The double-edged sword: Conserved functions of extracellular Hsp90 in wound healing and cancer

Cancers

Volumn 6, Issue 2, 2014, Pages 1065-1097

  Hance, Michael W ^a   Nolan, Krystal D ^a   Isaacs, Jennifer S ^a  

^a MEDICAL UNIVERSITY OF SOUTH CAROLINA   (United States)

Author keywords

Cancer; EMT; Extracellular Hsp90; Inflammation; Invasion; LRP1; MMPs; Motility; Wound healing

Indexed keywords

HEAT SHOCK PROTEIN 90; MATRIX METALLOPROTEINASE;

ANGIOGENESIS; CELL INVASION; CELL MOTILITY; ENZYME ACTIVITY; EPITHELIAL MESENCHYMAL TRANSITION; EXTRACELLULAR MATRIX; HUMAN; HYPOXIA; IMMUNOMODULATION; IMMUNOREGULATION; INFLAMMATION; MALIGNANT NEOPLASTIC DISEASE; METASTASIS; MOLECULAR PATHOLOGY; NONHUMAN; PROTEIN FUNCTION; PROTEIN LOCALIZATION; REVIEW; SIGNAL TRANSDUCTION; TUMOR GROWTH; TUMOR PROMOTION; WOUND HEALING;

EID: 84899990412     PISSN: None     EISSN: 20726694     Source Type: Journal    
DOI: 10.3390/cancers6021065     Document Type: Review

References (254)

1. Frydman, J. Folding of newly translated proteins in vivo: The role of molecular chaperones. Annu. Rev. Biochem. 2001, 70, 603-647.
2. Taipale, M.; Jarosz, D.F.; Lindquist, S. Hsp90 at the hub of protein homeostasis: Emerging mechanistic insights. Nat. Rev. Mol. Cell Biol. 2010, 11, 515-528.
3. Whitesell, L.; Lindquist, S.L. Hsp90 and the chaperoning of cancer. Nat. Rev. Cancer 2005, 5, 761-772.
4. Moulick, K.; Ahn, J.H.; Zong, H.; Rodina, A.; Cerchietti, L.; Gomes DaGama, E.M.; Caldas-Lopes, E.; Beebe, K.; Perna, F.; Hatzi, K. et al. Affinity-based proteomics reveal cancer-specific networks coordinated by hsp90. Nat. Chem. Biol. 2011, 7, 818-826.
5. Lambert, J.P.; Ivosev, G.; Couzens, A.L.; Larsen, B.; Taipale, M.; Lin, Z.Y.; Zhong, Q.; Lindquist, S.; Vidal, M.; Aebersold, R. et al. Mapping differential interactomes by affinity purification coupled with data-independent mass spectrometry acquisition. Nat. Methods 2013, 10, 1239-1245.
6. Taipale, M.; Krykbaeva, I.; Koeva, M.; Kayatekin, C.; Westover, K.D.; Karras, G.I.; Lindquist, S. Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 2012, 150, 987-1001.
7. Webb, C.P.; Hose, C.D.; Koochekpour, S.; Jeffers, M.; Oskarsson, M.; Sausville, E.; Monks, A.; Woude, G.F. The geldanamycins are potent inhibitors of the hepatocyte growth factor/scatter factor-met-urokinase plasminogen activator-plasmin proteolytic network. Cancer Res. 2000, 60, 342-349.
8. Xu, W.; Mimnaugh, E.; Rosser, M.F.; Nicchitta, C.; Marcu, M.; Yarden, Y.; Neckers, L. Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90. J. Biol. Chem. 2001, 276, 3702-3708.
9. Basso, A.D.; Solit, D.B.; Chiosis, G.; Giri, B.; Tsichlis, P.; Rosen, N. Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. J. Biol. Chem. 2002, 277, 39858-39866.
10. Gopal, U.; Bohonowych, J.E.; Lema-Tome, C.; Liu, A.; Garrett-Mayer, E.; Wang, B.; Isaacs, J.S. A novel extracellular Hsp90 mediated co-receptor function for LRP1 regulates EphA2 dependent glioblastoma cell invasion. PLoS One 2011, 6, e17649.
11. Breinig, M.; Mayer, P.; Harjung, A.; Goeppert, B.; Malz, M.; Penzel, R.; Neumann, O.; Hartmann, A.; Dienemann, H.; Giaccone, G. et al. Heat shock protein 90-sheltered overexpression of insulin-like growth factor 1 receptor contributes to malignancy of thymic epithelial tumors. Clin. Cancer Res. 2011, 17, 2237-2249.
12. Picard, D.; Khursheed, B.; Garabedian, M.J.; Fortin, M.G.; Lindquist, S.; Yamamoto, K.R. Reduced levels of Hsp90 compromise steroid receptor action in vivo. Nature 1990, 348, 166-168.
13. Isaacs, J.S.; Jung, Y.J.; Mimnaugh, E.G.; Martinez, A.; Cuttitta, F.; Neckers, L.M. Hsp90 regulates a von hippel lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. J. Biol. Chem. 2002, 277, 29936-29944.
