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Stroma as an Active Player in the Development of the Tumor Microenvironment

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Cancer Microenvironment

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Abstract

The stroma is a considerable part of the tumor microenvironment. Because of its complexity, it can influence both cancer and immune cells in their behavior and cross-talk. Aside from soluble products released by non-cancer and cancer cells, extracellular matrix components have been increasingly recognized as more than just minor players in the constitution, development and regulation of the tumor microenvironment. The variations in the connective scaffold architecture, induced by transforming growth factor beta, lysyl oxidase and metalloproteinase activity, create different conditions of ECM density and stiffness. They exert broad effects on immune cells (e.g. physical barriers, modulation by release of stored TGF-β1), mesenchymal cells (transition to myofibroblasts), epithelial cells (epithelial-to-mesenchymal transition), cancer cells (progression to metastatic phenotype) and stem cells (activation of differentiation addressed by the microenvironment characteristics). Physiological mechanisms of the wound healing process, as well as mechanisms of fibrosis in some chronic pathologies, closely recall aspects of cancer deregulated biology. Their elucidation can provide a better understanding of tumor microenvironment immunobiology. In the following short review, we will focus on some aspects of the fibrous stroma to highlight its active participation in the tumor microenvironment constitution, tumor progression and the local immunological network.

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References

  1. Pietras K, Ostman A (2010) Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res 316:1324–1331

    Article  PubMed  CAS  Google Scholar 

  2. Sautès-Fridman C, Cherfils-Vicini J, Damotte D, Fisson S, Fridman WH, Cremer I, Dieu-Nosjean MC (2011) Tumor microenvironment is multifaceted. Cancer Metastasis Rev 30:13–25

    Article  PubMed  Google Scholar 

  3. Wu Y, Antony S, Meitzler JL, Doroshow JH (2013) Molecular mechanisms underlying chronic inflammation-associated cancers. Cancer Lett 345:164–173

  4. Taipale J, Miyazono K, Heldin CH, Keski-Oja J (1994) Latent transforming growth factor-beta 1 associates to fibroblast extracellular matrix via latent TGF-beta binding protein. J Cell Biol 124:171–181

    Article  PubMed  CAS  Google Scholar 

  5. Unsöld C, Hyytiäinen M, Bruckner-Tuderman L, Keski-Oja J (2001) Latent TGF-beta binding protein LTBP-1 contains three potential extracellular matrix interacting domains. J Cell Sci 114:187–197

    PubMed  Google Scholar 

  6. Valenick LV, Hsia HC, Schwarzbauer JE (2005) Fibronectin fragmentation promotes alpha4beta1 integrin-mediated contraction of a fibrin-fibronectin provisional matrix. Exp Cell Res 309:48–55

    Article  PubMed  CAS  Google Scholar 

  7. Wipff PJ, Hinz B (2008) Integrins and the activation of latent transforming growth factor beta1 - an intimate relationship. Eur J Cell Biol 87:601–615

    Article  PubMed  CAS  Google Scholar 

  8. Monboisse JC, Oudart JB, Ramont L, Brassart-Pasco S, Maquart FX (2014) Matrikines from basement membrane collagens: A new anti-cancer strategy. Biochim Biophys Acta 1840:2589-2598

  9. Egeblad M, Rasch MG, Weaver VM (2010) Dynamic interplay between the collagen scaffold and tumor evolution. Curr Opin Cell Biol 22:697–706

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Friedl P, Bröcker EB, Zänker KS (1998) Integrins, cell matrix interactions and cell migration strategies: fundamental differences in leukocytes and tumor cells. Cell Adhes Commun 6:225–236

    Article  PubMed  CAS  Google Scholar 

  11. Friedl P, Bröcker EB (2000) T cell migration in three-dimensional extracellular matrix: guidance by polarity and sensations. Dev Immunol 7:249–266

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Miles FL, Sikes RA (2014) Insidious changes in stromal matrix fuel cancer progression. Mol Cancer Res 12:297–312

