97 [Google Scholar]
Kloxin AM, Benton JA, Anseth KS. 2010. In situ elasticity modulation with dynamic substrates to direct cell phenotype. Biomaterials 31:11–8 [Google Scholar]
Kloxin AM, Kasko AM, Salinas CN, Anseth KS. 2009. Photodegradable hydrogels for dynamic tuning of physical and chemical properties. Science 324:592359–63 [Google Scholar]
Kniazeva E, Kachgal S, Putnam AJ. 2011. Effects of extracellular matrix density and mesenchymal stem cells on neovascularization in vivo. Tissue Eng. A 17:7–8905–14 [Google Scholar]
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. 297:1C179–87 [Google Scholar]
Laklai H, Miroshnikova YA, Pickup MW, Collisson EA, Kim GE. et al. 2016. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat. Med. 22:5497–505 [Google Scholar]
Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T. et al. 1994. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367:6464645–48 [Google Scholar]
Lee EY, Parry G, Bissell MJ. 1984. Modulation of secreted proteins of mouse mammary epithelial cells by the collagenous substrata. J. Cell Biol. 98:1146–55 [Google Scholar]
Leight JL, Wozniak MA, Chen S, Lynch ML, Chen CS. 2012. Matrix rigidity regulates a switch between TGF-1-induced apoptosis and epithelial–mesenchymal transition. Mol. Biol. Cell 23:5781–91 [Google Scholar]
Leight JL, Alge DA, Maier AJ, Anseth KS. 2013. Direct measurement of matrix metalloproteinase activity in 3D cellular microenvironments using a fluorogenic peptide substrate. Biomaterials 34:37344–52 [Google Scholar]
Lesniak D, Xu Y, Deschenes J, Lai R, Thoms J. et al. 2009. β1-integrin circumvents the antiproliferative effects of trastuzumab in human epidermal growth factor receptor-2-positive breast cancer. Cancer Res 69:228620–28 [Google Scholar]
Levental KR, Yu H, Kass L, Lakins JN, Egeblad M. et al. 2009. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139:5891–906 [Google Scholar]
Li Z, Dranoff JA, Chan EP, Uemura M, Sévigny J, Wells RG. 2007. Transforming growth factor-β and substrate stiffness regulate portal fibroblast activation in culture. Hepatology 46:41246–56 [Google Scholar]
Lim ST, Chen XL, Lim Y, Hanson DA, Vo TT. et al. 2008. Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. Mol. Cell 29:19–22 [Google Scholar]
Liu J, Agarwal S. 2010. Mechanical signals activate vascular endothelial growth factor receptor-2 to upregulate endothelial cell proliferation during inflammation. J. Immunol. 185:21215–21 [Google Scholar]
Liu J, Tan Y, Zhang H, Zhang Y, Xu P. et al. 2012. Soft fibrin gels promote selection and growth of tumorigenic cells. Nat. Mater. 11:873–41 [Google Scholar]
Loessner D, Stok KS, Lutolf MP, Hutmacher DW, Clements JA, Rizzi SC. 2010. Bioengineered 3D platform to explore cell–ECM interactions and drug resistance of epithelial ovarian cancer cells. Biomaterials 31:328494–506 [Google Scholar]
Lutolf MP, Lauer-Fields JL, Schmoekel HG, Metters AT, Weber FE. et al. 2003. Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: engineering cell-invasion characteristics. PNAS 100:95413–18 [Google Scholar]
Malanchi I, Peinado H, Kassen D, Hussenet T, Metzger D. et al. 2008. Cutaneous cancer stem cell maintenance is dependent on β-catenin signalling. Nature 452:7187650–53 [Google Scholar]
Mammoto A, Connor KM, Mammoto T, Yung CW, Huh D. et al. 2009. A mechanosensitive transcriptional mechanism that controls angiogenesis. Nature 457:72331103–8 [Google Scholar]
Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A. et al. 2008. The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell 133:4704–15 [Google Scholar]
Martin SS, Vuori K. 2004. Regulation of Bcl-2 proteins during anoikis and amorphosis. Biochim. Biophys. Acta 1692:2–3145–57 [Google Scholar]
McGregor AL, Hsia C-R, Lammerding J. 2016. Squish and squeeze—the nucleus as a physical barrier during migration in confined environments. Curr. Opin. Cell Biol. 40:32–40 [Google Scholar]
McWhorter FY, Wang T, Nguyen P, Chung T, Liu WF. 2013. Modulation of macrophage phenotype by cell shape. PNAS 110:4317253–58 [Google Scholar]
