The fibrotic tumor stroma

Journal of Clinical Investigation

Volumn 128, Issue 1, 2018, Pages 16-25

  Yamauchi, Mitsuo ^a   Barker, Thomas H ^b   Gibbons, Don L ^c,d   Kurie, Jonathan M ^c,d  

^a UNIVERSITY OF NORTH CAROLINA   (United States)

^b University of Virginia   (United States)

^c Neck Medical Oncology ^*  (United States)

^d UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

COLLAGEN; FIBRONECTIN;

CANCER ASSOCIATED FIBROBLAST; CANCER MORTALITY; CARCINOGENESIS; CROSS LINKING; EXTRACELLULAR MATRIX; FIBROSIS; FIBROTIC TUMOR STROMA; HUMAN; IMMUNOSURVEILLANCE; MACROPHAGE ACTIVATION; MALIGNANT NEOPLASM; METASTASIS; MYELOID-DERIVED SUPPRESSOR CELL; NONHUMAN; PRIORITY JOURNAL; PROTEIN DEGRADATION; REVIEW; STROMA; TUMOR CELL; TUMOR MICROENVIRONMENT; ANIMAL; FIBROBLAST; IMMUNOLOGY; NEOPLASM; PATHOLOGY;

ANIMALS; EXTRACELLULAR MATRIX; FIBROBLASTS; FIBROSIS; HUMANS; NEOPLASM METASTASIS; NEOPLASMS;

EID: 85040170499     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI93554     Document Type: Review

References (185)

1. Brücher BL, Jamall IS. Epistemology of the origin of cancer: a new paradigm. BMC Cancer. 2014;14:331.
2. Guerra L, Odorisio T, Zambruno G, Castiglia D. Stromal microenvironment in type VII collagen-deficient skin: the ground for squamous cell carcinoma development. Matrix Biol. 2017;63:1–10.
3. Karampitsakos T, et al. Lung cancer in patients with idiopathic pulmonary fibrosis. Pulm Pharmacol Ther. 2017;45:1–10.
4. Neesse A, Algül H, Tuveson DA, Gress TM. Stromal biology and therapy in pancreatic cancer: a changing paradigm. Gut. 2015;64(9):1476–1484.
5. Laklai H, et al. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matri-cellular fibrosis and tumor progression. Nat Med. 2016;22(5):497–505.
6. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986;315(26):1650–1659.
7. Clark RA, Lanigan JM, DellaPelle P, Manseau E, Dvorak HF, Colvin RB. Fibronectin and fibrin provide a provisional matrix for epidermal cell migration during wound reepithelialization. J Invest Dermatol. 1982;79(5):264–269.
8. Barker TH, Engler AJ. The provisional matrix: setting the stage for tissue repair outcomes. Matrix Biol. 2017;60-61:1–4.
9. Comoglio PM, Trusolino L. Cancer: the matrix is now in control. Nat Med. 2005;11(11):1156–1159.
10. Brown AC, Fiore VF, Sulchek TA, Barker TH. Physical and chemical microenvironmental cues orthogonally control the degree and duration of fibrosis-associated epithelial-to-mesenchymal transitions. JPathol. 2013;229(1):25–35.
11. Piera-Velazquez S, Li Z, Jimenez SA. Role of endothelial-mesenchymal transition (EndoMT) in the pathogenesis of fibrotic disorders. Am J Pathol. 2011;179(3):1074–1080.
12. Naba A, Clauser KR, Ding H, Whittaker CA, Carr SA, Hynes RO. The extracellular matrix: tools and insights for the “omics” era. Matrix Biol. 2016;49:10–24.
13. Iacoviello L, et al. Type 1 plasminogen activator inhibitor as a common risk factor for cancer and ischaemic vascular disease: the EPICOR study. BMJ Open. 2013;3(11):e003725.
14. Eitzman DT, et al. Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J Clin Invest. 1996;97(1):232–237.
15. de Giorgio-Miller A, Bottoms S, Laurent G, Car-meliet P, Herrick S. Fibrin-induced skin fibrosis in mice deficient in tissue plasminogen activator. Am J Pathol. 2005;167(3):721–732.