14. Isaacs, J.S.; Xu, W.; Neckers, L. Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell 2003, 3, 213-217.
15. Bohonowych, J.E.; Gopal, U.; Isaacs, J.S. Hsp90 as a gatekeeper of tumor angiogenesis: Clinical promise and potential pitfalls. J. Oncol. 2010, 2010, doi:10.1155/2010/412985.
16. Neckers, L.; Workman, P. Hsp90 molecular chaperone inhibitors: Are we there yet? Clin. Cancer Res. 2012, 18, 64-76.
17. Luo, W.; Rodina, A.; Chiosis, G. Heat shock protein 90: Translation from cancer to alzheimer's disease treatment? BMC Neurosci. 2008, 9, doi:10.1186/1471-2202-9-S2-S7.
18. Kang, B.H.; Plescia, J.; Dohi, T.; Rosa, J.; Doxsey, S.J.; Altieri, D.C. Regulation of tumor cell mitochondrial homeostasis by an organelle-specific Hsp90 chaperone network. Cell 2007, 131, 257-270.
19. Chae, Y.C.; Caino, M.C.; Lisanti, S.; Ghosh, J.C.; Dohi, T.; Danial, N.N.; Villanueva, J.; Ferrero, S.; Vaira, V.; Santambrogio, L. et al. Control of tumor bioenergetics and survival stress signaling by mitochondrial Hsp90s. Cancer Cell 2012, 22, 331-344.
20. Radisky, D.C.; Stallings-Mann, M.; Hirai, Y.; Bissell, M.J. Single proteins might have dual but related functions in intracellular and extracellular microenvironments. Nat. Rev. Mol. Cell Biol. 2009, 10, 228-234.
21. Calderwood, S.K.; Mambula, S.S.; Gray, P.J., Jr. Extracellular heat shock proteins in cell signaling and immunity. Ann. NY Acad. Sci. 2007, 1113, 28-39.
22. Butler, G.S.; Dean, R.A.; Smith, D.; Overall, C.M. Membrane protease degradomics: Proteomic identification and quantification of cell surface protease substrates. Methods Mol. Biol. 2009, 528, 159-176.
23. Weidle, U.H.; Maisel, D.; Klostermann, S.; Schiller, C.; Weiss, E.H. Intracellular proteins displayed on the surface of tumor cells as targets for therapeutic intervention with antibody-related agents. Cancer Genomics Proteomics 2011, 8, 49-63.
24. Luo, B.; Lee, A.S. The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies. Oncogene 2013, 32, 805-818.
25. Hua, Y.; White-Gilbertson, S.; Kellner, J.; Rachidi, S.; Usmani, S.Z.; Chiosis, G.; Depinho, R.; Li, Z.; Liu, B. Molecular chaperone gp96 is a novel therapeutic target of multiple myeloma. Clin. Cancer Res. 2013, 19, 6242-6251.
26. Patel, P.D.; Yan, P.; Seidler, P.M.; Patel, H.J.; Sun, W.; Yang, C.; Que, N.S.; Taldone, T.; Finotti, P.; Stephani, R.A. et al. Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2. Nat. Chem. Biol. 2013, 9, 677-684.
27. Sherman, M.; Multhoff, G. Heat shock proteins in cancer. Ann. NY Acad. Sci. 2007, 1113, 192-201.
28. Powers, M.V.; Clarke, P.A.; Workman, P. Dual targeting of Hsc70 and Hsp72 inhibits Hsp90 function and induces tumor-specific apoptosis. Cancer Cell 2008, 14, 250-262.
29. Juhasz, K.; Lipp, A.M.; Nimmervoll, B.; Sonnleitner, A.; Hesse, J.; Haselgruebler, T.; Balogi, Z. The complex function of Hsp70 in metastatic cancer. Cancers 2013, 6, 42-66.
30. Srivastava, P.K.; DeLeo, A.B.; Old, L.J. Tumor rejection antigens of chemically induced sarcomas of inbred mice. Proc. Natl. Acad. Sci. USA 1986, 83, 3407-3411.
31. Udono, H.; Srivastava, P.K. Comparison of tumor-specific immunogenicities of stress-induced proteins gp96, Hsp90, and Hsp70. J. Immunol. 1994, 152, 5398-5403.
32. Suto, R.; Srivastava, P.K. A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Science 1995, 269, 1585-1588.
33. Srivastava, P.K.; Menoret, A.; Basu, S.; Binder, R.J.; McQuade, K.L. Heat shock proteins come of age: Primitive functions acquire new roles in an adaptive world. Immunity 1998, 8, 657-665.
34. Schild, H.; Rammensee, H.G. Gp96-The immune system's Swiss army knife. Nat. Immunol. 2000, 1, 100-101.
35. Zheng, H.; Dai, J.; Stoilova, D.; Li, Z. Cell surface targeting of heat shock protein gp96 induces dendritic cell maturation and antitumor immunity. J. Immunol. 2001, 167, 6731-6735.
36. Nicchitta, C.V.; Carrick, D.M.; Baker-Lepain, J.C. The messenger and the message: Gp96 (GRP94)-peptide interactions in cellular immunity. Cell Stress Chaperones 2004, 9, 325-331.