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Peranzoni E, Rivas-Caicedo A, Bougherara H, Salmon H, Donnadieu E (2013) Positive and negative influence of the matrix architecture on antitumor immune surveillance. Cell Mol Life Sci 70:4431–4448

    Article  PubMed  CAS  Google Scholar 

  14. Dvorak HF (1986) Tumors: wounds that do not heal. N Engl J Med 315:1650–1659

    Article  PubMed  CAS  Google Scholar 

  15. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545

    Article  PubMed  CAS  Google Scholar 

  16. Cassetta L, Cassol E, Poli G (2011) Macrophage polarization in health and disease. Sci World J 11:2391–2402

    Article  CAS  Google Scholar 

  17. Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M (2013) Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 229:176–185

    Article  PubMed  CAS  Google Scholar 

  18. Davies LC, Jenkins SJ, Allen JE, Taylor PR (2013) Tissue-resident macrophages. Nat Immunol 14:986–995

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Chambers SE, O’Neill CL, O’Doherty TM, Medina RJ, Stitt AW (2013) The role of immune-related myeloid cells in angiogenesis. Immunobiology 218:1370–1375

    Article  PubMed  CAS  Google Scholar 

  20. Pawelec G (2004) Tumour escape: antitumour effectors too much of a good thing? Cancer Immunol Immunother 53:262–274

    Article  PubMed  CAS  Google Scholar 

  21. Croci DO, Zacarías Fluck MF, Rico MJ, Matar P, Rabinovich GA, Scharovsky OG (2007) Dynamic cross-talk between tumor and immune cells in orchestrating the immunosuppressive network at the tumor microenvironment. Cancer Immunol Immunother 56:1687–1700

    Article  PubMed  Google Scholar 

  22. Weidenbusch M, Anders HJ (2012) Tissue microenvironments define and get reinforced by macrophage phenotypes in homeostasis or during inflammation, repair and fibrosis. J Innate Immun 4:463–477

    Article  PubMed  CAS  Google Scholar 

  23. Mantovani A (2012) MSCs, macrophages, and cancer: a dangerous ménage-à-trois. Cell Stem Cell 11:730–732

    Article  PubMed  CAS  Google Scholar 

  24. Galdiero MR, Garlanda C, Jaillon S, Marone G, Mantovani A (2013) Tumor associated macrophages and neutrophils in tumor progression. J Cell Physiol 228:1404–1412

    Article  PubMed  CAS  Google Scholar 

  25. Li B, Wang JH (2011) Fibroblasts and myofibroblasts in wound healing: force generation and measurement. J Tissue Viability 20:108–120

    Article  PubMed  PubMed Central  Google Scholar 

  26. Polanska UM, Orimo A (2013) Carcinoma-associated fibroblasts: non-neoplastic tumour-promoting mesenchymal cells. J Cell Physiol 228:1651–1657

    Article  PubMed  CAS  Google Scholar 

  27. Byun JS, Gardner K (2013) Wounds that will not heal: pervasive cellular reprogramming in cancer. Am J Pathol 182:1055–1064

    Article  PubMed  PubMed Central  Google Scholar 

  28. Liguori M, Solinas G, Germano G, Mantovani A, Allavena P (2011) Tumor-associated macrophages as incessant builders and destroyers of the cancer stroma. Cancers (Basel) 3:3740–3761

    Article  CAS  Google Scholar 

  29. Umemura N, Saio M, Suwa T, Kitoh Y, Bai J, Nonaka K, Ouyang GF, Okada M, Balazs M, Adany R, Shibata T, Takami T (2008) Tumor-infiltrating myeloid-derived suppressor cells are pleiotropic-inflamed monocytes/macrophages that bear M1- and M2-type characteristics. J Leukoc Biol 83:1136–1144

    Article  PubMed  CAS  Google Scholar 

  30. Carmi Y, Dotan S, Rider P, Kaplanov I, White MR, Baron R, Abutbul S, Huszar M, Dinarello CA, Apte RN, Voronov E (2013) The role of IL-1β in the early tumor cell-induced angiogenic response. J Immunol 190:3500–3509