16. Loskutoff DJ, Quigley JP. PAI-1, fibrosis, and the elusive provisional fibrin matrix. J Clin Invest. 2000;106(12):1441–1443.
17. Lluís F, et al. Urokinase-dependent plasminogen activation is required for efficient skeletal muscle regeneration in vivo. Blood. 2001;97(6):1703–1711.
18. Suelves M, et al. The plasminogen activation system in skeletal muscle regeneration: antagonistic roles of urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1). Front Biosci. 2005;10:2978–2985.
19. Peyrol S, Cordier JF, Grimaud JA. Intra-alveolar fibrosis of idiopathic bronchiolitis obliterans-organizing pneumonia. Cell-matrix patterns. Am J Pathol. 1990;137(1):155–170.
20. Chen LB, Buchanan JM. Mitogenic activity of blood components. I. Thrombin and prothrom-bin. Proc Natl Acad Sci U S A. 1975;72(1):131–135.
21. Chambers RC, Dabbagh K, McAnulty RJ, Gray AJ, Blanc-Brude OP, Laurent GJ. Thrombin stimulates fibroblast procollagen production via proteolytic activation of protease-activated receptor 1. Biochem J. 1998;333(pt 1):121–127.
22. Bogatkevich GS, Tourkina E, Silver RM, Ludwicka-Bradley A. Thrombin differentiates normal lung fibroblasts to a myofibroblast phenotype via the proteolytically activated receptor-1 and a protein kinase C-dependent pathway. JBiolChem. 2001;276(48):45184–45192.
23. Vidal B, et al. Fibrinogen drives dystrophic muscle fibrosis via a TGFβ/alternative macrophage activation pathway. Genes Dev. 2008;22(13):1747–1752.
24. Wynn TA. Cellular and molecular mechanisms of fibrosis. JPathol. 2008;214(2):199–210.
25. Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol. 2004;4(8):583–594.
26. Pankov R, Yamada KM. Fibronectin at a glance. JCellSci. 2002;115(pt 20):3861–3863.
27. Amatangelo MD, Bassi DE, Klein-Szanto AJ, Cukierman E. Stroma-derived three-dimensional matrices are necessary and sufficient to promote desmoplastic differentiation of normal fibroblasts. Am J Pathol. 2005;167(2):475–488.
28. Martino MM, Hubbell JA. The 12th-14th type III repeats of fibronectin function as a highly promiscuous growth factor-binding domain. FASEB J. 2010;24(12):4711–4721.
29. Miyamoto S, Teramoto H, Gutkind JS, Yamada KM. Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors. JCellBiol. 1996;135(6 pt 1):1633–1642.
30. Clark RA. Synergistic signaling from extracellular matrix-growth factor complexes. J Invest Dermatol. 2008;128(6):1354–1355.
31. Morgan MR, Humphries MJ, Bass MD. Synergistic control of cell adhesion by integrins and syndecans. Nat Rev Mol Cell Biol. 2007;8(12):957–969.
32. Wipff PJ, Rifkin DB, Meister JJ, Hinz B. Myo-fibroblast contraction activates latent TGF-β1 from the extracellular matrix. J Cell Biol. 2007;179(6):1311–1323.
33. Hinz B. The extracellular matrix and transforming growth factor-β1: tale of a strained relationship. Matrix Biol. 2015;47:54–65.
34. Cao L, et al. Detection of an integrin-binding mechanoswitch within fibronectin during tissue formation and fibrosis. ACSNano. 2017;11(7):7110–7117.
35. Markowski MC, Brown AC, Barker TH. Directing epithelial to mesenchymal transition through engineered microenvironments displaying orthogonal adhesive and mechanical cues. J Biomed Mater Res A. 2012;100(8):2119–2127.
36. Huang X, et al. Matrix stiffness-induced myofibroblast differentiation is mediated by intrinsic mechanotransduction. Am J Respir Cell Mol Biol. 2012;47(3):340–348.