37. Flynn, G.C.; Chappell, T.G.; Rothman, J.E. Peptide binding and release by proteins implicated as catalysts of protein assembly. Science 1989, 245, 385-390.
38. Arnold-Schild, D.; Hanau, D.; Spehner, D.; Schmid, C.; Rammensee, H.G.; de la Salle, H.; Schild, H. Cutting edge: Receptor-mediated endocytosis of heat shock proteins by professional antigen-presenting cells. J. Immunol. 1999, 162, 3757-3760.
39. Udono, H.; Srivastava, P.K. Heat shock protein 70-associated peptides elicit specific cancer immunity. J. Exp. Med. 1993, 178, 1391-1396.
40. Moroi, Y.; Mayhew, M.; Trcka, J.; Hoe, M.H.; Takechi, Y.; Hartl, F.U.; Rothman, J.E.; Houghton, A.N. Induction of cellular immunity by immunization with novel hybrid peptides complexed to heat shock protein 70. Proc. Natl. Acad. Sci. USA 2000, 97, 3485-3490.
41. Massa, C.; Guiducci, C.; Arioli, I.; Parenza, M.; Colombo, M.P.; Melani, C. Enhanced efficacy of tumor cell vaccines transfected with secretable hsp70. Cancer Res. 2004, 64, 1502-1508.
42. Ostergaard, L.; Simonsen, U.; Eskildsen-Helmond, Y.; Vorum, H.; Uldbjerg, N.; Honore, B.; Mulvany, M.J. Proteomics reveals lowering oxygen alters cytoskeletal and endoplasmatic stress proteins in human endothelial cells. Proteomics 2009, 9, 4457-4467.
43. Raiter, A.; Weiss, C.; Bechor, Z.; Ben-Dor, I.; Battler, A.; Kaplan, B.; Hardy, B. Activation of GRP78 on endothelial cell membranes by an ADAM15-derived peptide induces angiogenesis. J. Vasc. Res. 2010, 47, 399-411.
44. Zhang, Y.; Liu, R.; Ni, M.; Gill, P.; Lee, A.S. Cell surface relocalization of the endoplasmic reticulum chaperone and unfolded protein response regulator GRP78/BiP. J. Biol. Chem. 2010, 285, 15065-15075.
45. Ferrarini, M.; Heltai, S.; Zocchi, M.R.; Rugarli, C. Unusual expression and localization of heat-shock proteins in human tumor cells. Int. J. Cancer. 1992, 51, 613-619.
46. Tamura, Y.; Tsuboi, N.; Sato, N.; Kikuchi, K. 70 kDa heat shock cognate protein is a transformation-associated antigen and a possible target for the host's anti-tumor immunity. J. Immunol. 1993, 151, 5516-5524.
47. Multhoff, G.; Botzler, C.; Wiesnet, M.; Muller, E.; Meier, T.; Wilmanns, W.; Issels, R.D. A stress-inducible 72-kDa heat-shock protein (Hsp72) is expressed on the surface of human tumor cells, but not on normal cells. Int. J. Cancer 1995, 61, 272-279.
48. Berger, C.L.; Dong, Z.; Hanlon, D.; Bisaccia, E.; Edelson, R.L. A lymphocyte cell surface heat shock protein homologous to the endoplasmic reticulum chaperone, immunoglobulin heavy chain binding protein bip. Int. J. Cancer 1997, 71, 1077-1085.
49. Misra, U.K.; Gonzalez-Gronow, M.; Gawdi, G.; Wang, F.; Pizzo, S.V. A novel receptor function for the heat shock protein Grp78: Silencing of Grp78 gene expression attenuates alpha2M*-induced signalling. Cell. Signal. 2004, 16, 929-938.
50. Arap, M.A.; Lahdenranta, J.; Mintz, P.J.; Hajitou, A.; Sarkis, A.S.; Arap, W.; Pasqualini, R. Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands. Cancer Cell 2004, 6, 275-284.
51. Graner, M.W.; Cumming, R.I.; Bigner, D.D. The heat shock response and chaperones/heat shock proteins in brain tumors: Surface expression, release, and possible immune consequences. J. Neurosci. 2007, 27, 11214-11227.
52. Gonzalez-Gronow, M.; Selim, M.A.; Papalas, J.; Pizzo, S.V. GRP78: A multifunctional receptor on the cell surface. Antioxid. Redox Signal. 2009, 11, 2299-2306.
53. Ni, M.; Zhang, Y.; Lee, A.S. Beyond the endoplasmic reticulum: Atypical GRP78 in cell viability, signalling and therapeutic targeting. Biochem. J. 2011, 434, 181-188.
54. Misra, U.K.; Deedwania, R.; Pizzo, S.V. Activation and cross-talk between Akt, NF-κb, and unfolded protein response signaling in 1-LN prostate cancer cells consequent to ligation of cell surface-associated GRP78. J. Biol. Chem. 2006, 281, 13694-13707.