    Article  PubMed  CAS  Google Scholar 

  31. Garlanda C, Dinarello CA, Mantovani A (2013) The interleukin-1 family: back to the future. Immunity 39:1003–1018

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Rider P, Carmi Y, Voronov E, Apte RN (2013) Interleukin-1α. Semin Immunol 25:430–438

    Article  PubMed  CAS  Google Scholar 

  33. Perrot CY, Javelaud D, Mauviel A (2013) Insights into the Transforming Growth Factor-β Signaling Pathway in Cutaneous Melanoma. Ann Dermatol 25:135–144

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  34. Jakowlew SB (2006) Transforming growth factor-beta in cancer and metastasis. Cancer Metastasis Rev 25:435–457

    Article  PubMed  CAS  Google Scholar 

  35. Petrella BL, Vincenti MP (2012) Interleukin-1β mediates metalloproteinase-dependent renal cell carcinoma tumor cell invasion through the activation of CCAAT enhancer binding protein β. Cancer Med 1:17–27

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Yan C, Boyd DD (2007) Regulation of matrix metalloproteinase gene expression. J Cell Physiol 211:19–26

    Article  PubMed  CAS  Google Scholar 

  37. Oka M, Iwata C, Suzuki HI, Kiyono K, Morishita Y, Watabe T, Komuro A, Kano MR, Miyazono K (2008) Inhibition of endogenous TGF-beta signaling enhances lymphangiogenesis. Blood 111:4571–4579

    Article  PubMed  CAS  Google Scholar 

  38. Wong SF, Lai LC (2001) The role of TGFbeta in human cancers. Pathology 33:85–92

    Article  PubMed  CAS  Google Scholar 

  39. Kubiczkova L, Sedlarikova L, Hajek R, Sevcikova S (2012) TGF-β - an excellent servant but a bad master. J Transl Med 10:183

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Pickup M, Novitskiy S, Moses HL (2013) The roles of TGFβ in the tumour microenvironment. Nat Rev Cancer 13(11):788–799

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  41. Kinashi H, Ito Y, Mizuno M, Suzuki Y, Terabayashi T, Nagura F, Hattori R, Matsukawa Y, Mizuno T, Noda Y, Nishimura H, Nishio R, Maruyama S, Imai E, Matsuo S, Takei Y (2013) TGF-β1 promotes lymphangiogenesis during peritoneal fibrosis. J Am Soc Nephrol 24:1627–1642

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  42. Clavin NW, Avraham T, Fernandez J, Daluvoy SV, Soares MA, Chaudhry A, Mehrara BJ (2008) TGF-beta1 is a negative regulator of lymphatic regeneration during wound repair. Am J Physiol Heart Circ Physiol 295:H2113–H2127

    Article  PubMed  CAS  Google Scholar 

  43. Ji RC (2006) Lymphatic endothelial cells, tumor lymphangiogenesis and metastasis: New insights into intratumoral and peritumoral lymphatics. Cancer Metastasis Rev 25:677–694

    Article  PubMed  Google Scholar 

  44. Liu VC, Wong LY, Jang T, Shah AH, Park I, Yang X, Zhang Q, Lonning S, Teicher BA, Lee C (2007) Tumor evasion of the immune system by converting CD4 + CD25- T cells into CD4 + CD25+ T regulatory cells: role of tumor-derived TGF-beta. J Immunol 178:2883–2892

    Article  PubMed  CAS  Google Scholar 

  45. Burkholder B, Huang RY, Burgess R, Luo S, Jones VS, Zhang W, Lv ZQ, Gao CY, Wang BL, Zhang YM, Huang RP (2014) Tumor-induced perturbations of cytokines and immune cell networks. Biochim Biophys Acta 1845:182–201