37. Liu F, et al. Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression. JCellBiol. 2010;190(4):693–706.
38. Paszek MJ, et al. Tensional homeostasis and the malignant phenotype. Cancer Cell. 2005;8(3):241–254.
39. Sahai E, Marshall CJ. Differing modes of tumour cell invasion have distinct requirements for Rho/ ROCK signalling and extracellular proteolysis. Nat Cell Biol. 2003;5(8):711–719.
40. Goetz JG, et al. Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell. 2011;146(1):148–163.
41. Li S, et al. Hydrogels with precisely controlled integrin activation dictate vascular patterning and permeability. Nat Mater. 2017;16(9):953–961.
42. Hinz B. Matrix mechanics and regulation of the fibroblast phenotype. Periodontol2000. 2013;63(1):14–28.
43. Sottile J, Hocking DC. Fibronectin polymerization regulates the composition and stability of extracellular matrix fibrils and cell-matrix adhesions. MolBiolCell. 2002;13(10):3546–3559.
44. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19(11):1423–1437.
45. Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21(3):309–322.
46. Pietras K, Ostman A. Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res. 2010;316(8):1324–1331.
47. Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16(9):582–598.
48. Chang HY, et al. Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc Natl Acad Sci U S A. 2002;99(20):12877–12882.
49. Hematti P. Mesenchymal stromal cells and fibroblasts: a case of mistaken identity? Cytotherapy. 2012;14(5):516–521.
50. Micallef L, Vedrenne N, Billet F, Coulomb B, Darby IA, Desmoulière A. The myofibroblast, multiple origins for major roles in normal and pathological tissue repair. Fibrogenesis Tissue Repair. 2012;5(suppl 1):S5.
51. Rønnov-Jessen L, Petersen OW. Induction of alpha-smooth muscle actin by transforming growth factor-beta 1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia. LabInvest. 1993;68(6):696–707.
52. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002;3(5):349–363.
53. Rodemann HP, Müller GA. Characterization of human renal fibroblasts in health and disease: II. In vitro growth, differentiation, and collagen synthesis of fibroblasts from kidneys with interstitial fibrosis. Am J Kidney Dis. 1991;17(6):684–686.
54. Simian M, Hirai Y, Navre M, Werb Z, Lochter A, Bissell MJ. The interplay of matrix metalloproteinases, morphogens and growth factors is necessary for branching of mammary epithelial cells. Development. 2001;128(16):3117–3131.
55. Öhlund D, et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017;214(3):579–596.
56. Vaheri A, Enzerink A, Räsänen K, Salmenperä P. Nemosis, a novel way of fibroblast activation, in inflammation and cancer. Exp Cell Res. 2009;315(10):1633–1638.
57. Mishra DK, et al. Human lung fibroblasts inhibit non-small cell lung cancer metastasis in ex vivo 4D model. Ann Thorac Surg. 2015;100(4):1167–1174; discussion 1174.
58. David CJ, et al. TGF-β tumor suppression through a lethal EMT. Cell. 2016;164(5):1015–1030.
59. Li CX, et al. MicroRNA-21 preserves the fibrotic mechanical memory of mesenchymal stem cells. Nat Mater. 2017;16(3):379–389.
60. Liu F, et al. Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. Am J Physiol Lung Cell Mol Physiol. 2015;308(4):L344–L357.
61. Pankova D, et al. Cancer-associated fibroblasts induce a collagen cross-link switch in tumor stroma. Mol Cancer Res. 2016;14(3):287–295.
62. Franco-Barraza J, et al. Matrix-regulated integrin αvβ5 maintains α5β1-dependent desmoplastic traits prognostic of neoplastic recurrence. Elife. 2017;6:e20600.
63. Lafyatis R. Transforming growth factor β — at the centre of systemic sclerosis. Nat Rev Rheumatol. 2014;10(12):706–719.
64. Alameddine HS, Morgan JE. Matrix metalloproteinases and tissue inhibitor of metalloproteinases in inflammation and fibrosis of skeletal muscles. JNeuromusculDis. 2016;3(4):455–473.