Mi K, Xing Z. 2015. CD44⁺/CD24⁻ breast cancer cells exhibit phenotypic reversion in three-dimensional self-assembling peptide RADA16 nanofiber scaffold. Int. J. Nanomedicine 10:3043–53 [Google Scholar]
Midwood K, Sacre S, Piccinini AM, Inglis J, Trebaul A. et al. 2009. Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat. Med. 15:7774–80 [Google Scholar]
Miroshnikova YA, Jorgens DM, Spirio L, Auer M, Sarang-Sieminski AL, Weaver VM. 2011. Engineering strategies to recapitulate epithelial morphogenesis within synthetic three-dimensional extracellular matrix with tunable mechanical properties. Phys. Biol. 8:2026013 [Google Scholar]
Mouw JK, Yui Y, Damiano L, Bainer RO, Lakins JN. et al. 2014. Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Nat. Med. 20:4360–67 [Google Scholar]
Muranen T, Selfors LM, Worster DT, Iwanicki MP, Song L. et al. 2012. Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells. Cancer Cell 21:2227–39 [Google Scholar]
Nakagawa S, Pawelek P, Grinnell F. 1989. Long-term culture of fibroblasts in contracted collagen gels: effects on cell growth and biosynthetic activity. J. Investig. Dermatol. 93:6792–98 [Google Scholar]
Nelson MT, Short A, Cole SL, Gross AC, Winter J. et al. 2014. Preferential, enhanced breast cancer cell migration on biomimetic electrospun nanofiber “cell highways.”. BMC Cancer 14:825 [Google Scholar]
Nemir S, West JL. 2010. Synthetic materials in the study of cell response to substrate rigidity. Ann. Biomed. Eng. 38:12–20 [Google Scholar]
Nguyen-Ngoc K-V, Cheung KJ, Brenot A, Shamir ER, Gray RS. et al. 2012. ECM microenvironment regulates collective migration and local dissemination in normal and malignant mammary epithelium. PNAS 109:39E2595–604 [Google Scholar]
Nishikawa H, Sakaguchi S. 2014. Regulatory T cells in cancer immunotherapy. Curr. Opin. Immunol. 27:11–7 [Google Scholar]
O'Brien CA, Pollett A, Gallinger S, Dick JE. 2007. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445:7123106–10 [Google Scholar]
O'Connor RS, Hao X, Shen K, Bashour K, Akimova T. et al. 2012. Substrate rigidity regulates human T cell activation and proliferation. J. Immunol. 189:31330–39 [Google Scholar]
Ohlund D, Elyada E, Tuveson D. 2014. Fibroblast heterogeneity in the cancer wound. J. Exp. Med. 211:81503–23 [Google Scholar]
Okamura Y, Watari M, Jerud ES, Young DW, Ishizaka ST. et al. 2001. The extra domain A of fibronectin activates Toll-like receptor 4. J. Biol. Chem. 276:1310229–33 [Google Scholar]
Oskarsson T, Acharyya S, Zhang XH, Vanharanta S, Tavazoie SF. et al. 2011. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat. Med. 17:7867–74 [Google Scholar]
Oskarsson T, Batlle E, Massagué J. 2014. Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell 14:3306–21 [Google Scholar]
Oudin MJ, Jonas O, Kosciuk T, Broye LC, Guido BC. et al. 2016. Tumor cell-driven extracellular matrix remodeling enables haptotaxis during metastatic progression. Cancer Discov 6:5516–31 [Google Scholar]
Overstreet MG, Gaylo A, Angermann BR, Hughson A, Hyun Y-M. et al. 2013. Inflammation-induced interstitial migration of effector CD4⁺ T cells is dependent on integrin α_V. Nat. Immunol. 14:9949–58 [Google Scholar]
Özdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu C-C. et al. 2014. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25:6719–34 [Google Scholar]
Palazon A, Goldrath AW, Nizet V, Johnson RS. 2014. HIF transcription factors, inflammation, and immunity. Immunity 41:4518–28 [Google Scholar]
Parekh A, Ruppender NS, Branch KM, Sewell-Loftin MK, Lin J. et al. 2011. Sensing and modulation of invadopodia across a wide range of rigidities. Biophys. J. 100:3573–82 [Google Scholar]
Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI. et al. 2005. Tensional homeostasis and the malignant phenotype. Cancer Cell 8:3241–54 [Google Scholar]
Pathak A, Kumar S. 2012. Independent regulation of tumor cell migration by matrix stiffness and confinement. PNAS 109:2610334–39 [Google Scholar]
Pelham RJ, Wang YL. 1997. Cell locomotion and focal adhesions are regulated by the mechanical properties of the substrate. PNAS 194:3348–49 [Google Scholar]
Pickup MW, Laklai H, Acerbi I, Owens P, Gorska AE. et al. 2013. Stromally derived lysyl oxidase promotes metastasis of transforming growth factor-β-deficient mouse mammary carcinomas. Cancer Res 73:175336–46 [Google Scholar]