55. Shani, G.; Fischer, W.H.; Justice, N.J.; Kelber, J.A.; Vale, W.; Gray, P.C. GRP78 and cripto form a complex at the cell surface and collaborate to inhibit transforming growth factor beta signaling and enhance cell growth. Mol. Cell. Biol. 2008, 28, 666-677.
56. Philippova, M.; Ivanov, D.; Joshi, M.B.; Kyriakakis, E.; Rupp, K.; Afonyushkin, T.; Bochkov, V.; Erne, P.; Resink, T.J. Identification of proteins associating with glycosylphosphatidylinositol-anchored T-cadherin on the surface of vascular endothelial cells: Role for Grp78/BiP in T-cadherin-dependent cell survival. Mol. Cell. Biol. 2008, 28, 4004-4017.
57. Kern, J.; Untergasser, G.; Zenzmaier, C.; Sarg, B.; Gastl, G.; Gunsilius, E.; Steurer, M. GRP-78 secreted by tumor cells blocks the antiangiogenic activity of bortezomib. Blood 2009, 114, 3960-3967.
58. Asea, A.; Kraeft, S.K.; Kurt-Jones, E.A.; Stevenson, M.A.; Chen, L.B.; Finberg, R.W.; Koo, G.C.; Calderwood, S.K. Hsp70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat. Med. 2000, 6, 435-442.
59. Vabulas, R.M.; Ahmad-Nejad, P.; Ghose, S.; Kirschning, C.J.; Issels, R.D.; Wagner, H. Hsp70 as endogenous stimulus of the toll/interleukin-1 receptor signal pathway. J. Biol. Chem. 2002, 277, 15107-15112.
60. Morales, C.; Rachidi, S.; Hong, F.; Sun, S.; Ouyang, X.; Wallace, C.; Zhang, Y.; Garret-Mayer, E.; Wu, J.; Liu, B. et al. Immune chaperone gp96 drives the contributions of macrophages to inflammatory colon tumorigenesis. Cancer Res. 2014, 74, 446-459.
61. Gastpar, R.; Gehrmann, M.; Bausero, M.A.; Asea, A.; Gross, C.; Schroeder, J.A.; Multhoff, G. Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res. 2005, 65, 5238-5247.
62. Mambula, S.S.; Calderwood, S.K. Heat shock protein 70 is secreted from tumor cells by a nonclassical pathway involving lysosomal endosomes. J. Immunol. 2006, 177, 7849-7857.
63. Schmitt, E.; Gehrmann, M.; Brunet, M.; Multhoff, G.; Garrido, C. Intracellular and extracellular functions of heat shock proteins: Repercussions in cancer therapy. J. Leukoc. Biol. 2007, 81, 15-27.
64. Sims, J.D.; McCready, J.; Jay, D.G. Extracellular heat shock protein (Hsp)70 and Hsp90α assist in matrix metalloproteinase-2 activation and breast cancer cell migration and invasion. PLoS One 2011, 6, e18848.
65. Ullrich, S.J.; Robinson, E.A.; Law, L.W.; Willingham, M.; Appella, E. A mouse tumor-specific transplantation antigen is a heat shock-related protein. Proc. Natl. Acad. Sci. USA 1986, 83, 3121-3125.
66. Srivastava, P. Roles of heat-shock proteins in innate and adaptive immunity. Nat. Rev. Immunol. 2002, 2, 185-194.
67. Kurotaki, T.; Tamura, Y.; Ueda, G.; Oura, J.; Kutomi, G.; Hirohashi, Y.; Sahara, H.; Torigoe, T.; Hiratsuka, H.; Sunakawa, H. et al. Efficient cross-presentation by heat shock protein 90-peptide complex-loaded dendritic cells via an endosomal pathway. J. Immunol. 2007, 179, 1803-1813.
68. Murshid, A.; Gong, J.; Calderwood, S.K. Heat shock protein 90 mediates efficient antigen cross presentation through the scavenger receptor expressed by endothelial cells-I. J. Immunol. 2010, 185, 2903-2917.
69. Oura, J.; Tamura, Y.; Kamiguchi, K.; Kutomi, G.; Sahara, H.; Torigoe, T.; Himi, T.; Sato, N. Extracellular heat shock protein 90 plays a role in translocating chaperoned antigen from endosome to proteasome for generating antigenic peptide to be cross-presented by dendritic cells. Int. Immunol. 2011, 23, 223-237.
70. Basu, S.; Binder, R.J.; Ramalingam, T.; Srivastava, P.K. CD91 is a common receptor for heat shock proteins gp96, Hsp90, Hsp70, and calreticulin. Immunity 2001, 14, 303-313.
71. Binder, R.J.; Vatner, R.; Srivastava, P. The heat-shock protein receptors: Some answers and more questions. Tissue Antigens 2004, 64, 442-451.
72. El Hamidieh, A.; Grammatikakis, N.; Patsavoudi, E. Cell surface Cdc37 participates in extracellular Hsp90 mediated cancer cell invasion. PLoS One 2012, 7, e42722.