65. Yamauchi M, Sricholpech M. Lysine posttranslational modifications of collagen. Essays Biochem. 2012;52:113–133.
66. Myllyharju J, Kivirikko KI. Collagens, modifying enzymes and their mutations in humans, flies and worms. Trends Genet. 2004;20(1):33–43.
67. Bella J, Hulmes DJ. Fibrillar collagens. Subcell Biochem. 2017;82:457–490.
68. Valtavaara M, Papponen H, Pirttilä AM, Hiltunen K, Helander H, Myllylä R. Cloning and characterization of a novel human lysyl hydroxylase isoform highly expressed in pancreas and muscle. JBiolChem. 1997;272(11):6831–6834.
69. Valtavaara M, Szpirer C, Szpirer J, Myllylä R. Primary structure, tissue distribution, and chromosomal localization of a novel isoform of lysyl hydroxylase (lysyl hydroxylase 3). JBiolChem. 1998;273(21):12881–12886.
70. Kivirikko KI, Myllylä R, Pihlajaniemi T. Protein hydroxylation: prolyl 4-hydroxylase, an enzyme with four cosubstrates and a multifunctional subunit. FASEB J. 1989;3(5):1609–1617.
71. Schegg B, Hülsmeier AJ, Rutschmann C, Maag C, Hennet T. Core glycosylation of collagen is initiated by two β(1-O)galactosyltransferases. Mol CellBiol. 2009;29(4):943–952.
72. Sricholpech M, Perdivara I, Nagaoka H, Yokoya-ma M, Tomer KB, Yamauchi M. Lysyl hydroxylase 3 glucosylates galactosylhydroxylysine residues in type I collagen in osteoblast culture. JBiolChem. 2011;286(11):8846–8856.
73. Sricholpech M, et al. Lysyl hydroxylase 3-mediated glucosylation in type I collagen: molecular loci and biological significance. J Biol Chem. 2012;287(27):22998–23009.
74. Terajima M, et al. Glycosylation and crosslinking in bone type I collagen. JBiolChem. 2014;289(33):22636–22647.
75. Terajima M, et al. Cyclophilin-B modulates collagen cross-linking by differentially affecting lysine hydroxylation in the helical and telopeptidyl domains of tendon type I collagen. J Biol Chem. 2016;291(18):9501–9512.
76. Ishikawa Y, Boudko S, Bächinger HP. Ziploc-ing the structure: triple helix formation is coordinated by rough endoplasmic reticulum resident PPIases. Biochim Biophys Acta. 2015;1850(10):1983–1993.
77. Cabral WA, et al. Abnormal type I collagen post-translational modification and crosslinking in a cyclophilin B KO mouse model of recessive osteogenesis imperfecta. PLoSGenet. 2014;10(6):e1004465.
78. Heard ME, et al. Sc65-null mice provide evidence for a novel endoplasmic reticulum complex regulating collagen lysyl hydroxylation. PLoSGenet. 2016;12(4):e1006002.
79. Gjaltema RA, van der Stoel MM, Boersema M, Bank RA. Disentangling mechanisms involved in collagen pyridinoline cross-linking: the immu-nophilin FKBP65 is critical for dimerization of lysyl hydroxylase 2. Proc Natl Acad Sci U S A. 2016;113(26):7142–7147.
80. Chen Y, et al. FKBP65-dependent peptidyl-prolyl isomerase activity potentiates the lysyl hydroxylase 2-driven collagen cross-link switch. SciRep. 2017;7:46021.
81. Gjaltema RA, Bank RA. Molecular insights into prolyl and lysyl hydroxylation of fibrillar collagens in health and disease. Crit Rev Biochem Mol Biol. 2017;52(1):74–95.
82. Duran I, et al. A chaperone complex formed by HSP47, FKBP65, and BiP modulates telopeptide lysyl hydroxylation of type I procollagen. J Bone Miner Res. 2017;32(6):1309–1319.
83. Eyre DR, Weis MA. Bone collagen: new clues to its mineralization mechanism from recessive osteogenesis imperfecta. CalcifTissueInt. 2013;93(4):338–347.