  46. Horiguchi M, Ota M, Rifkin DB (2012) Matrix control of transforming growth factor-β function. J Biochem 152:321–329

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  47. Taipale J, Saharinen J, Keski-Oja J (1998) Extracellular matrix-associated transforming growth factor-beta: role in cancer cell growth and invasion. Adv Cancer Res 75:87–134

    Article  PubMed  CAS  Google Scholar 

  48. Shahinian H, Loessner D, Biniossek ML, Kizhakkedathu JN, Clements JA, Magdolen V, Schilling O (2014) Secretome and degradome profiling shows that Kallikrein-related peptidases 4, 5, 6, and 7 induce TGFβ-1 signaling in ovarian cancer cells. Mol Oncol 8:68–82

  49. Xiao Q, Ge G (2012) Lysyl oxidase, extracellular matrix remodeling and cancer metastasis. Cancer Microenviron 5:261–273

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  50. Kim YM, Kim EC, Kim Y (2011) The human lysyl oxidase-like 2 protein functions as an amine oxidase toward collagen and elastin. Mol Biol Rep 38:145–149

    Article  PubMed  CAS  Google Scholar 

  51. Cano A, Santamaría PG, Moreno-Bueno G (2012) LOXL2 in epithelial cell plasticity and tumor progression. Future Oncol 8:1095–1108

    Article  PubMed  CAS  Google Scholar 

  52. Zaffryar-Eilot S, Marshall D, Voloshin T, Bar-Zion A, Spangler R, Kessler O, Ghermazien H, Brekhman V, Suss-Toby E, Adam D, Shaked Y, Smith V, Neufeld G (2013) Lysyl oxidase-like-2 promotes tumour angiogenesis and is a potential therapeutic target in angiogenic tumours. Carcinogenesis 34:2370–2379

    Article  PubMed  CAS  Google Scholar 

  53. Barker HE, Bird D, Lang G, Erler JT (2013) Tumor-secreted LOXL2 activates fibroblasts through FAK signaling. Mol Cancer Res 11:1425–1436

    Article  PubMed  CAS  Google Scholar 

  54. Sion AM, Figg WD (2006) Lysyl oxidase (LOX) and hypoxia-induced metastases. Cancer Biol Ther 5:909–911

    Article  PubMed  CAS  Google Scholar 

  55. Pickup MW, Laklai H, Acerbi I, Owens P, Gorska AE, Chytil A, Aakre M, Weaver VM, Moses HL (2013) Stromally derived lysyl oxidase promotes metastasis of transforming growth factor-β-deficient mouse mammary carcinomas. Cancer Res 73:5336–5346

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  56. Leask A, Hutchenreuther J (2014) Activation of latent TGFβ by α(v)β (1) integrin: of potential importance in myofibroblast activation in fibrosis. J Cell Commun Signal 8:171–172

  57. Wipff PJ, Rifkin DB, Meister JJ, Hinz B (2007) Myofibroblast contraction activates latent TGF-β 1 from the extracellular matrix. J Cell Biol 179:1311–1323

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  58. Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, Fong SF, Csiszar K, Giaccia A, Weninger W, Yamauchi M, Gasser DL, Weaver VM (2009) Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139:891–906

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  59. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA (2002) Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 3:349–363

    Article  PubMed  CAS  Google Scholar 

  60. Calon A, Tauriello DV, Batlle E (2014) TGF-beta in CAF-mediated tumor growth and metastasis. Semin Cancer Biol 25:15–22

  61. Desmoulière A, Chaponnier C, Gabbiani G (2005) Tissue repair, contraction, and the myofibroblast. Wound Repair Regen 13:7–12

    Article  PubMed  Google Scholar 

  62. Montesano R, Orci L (1988) Transforming growth factor beta stimulates collagen-matrix contraction by fibroblasts: implications for wound healing. Proc Natl Acad Sci U S A 85:4894–4897

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  63. Buscemi L, Ramonet D, Klingberg F, Formey A, Smith-Clerc J, Meister JJ, Hinz B (2011) The single-molecule mechanics of the latent TGF-β1 complex. Curr Biol 21:2046–2054