73. Song, X.; Wang, X.; Zhuo, W.; Shi, H.; Feng, D.; Sun, Y.; Liang, Y.; Fu, Y.; Zhou, D.; Luo, Y. The regulatory mechanism of extracellular Hsp90α on matrix metalloproteinase-2 processing and tumor angiogenesis. J. Biol. Chem. 2010, 285, 40039-40049.
74. Cheng, C.F.; Sahu, D.; Tsen, F.; Zhao, Z.; Fan, J.; Kim, R.; Wang, X.; O'Brien, K.; Li, Y.; Kuang, Y. et al. A fragment of secreted hsp90α carries properties that enable it to accelerate effectively both acute and diabetic wound healing in mice. J. Clin. Investig. 2011, 121, 4348-4361.
75. Sahu, D.; Zhao, Z.; Tsen, F.; Cheng, C.F.; Park, R.; Situ, A.J.; Dai, J.; Eginli, A.; Shams, S.; Chen, M. et al. A potentially common peptide target in secreted heat shock protein-90alpha for hypoxia-inducible factor-1alpha-positive tumors. Mol. Biol. Cell 2012, 23, 602-613.
76. Bohonowych, J.; Hance, M.; Nolan, K.; Defee, M.; Parsons, C; Isaacs, J. Extracellular Hsp90 mediates an NF-Kb dependent inflammatory stromal program: Implications for the prostate tumor microenvironment. Prostate 2014, 74, 395-407.
77. Basu, S.; Binder, R.J.; Suto, R; Anderson, K.M.; Srivastava, P.K. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-Kb pathway. Int. Immunol. 2000, 12, 1539-1546.
78. Clayton, A.; Turkes, A.; Navabi, H.; Mason, M.D.; Tabi, Z. Induction of heat shock proteins in B-cell exosomes. J. Cell Sei. 2005, 118, 3631-3638.
79. Yu, X.; Harris, S.L.; Levine, A.J. The regulation of exosome secretion: A novel function of the p53 protein. Cancer Res. 2006, 66, 4795-4801.
80. Cheng, C.F.; Fan, J.; Fedesco, M; Guan, S.; Li, Y.; Bandyopadhyay, B.; Bright, A.M.; Yerushalmi, D.; Liang, M; Chen, M; et al. Transforming growth factor a (TGFa)-stimulated secretion of Hsp90a: Using the receptor LRP-1/CD91 to promote human skin cell migration against a TGFß-rich environment during wound healing. Mol. Cell. Biol. 2008, 28, 3344-3358.
81. McCready, J.; Sims, J.D.; Chan, D.; Jay, D.G Secretion of extracellular Hsp90alpha via exosomes increases cancer cell motility: A role for plasminogen activation. BMC Cancer 2010, 10, doi:10.1186/1471-2407-10-294.
82. Ramteke, A.; Ting, H.; Agarwal, C; Mateen, S.; Somasagara, R; Hussain, A.; Graner, M; Frederick, B.; Agarwal, R.; Deep, G. Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules. Mol. Carcinog. 2013, doi:10.1002/mc.22124.
83. Liao, D.F.; Jin, Z.G; Baas, A.S.; Daum, G; Gygi, S.P.; Aebersold, R.; Berk, B.C. Purification and identification of secreted oxidative stress-induced factors from vascular smooth muscle cells. J. Biol. Chem. 2000, 275, 189-196.
84. Yang, Y.; Rao, R.; Shen, J.; Tang, Y.; Fiskus, W.; Nechtman, J.; Atadja, P.; Bhalla, K. Role of acetylation and extracellular location of heat shock protein 90a in tumor cell invasion. Cancer Res. 2008, 68, 4833-4842.
85. Lv, L.H.; Wan, Y.L.; Lin, Y.; Zhang, W.; Yang, M; Li, G.L.; Lin, H.M.; Shang, C.Z.; Chen, Y.J.; Min, J. Anticancer drugs cause release of exosomes with heat shock proteins from human hepatocellular carcinoma cells that elicit effective natural killer cell antitumor responses in vitro. J. Biol. Chem. 2012, 287, 15874-15885.
86. Lei, H.; Venkatakrishnan, A.; Yu, S.; Kazlauskas, A. Protein kinase A-dependent translocation of Hsp90a impairs endothelial nitric-oxide synthase activity in high glucose and diabetes. J. Biol. Chem. 2007, 252, 9364-9371.
87. Wang, X.; Song, X.; Zhuo, W.; Fu, Y.; Shi, H.; Liang, Y.; Tong, M; Chang, G; Luo, Y. The regulatory mechanism of Hsp90a secretion and its function in tumor malignancy. Proc. Natl. Acad. Sei. USA 2009, 106, 21288-21293.
88. Song, X.; Luo, Y. The regulatory mechanism of hsp90a secretion from endothelial cells and its role in angiogenesis during wound healing. Biochem. Biophys. Res. Commun. 2010, 398, 111-117.
89. Li, W.; Li, Y.; Guan, S.; Fan, J.; Cheng, C.F.; Bright, A.M.; Chinn, C; Chen, M; Woodley, D.T. Extracellular heat shock protein-90a: Linking hypoxia to skin cell motility and wound healing. EMBO J. 2007, 26, 1221-1233.