84. Kang H, Aryal ACS, Marini JC. Osteogenesis imperfecta: new genes reveal novel mechanisms in bone dysplasia. TranslRes. 2017;181:27–48.
85. Csiszar K. Lysyl oxidases: a novel multifunctional amine oxidase family. Prog Nucleic Acid Res Mol Biol. 2001;70:1–32.
86. Kagan HM, Li W. Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. JCellBiochem. 2003;88(4):660–672.
87. Trackman PC. Enzymatic and non-enzymatic functions of the lysyl oxidase family in bone. Matrix Biol. 2016;52-54:7–18.
88. Yamauchi M, Mechanic GL. Cross-linking of collagen. In: Nimni ME, ed. Collagen. Boca Raton, Florida, USA: CRC Press; 1988:157–172.
89. Yamauchi M, Chandler GS, Tanzawa H, Katz EP. Cross-linking and the molecular packing of corneal collagen. Biochem Biophys Res Commun. 1996;219(2):311–315.
90. Tanzer ML, Housley T, Berube L, Fairweather R, Franzblau C, Gallop PM. Structure of two histidine-containing crosslinks from collagen. JBiolChem. 1973;248(2):393–402.
91. Bernstein PH, Mechanic GL. A natural histidine-based imminium cross-link in collagen and its location. J Biol Chem. 1980;255(21):10414–10422.
92. Bailey AJ, Paul RG, Knott L. Mechanisms of maturation and ageing of collagen. MechAgeing Dev. 1998;106(1-2):1–56.
93. Kirschmann DA, Seftor EA, Nieva DR, Mariano EA, Hendrix MJ. Differentially expressed genes associated with the metastatic phenotype in breast cancer. Breast Cancer Res Treat. 1999;55(2):127–136.
94. Akiri G, et al. Lysyl oxidase-related protein-1 promotes tumor fibrosis and tumor progression in vivo. Cancer Res. 2003;63(7):1657–1666.
95. Barry-Hamilton V, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med. 2010;16(9):1009–1017.
96. Cox TR, et al. LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cancer Res. 2013;73(6):1721–1732.
97. Barker HE, Cox TR, Erler JT. The rationale for targeting the LOX family in cancer. Nat Rev Cancer. 2012;12(8):540–552.
98. Park JS, Lee JH, Lee YS, Kim JK, Dong SM, Yoon DS. Emerging role of LOXL2 in the promotion of pancreas cancer metastasis. Oncotarget. 2016;7(27):42539–42552.
99. Martin A, et al. Lysyl oxidase-like 2 represses Notch1 expression in the skin to promote squamous cell carcinoma progression. EMBO J. 2015;34(8):1090–1109.
100. Wong CC, et al. Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proc Natl Acad Sci U S A. 2011;108(39):16369–16374.
101. Levental KR, et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 2009;139(5):891–906.
102. Brinckmann J, et al. Different pattern of collagen cross-links in two sclerotic skin diseases: lipoder-matosclerosis and circumscribed scleroderma. JInvestDermatol. 2001;117(2):269–273.
103. Uzawa K, Marshall MK, Katz EP, Tanzawa H, Yeowell HN, Yamauchi M. Altered posttranslational modifications of collagen in keloid. Biochem Biophys Res Commun. 1998;249(3):652–655.
104. Last JA, King TE, Nerlich AG, Reiser KM. Collagen cross-linking in adult patients with acute and chronic fibrotic lung disease. Molecular markers for fibrotic collagen. Am Rev Respir Dis. 1990;141(2):307–313.
105. Gerriets JE, Reiser KM, Last JA. Lung collagen cross-links in rats with experimentally induced pulmonary fibrosis. Biochim Biophys Acta. 1996;1316(2):121–131.
106. Ricard-Blum S, Liance M, Houin R, Grimaud JA, Vuitton DA. Covalent cross-linking of liver collagen by pyridinoline increases in the course of experimental alveolar echinococcosis. Parasite. 1995;2(2):113–118.