Pickup MW, Mouw JK, Weaver VM. 2014. The extracellular matrix modulates the hallmarks of cancer. EMBO Rep 15:121243–53 [Google Scholar]
Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ. et al. 2007. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. PNAS 104:3973–78 [Google Scholar]
Provenzano PP, Eliceiri KW, Campbell JM, Inman DR, White JG, Keely PJ. 2006. Collagen reorganization at the tumor–stromal interface facilitates local invasion. BMC Med 4:138 [Google Scholar]
Provenzano PP, Inman DR, Eliceiri KW, Keely PJ. 2009. Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK–ERK linkage. Oncogene 28:494326–43 [Google Scholar]
Reichert JC, Quent VMC, Burke LJ, Stansfield SH, Clements JA, Hutmacher DW. 2010. Mineralized human primary osteoblast matrices as a model system to analyse interactions of prostate cancer cells with the bone microenvironment. Biomaterials 31:317928–36 [Google Scholar]
Riching KM, Cox BL, Salick MR, Pehlke C, Riching AS. et al. 2015. 3D collagen alignment limits protrusions to enhance breast cancer cell persistence. Biophys. J. 107:112546–58 [Google Scholar]
Rijal G, Li W. 2016. 3D scaffolds in breast cancer research. Biomaterials 81:135–56 [Google Scholar]
Roscoe JP, Owsianka AM. 1982. Alginate: a reversible semi-solid medium for investigating cell transformation. Br. J. Cancer 46:6965–69 [Google Scholar]
Rubashkin MG, Cassereau L, Bainer R, DuFort CC, Yui Y. et al. 2014. Force engages vinculin and promotes tumor progression by enhancing PI3K activation of phosphatidylinositol (3,4,5)-triphosphate. Cancer Res 74:174597–611 [Google Scholar]
Ruffell B, Affara NI, Coussens LM. 2012. Differential macrophage programming in the tumor microenvironment. Trends Immunol 33:3119–26 [Google Scholar]
Rybinski B, Franco-Barraza J, Cukierman E. 2014. The wound healing, chronic fibrosis, and cancer progression triad. Physiol. Genom. 46:7223–44 [Google Scholar]
Saha S, Duan X, Wu L, Lo P-K, Chen H, Wang Q. 2012. Electrospun fibrous scaffolds promote breast cancer cell alignment and epithelial–mesenchymal transition. Langmuir 28:42028–34 [Google Scholar]
Sahoo SK, Panda AK, Labhasetwar V. 2005. Characterization of porous PLGA/PLA microparticles as a scaffold for three dimensional growth of breast cancer cells. Biomacromolecules 6:21132–39 [Google Scholar]
Salomon G, Schiffmann J. 2014. Real-time elastography for the detection of prostate cancer. Curr. Urol. Rep. 15:3392 [Google Scholar]
Sanz-Moreno V, Gadea G, Ahn J, Paterson H, Marra P. et al. 2008. Rac activation and inactivation control plasticity of tumor cell movement. Cell 135:3510–23 [Google Scholar]
Schober M, Fuchs E. 2011. Tumor-initiating stem cells of squamous cell carcinomas and their control by TGF-β and integrin/focal adhesion kinase (FAK) signaling. PNAS 108:2610544–49 [Google Scholar]
Schrader J, Gordon-Walker TT, Aucott RL, van Deemter M, Quaas A. et al. 2011. Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology 53:41192–205 [Google Scholar]
Schwartz MA, McRoberts K, Coyner M, Andarawewa KL, Frierson HF. et al. 2008. Integrin agonists as adjuvants in chemotherapy for melanoma. Clin. Cancer Res. 14:196193–97 [Google Scholar]
Seguin L, Kato S, Franovic A, Camargo MF, Lesperance J. et al. 2014. An integrin β₃-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition. Nat. Cell Biol. 16:5457–68 [Google Scholar]
Shi M, He X, Wei W, Wang J, Zhang T, Shen X. 2015. Tenascin-C induces resistance to apoptosis in pancreatic cancer cell through activation of ERK/NF-κB pathway. Apoptosis 20:6843–57 [Google Scholar]
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. 297:2574–84 [Google Scholar]
Soofi SS, Last JA, Liliensiek SJ, Nealey PF, Murphy CJ. 2009. The elastic modulus of Matrigel^TM as determined by atomic force microscopy. J. Struct. Biol. 167:3216–19 [Google Scholar]
Spill F, Reynolds DS, Kamm RD, Zaman MH. 2016. Impact of the physical microenvironment on tumor progression and metastasis. Curr. Opin. Biotechnol. 40:41–48 [Google Scholar]