    Article  PubMed  CAS  Google Scholar 

  64. Scharenberg MA, Pippenger BE, Sack R, Zingg D, Ferralli J, Schenk S, Martin I, Chiquet-Ehrismann R (2014) TGF-β-induced differentiation into myofibroblasts involves specific regulation of two MKL1 isoforms. J Cell Sci 127:1079–1091

  65. Vi L, de Lasa C, DiGuglielmo GM, Dagnino L (2011) Integrin-linked kinase is required for TGF-β1 induction of dermal myofibroblast differentiation. J Investig Dermatol 131:586–593

    Article  PubMed  CAS  Google Scholar 

  66. Huang X, Yang N, Fiore VF, Barker TH, Sun Y, Morris SW, Ding Q, Thannickal VJ, Zhou Y (2012) Matrix stiffness-induced myofibroblast differentiation is mediated by intrinsic mechanotransduction. Am J Respir Cell Mol Biol 47:340–348

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  67. Driskell RR, Lichtenberger BM, Hoste E, Kretzschmar K, Simons BD, Charalambous M, Ferron SR, Herault Y, Pavlovic G, Ferguson-Smith AC, Watt FM (2013) Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature 504:277–281

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  68. Baglole CJ, Ray DM, Bernstein SH, Feldon SE, Smith TJ, Sime PJ, Phipps RP (2006) More than structural cells, fibroblasts create and orchestrate the tumor microenvironment. Immunol Investig 35:297–325

    Article  CAS  Google Scholar 

  69. Chien AJ, Conrad WH, Moon RT (2009) A Wnt survival guide: from flies to human disease. J Investig Dermatol 129:1614–1627

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  70. Clevers H, Nusse R (2012) Wnt/β-catenin signaling and disease. Cell 149:1192–1205

    Article  PubMed  CAS  Google Scholar 

  71. Chen D, Jarrell A, Guo C, Lang R, Atit R (2012) Dermal β-catenin activity in response to epidermal Wnt ligands is required for fibroblast proliferation and hair follicle initiation. Development 139:1522–1533

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  72. O’Reilly S (2014) Innate immunity in systemic sclerosis pathogenesis. Clin Sci (Lond) 126:329–337

    Article  Google Scholar 

  73. Wei J, Fang F, Lam AP, Sargent JL, Hamburg E, Hinchcliff ME, Gottardi CJ, Atit R, Whitfield ML, Varga J (2012) Wnt/β-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells. Arthritis Rheum 64:2734–2745

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  74. Beyer C, Schramm A, Akhmetshina A, Dees C, Kireva T, Gelse K, Sonnylal S, de Crombrugghe B, Taketo MM, Distler O, Schett G, Distler JH (2012) β-catenin is a central mediator of pro-fibrotic Wnt signaling in systemic sclerosis. Ann Rheum Dis 71:761–767

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  75. Clevers H, Nusse R (2012) Wnt/beta-catenin signaling and disease. Cell 149:1192–1205

    Article  PubMed  CAS  Google Scholar 

  76. Kato S, Hayakawa Y, Sakurai H, Saiki I, Yokoyama S (2014) Mesenchymal-transitioned cancer cells instigate the invasion of epithelial cancer cells through secretion of WNT3 and WNT5B. Cancer Sci 105:281–289

  77. Díaz Prado SM, Medina Villaamil V, Aparicio Gallego G, Blanco Calvo M, López Cedrún JL, Sironvalle Soliva S, Valladares Ayerbes M, García Campelo R, Antón Aparicio LM (2009) Expression of Wnt gene family and frizzled receptors in head and neck squamous cell carcinomas. Virchows Arch 455:67–75

    Article  PubMed  Google Scholar 

  78. Qurrat-Ul-Ain, Seemab U, Nawaz S, Rashid S (2011) Integrative analyses of conserved WNT clusters and their co-operative behaviour in human breast cancer. Bioinformation 7:339–46