107. Brenner DA, et al. New aspects of hepatic fibrosis. JHepatol. 2000;32(1 Suppl):32–38.
108. Perepelyuk M, et al. Hepatic stellate cells and portal fibroblasts are the major cellular sources of collagens and lysyl oxidases in normal liver and early after injury. Am J Physiol Gastrointest Liver Physiol. 2013;304(6):G605–G614.
109. van der Slot AJ, et al. Identification of PLOD2 as telopeptide lysyl hydroxylase, an important enzyme in fibrosis. JBiolChem. 2003;278(42):40967–40972.
110. van der Slot AJ, et al. Increased formation of pyridinoline cross-links due to higher telopeptide lysyl hydroxylase levels is a general fibrotic phenomenon. Matrix Biol. 2004;23(4):251–257.
111. Xu Y, et al. Procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 promotes hypoxia-induced glioma migration and invasion. Oncotarget. 2017;8(14):23401–23413.
112. Gilkes DM, et al. Procollagen lysyl hydroxylase 2 is essential for hypoxia-induced breast cancer metastasis. Mol Cancer Res. 2013;11(5):456–466.
113. Eisinger-Mathason TS, et al. Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis. Cancer Discov. 2013;3(10):1190–1205.
114. Noda T, et al. PLOD2 induced under hypoxia is a novel prognostic factor for hepatocellular carcinoma after curative resection. Liver Int. 2012;32(1):110–118.
115. Chen Y, et al. Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma. J Clin Invest. 2015;125(3):1147–1162.
116. Sada M, et al. Hypoxic stellate cells of pancreatic cancer stroma regulate extracellular matrix fiber organization and cancer cell motility. Cancer Lett. 2016;372(2):210–218.
117. Wang M, et al. HIF-1α promoted vasculogenic mimicry formation in hepatocellular carcinoma through LOXL2 up-regulation in hypoxic tumor microenvironment. J Exp Clin Cancer Res. 2017;36(1):60.
118. Kasashima H, et al. Lysyl oxidase is associated with the epithelial-mesenchymal transition of gastric cancer cells in hypoxia. Gastric Cancer. 2016;19(2):431–442.
119. Miller BW, et al. Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy. EMBO Mol Med. 2015;7(8):1063–1076.
120. Ji F, et al. Hypoxia inducible factor 1α-mediated LOX expression correlates with migration and invasion in epithelial ovarian cancer. Int J Oncol. 2013;42(5):1578–1588.
121. Erler JT, et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell. 2009;15(1):35–44.
122. Chang J, Erler J. Hypoxia-mediated metastasis. AdvExpMedBiol. 2014;772:55–81.
123. Conklin MW, et al. Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am J Pathol. 2011;178(3):1221–1232.
124. Myllylä R, et al. Expanding the lysyl hydroxylase toolbox: new insights into the localization and activities of lysyl hydroxylase 3 (LH3). JCell Physiol. 2007;212(2):323–329.
125. Gascard P, Tlsty TD. Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev. 2016;30(9):1002–1019.
126. Chen Y, et al. Lysyl hydroxylase 2 is secreted by tumor cells and can modify collagen in the extracellular space. J Biol Chem. 2016;291(50):25799–25808.
127. Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161(2):205–214.
128. Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol. 2014;14(3):141–153.
129. Nowarski R, Jackson R, Flavell RA. The stromal intervention: regulation of immunity and inflammation at the epithelial-mesenchymal barrier. Cell. 2017;168(3):362–375.
130. Hallmann R, et al. The regulation of immune cell trafficking by the extracellular matrix. Curr Opin Cell Biol. 2015;36:54–61.
131. Mouw JK, Ou G, Weaver VM. Extracellular matrix assembly: a multiscale deconstruction. Nat Rev Mol Cell Biol. 2014;15(12):771–785.
132. Lämmermann T, et al. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature. 2008;453(7191):51–55.
133. Wolf K, Müller R, Borgmann S, Bröcker EB, Friedl P. Amoeboid shape change and contact guidance: T-lymphocyte crawling through fibrillar collagen is independent of matrix remodeling by MMPs and other proteases. Blood. 2003;102(9):3262–3269.