90. Li, W.; Tsen, F.; Sahu, D.; Bhatia, A.; Chen, M.; Multhoff, G.; Woodley, D.T. Extracellular Hsp90 (eHsp90) as the actual target in clinical trials: Intentionally or unintentionally. Int. Rev. Cell Mol. Biol. 2013, 303, 203-235.
91. Thomaidou, D.; Patsavoudi, E. Identification of a novel neuron-specific surface antigen in the developing nervous system, by monoclonal antibody 4C5. Neuroscience 1993, 53, 813-827.
92. Sidera, K.; Samiotaki, M.; Yfanti, E.; Panayotou, G.; Patsavoudi, E. Involvement of cell surface Hsp90 in cell migration reveals a novel role in the developing nervous system. J. Biol. Chem. 2004, 279, 45379-45388.
93. Thomaidou, D.; Yfanti, E.; Patsavoudi, E. Expression of the 4C5 antigen during development and after injury of the rat sciatic nerve. J. Neurosci. Res. 1996, 46, 24-33.
94. Yfanti, E.; Sidera, K.; Margaritis, L.H.; Patsavoudi, E. The 4C5 antigen is associated with schwann cell migration during development and regeneration of the rat peripheral nervous system. Glia 2004, 45, 39-53.
95. Guenard, V.; Kleitman, N.; Morrissey, T.K.; Bunge, R.P.; Aebischer, P. Syngeneic schwann cells derived from adult nerves seeded in semipermeable guidance channels enhance peripheral nerve regeneration. J. Neurosci. 1992, 12, 3310-3320.
96. Thomaidou, D.; Dori, I.; Patsavoudi, E. Developmental expression and functional characterization of the 4C5 antigen in the postnatal cerebellar cortex. J. Neurochem. 1995, 64, 1937-1944.
97. Ishimoto, T.; Kamei, A.; Koyanagi, S.; Nishide, N.; Uyeda, A.; Kasai, M.; Taguchi, T. Hsp90 has neurite-promoting activity in vitro for telencephalic and spinal neurons of chick embryos. Biochem. Biophys. Res. Commun. 1998, 253, 283-287.
98. Sarkar, A.A.; Zohn, I.E. Hectd1 regulates intracellular localization and secretion of Hsp90 to control cellular behavior of the cranial mesenchyme. J. Cell Biol. 2012, 196, 789-800.
99. Martin, P. Wound healing-Aiming for perfect skin regeneration. Science 1997, 276, 75-81.
100. Woodley, D.T.; Fan, J.; Cheng, C.F.; Li, Y.; Chen, M.; Bu, G.; Li, W. Participation of the lipoprotein receptor LRP1 in hypoxia-Hsp90α autocrine signaling to promote keratinocyte migration. J. Cell Sci. 2009, 122, 1495-1498.
101. Campana, W.M.; Li, X.; Dragojlovic, N.; Janes, J.; Gaultier, A.; Gonias, S.L. The low-density lipoprotein receptor-related protein is a pro-survival receptor in schwann cells: Possible implications in peripheral nerve injury. J. Neurosci. 2006, 26, 11197-11207.
102. Mantuano, E.; Jo, M.; Gonias, S.L.; Campana, W.M. Low density lipoprotein receptor-related protein (LRP1) regulates Rac1 and Rhoa reciprocally to control schwann cell adhesion and migration. J. Biol. Chem. 2010, 285, 14259-14266.
103. Gonias, S.L.; Campana, W.M. LDL receptor-related protein-1: A regulator of inflammation in atherosclerosis, cancer, and injury to the nervous system. Am. J. Pathol. 2014, 184, 18-27.
104. Herz, J.; Strickland, D.K. Lrp: A multifunctional scavenger and signaling receptor. J. Clin. Investig. 2001, 108, 779-784.
105. Mantuano, E.; Henry, K.; Yamauchi, T.; Hiramatsu, N.; Yamauchi, K.; Orita, S.; Takahashi, K.; Lin, J.H.; Gonias, S.L.; Campana, W.M. The unfolded protein response is a major mechanism by which LRP1 regulates schwann cell survival after injury. J. Neurosci. 2011, 31, 13376-13385.
106. Koong, A.C.; Denko, N.C.; Hudson, K.M.; Schindler, C.; Swiersz, L.; Koch, C.; Evans, S.; Ibrahim, H.; Le, Q.T.; Terris, D.J. et al. Candidate genes for the hypoxic tumor phenotype. Cancer Res. 2000, 60, 883-887.
107. Montel, V.; Gaultier, A.; Lester, R.D.; Campana, W.M.; Gonias, S.L. The low-density lipoprotein receptor-related protein regulates cancer cell survival and metastasis development. Cancer Res. 2007, 67, 9817-9824.
108. Castellano, J.; Aledo, R.; Sendra, J.; Costales, P.; Juan-Babot, O.; Badimon, L.; Llorente-Cortes, V. Hypoxia stimulates low-density lipoprotein receptor-related protein-1 expression through hypoxia-inducible factor-1alpha in human vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 2011, 31, 1411-1420.