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  79. Wend P, Runke S, Wend K, Anchondo B, Yesayan M, Jardon M, Hardie N, Loddenkemper C, Ulasov I, Lesniak MS, Wolsky R, Bentolila LA, Grant SG, Elashoff D, Lehr S, Latimer JJ, Bose S, Sattar H, Krum SA, Miranda-Carboni GA (2013) WNT10B/β-catenin signalling induces HMGA2 and proliferation in metastatic triple-negative breast cancer. EMBO Mol Med 5:264–279

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  80. Bochet L, Lehuédé C, Dauvillier S, Wang YY, Dirat B, Laurent V, Dray C, Guiet R, Maridonneau-Parini I, Le Gonidec S, Couderc B, Escourrou G, Valet P, Muller C (2013) Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer. Cancer Res 73:5657–5668

    Article  PubMed  CAS  Google Scholar 

  81. Kakudo N, Kushida S, Suzuki K, Ogura T, Notodihardjo PV, Hara T, Kusumoto K (2012) Effects of transforming growth factor-beta1 on cell motility, collagen gel contraction, myofibroblastic differentiation, and extracellular matrix expression of human adipose-derived stem cell. Hum Cell 25:87–95

    Article  PubMed  CAS  Google Scholar 

  82. Baarsma HA, Spanjer AI, Haitsma G, Engelbertink LH, Meurs H, Jonker MR, Timens W, Postma DS, Kerstjens HA, Gosens R (2011) Activation of WNT/β-catenin signaling in pulmonary fibroblasts by TGF-β1 is increased in chronic obstructive pulmonary disease. PLoS One 6:e25450

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  83. van Dekken H, Wink JC, Vissers KJ, Franken PF (2007) Ruud Schouten W, J Hop WC, Kuipers EJ, Fodde R, Janneke van der Woude C. Wnt pathway-related gene expression during malignant progression in ulcerative colitis. Acta Histochem 109:266–272

    Article  PubMed  Google Scholar 

  84. Rieder F, Kessler SP, West GA, Bhilocha S, de la Motte C, Sadler TM, Gopalan B, Stylianou E, Fiocchi C (2011) Inflammation-induced endothelial-to-mesenchymal transition: a novel mechanism of intestinal fibrosis. Am J Pathol 179:2660–2673

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  85. Blaauboer ME, Emson CL, Verschuren L, van Erk M, Turner SM, Everts V, Hanemaaijer R, Stoop R (2013) Novel combination of collagen dynamics analysis and transcriptional profiling reveals fibrosis-relevant genes and pathways. Matrix Biol 32:424–431

    Article  PubMed  CAS  Google Scholar 

  86. Shih YR, Tseng KF, Lai HY, Lin CH, Lee OK (2011) Matrix stiffness regulation of integrin-mediated mechanotransduction during osteogenic differentiation of human mesenchymal stem cells. J Bone Miner Res 26:730–738

    Article  PubMed  CAS  Google Scholar 

  87. Lui C, Lee K, Nelson CM (2012) Matrix compliance and RhoA direct the differentiation of mammary progenitor cells. Biomech Model Mechanobiol 11:1241–1297

    Article  PubMed  PubMed Central  Google Scholar 

  88. Calvo F, Ege N, Grande-Garcia A, Hooper S, Jenkins RP, Chaudhry SI, Harrington K, Williamson P, Moeendarbary E, Charras G, Sahai E (2013) Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat Cell Biol 15:637–646

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The author thanks the support of IAA500200917; CZ.1.05/2.1.00/03.0124 (Project ExAM); Anna Villa and Felice Rusconi Foundation, Varese (IT); UniCredit Bank, Prague (CZ); Manghi Group s.r.o., Prague (CZ); ARPA Foundation, Pisa (IT); RVO 61388971 and RVO 67985904 (CZ).

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Vannucci, L. Stroma as an Active Player in the Development of the Tumor Microenvironment. Cancer Microenvironment 8, 159–166 (2015). https://doi.org/10.1007/s12307-014-0150-x

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