134. Bruckner P. Suprastructures of extracellular matrices: paradigms of functions controlled by aggregates rather than molecules. CellTissueRes. 2010;339(1):7–18.
135. Riopel MM, Li J, Liu S, Leask A, Wang R. β1 Integrin-extracellular matrix interactions are essential for maintaining exocrine pancreas architecture and function. LabInvest. 2013;93(1):31–40.
136. Wu C, et al. Endothelial basement membrane laminin alpha5 selectively inhibits T lymphocyte extravasation into the brain. NatMed. 2009;15(5):519–527.
137. Kenne E, Soehnlein O, Genové G, Rotzius P, Eriksson EE, Lindbom L. Immune cell recruitment to inflammatory loci is impaired in mice deficient in basement membrane protein laminin alpha4. J Leukoc Biol. 2010;88(3):523–528.
138. Alexander J, Cukierman E. Stromal dynamic reciprocity in cancer: intricacies of fibroblastic-ECM interactions. Curr Opin Cell Biol. 2016;42:80–93.
139. Costea DE, et al. Identification of two distinct carcinoma-associated fibroblast subtypes with differential tumor-promoting abilities in oral squamous cell carcinoma. Cancer Res. 2013;73(13):3888–3901.
140. De Boeck A, et al. Differential secretome analysis of cancer-associated fibroblasts and bone marrow-derived precursors to identify microenvironmental regulators of colon cancer progression. Proteomics. 2013;13(2):379–388.
141. Lotti F, et al. Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J Exp Med. 2013;210(13):2851–2872.
142. Erez N, Truitt M, Olson P, Arron ST, Hanahan D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-κB-dependent manner. Cancer Cell. 2010;17(2):135–147.
143. Feig C, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013;110(50):20212–20217.
144. + T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology. 2013;145(5):1121–1132.
145. Chang CH, et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell. 2015;162(6):1229–1241.
146. Su X, Ye J, Hsueh EC, Zhang Y, Hoft DF, Peng G. Tumor microenvironments direct the recruitment and expansion of human Th17 cells. J Immunol. 2010;184(3):1630–1641.
147. Barnas JL, Simpson-Abelson MR, Brooks SP, Kelleher RJ, Bankert RB. Reciprocal functional modulation of the activation of T lymphocytes and fibroblasts derived from human solid tumors. JImmunol. 2010;185(5):2681–2692.
148. + regulatory T cells by TGF-β induction of transcription factor Foxp3. JExpMed. 2003;198(12):1875–1886.
149. De Monte L, et al. Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer. JExp Med. 2011;208(3):469–478.
150. Schaefer L. Complexity of danger: the diverse nature of damage-associated molecular patterns. JBiolChem. 2014;289(51):35237–35245.
151. Schaefer L, Tredup C, Gubbiotti MA, Iozzo RV. Proteoglycan neofunctions: regulation of inflammation and autophagy in cancer biology. FEBS J. 2017;284(1):10–26.
152. Salmon H, et al. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. JClin Invest. 2012;122(3):899–910.
153. Hartmann N, et al. Prevailing role of contact guidance in intrastromal T-cell trapping in human pancreatic cancer. Clin Cancer Res. 2014;20(13):3422–3433.
154. Wolf K, et al. Physical limits of cell migration: control by ECM space and nuclear deformation and tuning by proteolysis and traction force. JCell Biol. 2013;201(7):1069–1084.
155. Carstens JL, et al. Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer. Nat Commun. 2017;8:15095.
156. Smigiel KS, Parks WC. Matrix metalloproteinases and leukocyte activation. ProgMolBiolTranslSci. 2017;147:167–195.
157. Liu YM, Nepali K, Liou JP. Idiopathic pulmonary fibrosis: current status, recent progress, and emerging targets. JMedChem. 2017;60(2):527–553.
158. Di Sario A, et al. Effect of pirfenidone on rat hepatic stellate cell proliferation and collagen production. JHepatol. 2002;37(5):584–591.