109. Majno, G.; Gabbiani, G.; Hirschel, B.J.; Ryan, G.B.; Statkov, P.R. Contraction of granulation tissue in vitro: Similarity to smooth muscle. Science 1971, 173, 548-550.
110. Vaughan, M.B.; Howard, E.W.; Tomasek, J.J. Transforming growth factor-beta1 promotes the morphological and functional differentiation of the myofibroblast. Exp. Cell Res. 2000, 257, 180-189.
111. Hinz, B.; Mastrangelo, D.; Iselin, C.E.; Chaponnier, C.; Gabbiani, G. Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation. Am. J. Pathol. 2001, 159, 1009-1020.
112. Hinz, B.; Phan, S.H.; Thannickal, V.J.; Prunotto, M.; Desmouliere, A.; Varga, J.; de Wever, O.; Mareel, M.; Gabbiani, G. Recent developments in myofibroblast biology: Paradigms for connective tissue remodeling. Am. J. Pathol. 2012, 180, 1340-1355.
113. Mirastschijski, U.; Haaksma, C.J.; Tomasek, J.J.; Agren, M.S. Matrix metalloproteinase inhibitor GM 6001 attenuates keratinocyte migration, contraction and myofibroblast formation in skin wounds. Exp. Cell Res. 2004, 299, 465-475.
114. Eustace, B.K.; Sakurai, T.; Stewart, J.K.; Yimlamai, D.; Unger, C.; Zehetmeier, C.; Lain, B.; Torella, C.; Henning, S.W.; Beste, G. et al. Functional proteomic screens reveal an essential extracellular role for Hsp90α in cancer cell invasiveness. Nat. Cell Biol. 2004, 6, 507-514.
115. Stellas, D.; El Hamidieh, A.; Patsavoudi, E. Monoclonal antibody 4C5 prevents activation of MMP2 and MMP9 by disrupting their interaction with extracellular HSP90 and inhibits formation of metastatic breast cancer cell deposits. BMC Cell Biol. 2010, 11, e51.
116. Yamashita, C.M.; Dolgonos, L.; Zemans, R.L.; Young, S.K.; Robertson, J.; Briones, N.; Suzuki, T.; Campbell, M.N.; Gauldie, J.; Radisky, D.C. et al. Matrix metalloproteinase 3 is a mediator of pulmonary fibrosis. Am. J. Pathol. 2011, 179, 1733-1745.
117. Correia, A.L.; Mori, H.; Chen, E.I.; Schmitt, F.C.; Bissell, M.J. The hemopexin domain of MMP3 is responsible for mammary epithelial invasion and morphogenesis through extracellular interaction with Hsp90α. Genes Dev. 2013, 27, 805-817.
118. Tsutsumi, S.; Scroggins, B.; Koga, F.; Lee, M.J.; Trepel, J.; Felts, S.; Carreras, C.; Neckers, L. A small molecule cell-impermeant Hsp90 antagonist inhibits tumor cell motility and invasion. Oncogene 2008, 27, 2478-2487.
119. Luo, L.Y.; Herrera, I.; Soosaipillai, A.; Diamandis, E.P. Identification of heat shock protein 90 and other proteins as tumour antigens by serological screening of an ovarian carcinoma expression library. Br. J. Cancer 2002, 87, 339-343.
120. Cid, C.; Regidor, I.; Poveda, P.D.; Alcazar, A. Expression of heat shock protein 90 at the cell surface in human neuroblastoma cells. Cell Stress Chaperones 2009, 14, 321-327.
121. Hance, M.W.; Dole, K.; Gopal, U.; Bohonowych, J.E.; Jezierska-Drutel, A.; Neumann, C.A.; Liu, H.; Garraway, I.P.; Isaacs, J.S. Secreted Hsp90 is a novel regulator of the epithelial to mesenchymal transition (EMT) in prostate cancer. J. Biol. Chem. 2012, 287, 37732-37744.
122. Becker, B.; Multhoff, G.; Farkas, B.; Wild, P.J.; Landthaler, M.; Stolz, W.; Vogt, T. Induction of Hsp90 protein expression in malignant melanomas and melanoma metastases. Exp. Dermatol. 2004, 13, 27-32.
123. Hegmans, J.P.; Bard, M.P.; Hemmes, A.; Luider, T.M.; Kleijmeer, M.J.; Prins, J.B.; Zitvogel, L.; Burgers, S.A.; Hoogsteden, H.C.; Lambrecht, B.N. Proteomic analysis of exosomes secreted by human mesothelioma cells. Am. J. Pathol. 2004, 164, 1807-1815.
124. Burgess, E.F.; Ham, A.J.; Tabb, D.L.; Billheimer, D.; Roth, B.J.; Chang, S.S.; Cookson, M.S.; Hinton, T.J.; Cheek, K.L.; Hill, S. et al. Prostate cancer serum biomarker discovery through proteomic analysis of α-2 macroglobulin protein complexes. Proteomics Clin. Appl. 2008, 2, 1223-1233.