Stern R, Asari AA, Sugahara KN. 2006. Hyaluronan fragments: an information-rich system. Eur. J. Cell Biol. 85:8699–715 [Google Scholar]
Stylianopoulos T, Martin JD, Chauhan VP, Jain SR, Diop-Frimpong B. et al. 2012. Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors. PNAS 109:3815101–8 [Google Scholar]
Stylianopoulos T, Martin JD, Snuderl M, Mpekris F, Jain SR, Jain RK. 2013. Co-evolution of solid stress and interstitial fluid pressure in tumors during progression: implications for vascular collapse. Cancer Res 73:133833–41 [Google Scholar]
Sun C, Wu MH, Yuan SY. 2011. Nonmuscle myosin light-chain kinase deficiency attenuates atherosclerosis in apolipoprotein E-deficient mice via reduced endothelial barrier dysfunction and monocyte migration. Circulation 124:148–57 [Google Scholar]
Taddei I, Deugnier M-A, Faraldo MM, Petit V, Bouvard D. et al. 2008. β1 integrin deletion from the basal compartment of the mammary epithelium affects stem cells. Nat. Cell Biol. 10:6716–22 [Google Scholar]
Tanentzapf G, Devenport D, Godt D, Brown NH. 2007. Integrin-dependent anchoring of a stem-cell niche. Nat. Cell Biol. 9:121413–18 [Google Scholar]
Tokuda EY, Leight JL, Anseth KS. 2014. Modulation of matrix elasticity with PEG hydrogels to study melanoma drug responsiveness. Biomaterials 35:144310–18 [Google Scholar]
Van Goethem E, Poincloux R, Gauffre F, Maridonneau-Parini I, Le Cabec V. 2010. Matrix architecture dictates three-dimensional migration modes of human macrophages: differential involvement of proteases and podosome-like structures. J. Immunol. 184:21049–61 [Google Scholar]
Velarde MC, Demaria M, Campisi J. 2013. Senescent cells and their secretory phenotype as targets for cancer therapy. Interdiscip. Top. Gerontol. 38:17–27 [Google Scholar]
Venkatesh SK, Yin M, Ehman RL. 2013. Magnetic resonance elastography of liver: technique, analysis, and clinical applications. J. Magn. Reson. Imaging 37:3544–55 [Google Scholar]
Wallace DG, Rosenblatt J. 2003. Collagen gel systems for sustained delivery and tissue engineering. Adv. Drug Deliv. Rev. 55:121631–49 [Google Scholar]
Wang HB, Dembo M, Wang YL. 2000. Substrate flexibility regulates growth and apoptosis of normal but not transformed cells. Am. J. Physiol. Cell Physiol. 279:5C1345–50 [Google Scholar]
Wang L, Shelton RM, Cooper PR, Lawson M, Triffitt JT,. et al. 2003. Evaluation of sodium alginate for bone marrow cell tissue engineering. Biomaterials 24:203475–81 [Google Scholar]
Weathington NM, van Houwelingen AH, Noerager BD, Jackson PL, Kraneveld AD. et al. 2006. A novel peptide CXCR ligand derived from extracellular matrix degradation during airway inflammation. Nat. Med. 12:3317–23 [Google Scholar]
Weaver VM, Lelièvre S, Lakins JN, Chrenek MA, Jones JCR. et al. 2002. β4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium. Cancer Cell 2:3205–16 [Google Scholar]
West ER, Xu M, Woodruff TK, Shea LD. 2007. Physical properties of alginate hydrogels and their effects on in vitro follicle development. Biomaterials 28:30443–48 [Google Scholar]
West JL, Hubbell JA. 1999. Polymeric biomaterials with degradation sites for proteases involved in cell migration. Macromolecules 32:1241–44 [Google Scholar]
White DE, Rayment JH, Muller WJ. 2006. Addressing the role of cell adhesion in tumor cell dormancy. Cell Cycle 5:161756–59 [Google Scholar]
Wieczorek E, Jablonska E, Wasowicz W, Reszka E. 2015. Matrix metalloproteinases and genetic mouse models in cancer research: a mini-review. Tumour Biol. 36:1163–75 [Google Scholar]
Wilson WR, Hay MP. 2011. Targeting hypoxia in cancer therapy. Nat. Rev. Cancer 11:6393–410 [Google Scholar]
Wolf K, Mazo I, Leung H, Engelke K, Von Andrian UH. et al. 2003. Compensation mechanism in tumor cell migration: mesenchymal–amoeboid transition after blocking of pericellular proteolysis. J. Cell Biol. 160:2267–77 [Google Scholar]
Yu X, Machesky LM. 2012. Cells assemble invadopodia-like structures and invade into Matrigel in a matrix metalloprotease dependent manner in the circular invasion assay. PLOS ONE 7:2e30605 [Google Scholar]
Zhao B, Wei X, Li W, Udan RS, Yang Q. et al. 2007. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev 21:2747–61 [Google Scholar]