159. Hewitson TD, et al. Pirfenidone reduces in vitro rat renal fibroblast activation and mitogenesis. J Nephrol. 2001;14(6):453–460.
160. Ozes ON, Blatt LM. Development of a high throughput collagen assay using a cellular model of idiopathic pulmonary fibrosis. Chest. 2006;130:230S.
161. Grattendick KJ, Nakashima JM, Feng L, Giri SN, Margolin SB. Effects of three anti-TNF-α drugs: etanercept, infliximab and pirfenidone on release of TNF-α in medium and TNF-α associated with the cell in vitro. Int Immunopharmacol. 2008;8(5):679–687.
162. Schaefer CJ, Ruhrmund DW, Pan L, Seiwert SD, Kossen K. Antifibrotic activities of pirfenidone in animal models. Eur Respir Rev. 2011;20(120):85–97.
163. Selman M, King TE, Pardo A, American Thoracic Society, European Respiratory Society, American College of Chest Physicians. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 2001;134(2):136–151.
164. Wollin L, Maillet I, Quesniaux V, Holweg A, Ryf-fel B. Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J Pharmacol Exp Ther. 2014;349(2):209–220.
165. Wang J, Chen J, Guo Y, Wang B, Chu H. Strategies targeting angiogenesis in advanced non-small cell lung cancer. Oncotarget. 2017;8(32):53854–53872.
166. Henderson NC, et al. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med. 2013;19(12):1617–1624.
167. Stylianopoulos T. The solid mechanics of cancer and strategies for improved therapy. J Biomech Eng. 2017;139(2):10.1115/1.4034991.
168. Polydorou C, Mpekris F, Papageorgis P, Voutouri C, Stylianopoulos T. Pirfenidone normalizes the tumor microenvironment to improve chemotherapy. Oncotarget. 2017;8(15):24506–24517.
169. Mpekris F, et al. Sonic-hedgehog pathway inhibition normalizes desmoplastic tumor microenvironment to improve chemo- and nanotherapy. JControlRelease. 2017;261:105–112.
170. Chang J, et al. Pre-clinical evaluation of small molecule LOXL2 inhibitors in breast cancer. Oncotarget. 2017;8(16):26066–26078.
171. Cox TR, et al. The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature. 2015;522(7554):106–110.
172. Baker AM, Bird D, Lang G, Cox TR, Erler JT. Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK. Oncogene. 2013;32(14):1863–1868.
173. Baker AM, et al. Lysyl oxidase plays a critical role in endothelial cell stimulation to drive tumor angiogenesis. Cancer Res. 2013;73(2):583–594.
174. Baker AM, et al. The role of lysyl oxidase in SRC-dependent proliferation and metastasis of colorectal cancer. J Natl Cancer Inst. 2011;103(5):407–424.
175. Meissner EG, et al. Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial. Liver Int. 2016;36(12):1783–1792.
176. Miller BW, et al. Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy. EMBO Mol Med. 2015;7(8):1063–1076.
177. Benson AB, et al. A phase II randomized, double-blind, placebo-controlled study of simtuzumab or placebo in combination with gemcitabine for the first-line treatment of pancreatic adenocarcinoma. Oncologist. 2017;22(3):241–e15.
178. Hecht JR, Benson AB, Vyushkov D, Yang Y, Bendell J, Verma U. A phase II, randomized, double-blind, placebo-controlled study of simtuzumab in combination with FOLFIRI for the second-line treatment of metastatic KRAS mutant colorectal adenocarcinoma. Oncologist. 2017;22(3):243–e23.
179. Rhim AD, et al. EMT and dissemination precede pancreatic tumor formation. Cell. 2012; 148(1–2):349–361.
180. Du H, Pang M, Hou X, Yuan S, Sun L. PLOD2 in cancer research. BiomedPharmacother. 2017;90:670–676.
181. Olive KP, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324(5933):1457–1461.
182. Rhim AD, et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014;25(6):735–747.
183. Özdemir BC, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014;25(6):719–734.
184. Sherman MH, et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell. 2014;159(1):80–93.
185. Beatty GL, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331(6024):1612–1616.