125. Sun, Y.; Zang, Z.; Xu, X.; Zhang, Z.; Zhong, L.; Zan, W.; Zhao, Y.; Sun, L. Differential proteomics identification of HSP90 as potential serum biomarker in hepatocellular carcinoma by two-dimensional electrophoresis and mass spectrometry. Int. J. Mol. Sci. 2010, 11, 1423-1433.
126. Vidal, C.I.; Mintz, P.J.; Lu, K.; Ellis, L.M.; Manenti, L.; Giavazzi, R.; Gershenson, D.M.; Broaddus, R.; Liu, J.; Arap, W. et al. An Hsp90-mimic peptide revealed by fingerprinting the pool of antibodies from ovarian cancer patients. Oncogene 2004, 23, 8859-8867.
127. Conroy, S.E.; Sasieni, P.D.; Fentiman, I.; Latchman, D.S. Autoantibodies to the 90 kDa heat shock protein and poor survival in breast cancer patients. Eur. J. Cancer 1998, 34, 942-943.
128. Trieb, K.; Gerth, R.; Holzer, G.; Grohs, J.G.; Berger, P.; Kotz, R. Antibodies to heat shock protein 90 in osteosarcoma patients correlate with response to neoadjuvant chemotherapy. Br. J. Cancer 2000, 82, 85-87.
129. Chen, J.S.; Hsu, Y.M.; Chen, C.C.; Chen, L.L.; Lee, C.C.; Huang, T.S. Secreted heat shock protein 90α induces colorectal cancer cell invasion through CD91/LRP-1 and NF-κb-mediated integrin alphaV expression. J. Biol. Chem. 2010, 285, 25458-25466.
130. Hendrix, A.; Maynard, D.; Pauwels, P.; Braems, G.; Denys, H.; van den Broecke, R.; Lambert, J.; van Belle, S.; Cocquyt, V.; Gespach, C. et al. Effect of the secretory small GTPase Rab27b on breast cancer growth, invasion, and metastasis. J. Natl. Cancer Inst. 2010, 102, 866-880.
131. Sidera, K.; Patsavoudi, E. Extracellular Hsp90: Conquering the cell surface. Cell Cycle 2008, 7, 1564-1568.
132. Li, W.; Sahu, D.; Tsen, F. Secreted heat shock protein-90 (Hsp90) in wound healing and cancer. Biochim. Biophys. Acta 2012, 1823, 730-741.
133. Sidera, K.; Gaitanou, M.; Stellas, D.; Matsas, R.; Patsavoudi, E. A critical role for Hsp90 in cancer cell invasion involves interaction with the extracellular domain of HER-2. J. Biol. Chem. 2008, 283, 2031-2041.
134. Lagarrigue, F.; Dupuis-Coronas, S.; Ramel, D.; Delsol, G.; Tronchere, H.; Payrastre, B.; Gaits-Iacovoni, F. Matrix metalloproteinase-9 is upregulated in nucleophosmin-anaplastic lymphoma kinase-positive anaplastic lymphomas and activated at the cell surface by the chaperone heat shock protein 90 to promote cell invasion. Cancer Res. 2010, 70, 6978-6987.
135. Stellas, D.; Karameris, A.; Patsavoudi, E. Monoclonal antibody 4C5 immunostains human melanomas and inhibits melanoma cell invasion and metastasis. Clin. Cancer Res. 2007, 13, 1831-1838.
136. Fidler, I.J. Critical determinants of metastasis. Semin. Cancer Biol. 2002, 12, 89-96.
137. Overall, C.M.; Kleifeld, O. Tumour microenvironment opinion: Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat. Rev. Cancer 2006, 6, 227-239.
138. Page-McCaw, A.; Ewald, A.J.; Werb, Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat. Rev. Mol. Cell Biol. 2007, 8, 221-233.
139. Stebbins, C.E.; Russo, A.A.; Schneider, C.; Rosen, N.; Hartl, F.U.; Pavletich, N.P. Crystal structure of an Hsp90-geldanamycin complex: Targeting of a protein chaperone by an antitumor agent. Cell 1997, 89, 239-250.
140. Yarden, Y.; Sliwkowski, M.X. Untangling the ErbB signalling network. Nat. Rev. Mol. Cell Biol. 2001, 2, 127-137.
141. Thuringer, D.; Hammann, A.; Benikhlef, N.; Fourmaux, E.; Bouchot, A.; Wettstein, G.; Solary, E.; Garrido, C. Transactivation of the epidermal growth factor receptor by heat shock protein 90 via toll-like receptor 4 contributes to the migration of glioblastoma cells. J. Biol. Chem. 2011, 286, 3418-3428.
142. Wu, S.; Dole, K.; Hong, F.; Noman, A.S.; Issacs, J.; Liu, B.; Li, Z. Chaperone gp96-independent inhibition of endotoxin response by chaperone-based peptide inhibitors. J. Biol. Chem. 2012, 287, 19896-19903.
143. McCawley, L.J.; Matrisian, L.M. Matrix metalloproteinases: They're not just for matrix anymore! Curr. Opin. Cell Biol. 2001, 13, 534-540.
144. Alter, N.M. Mechanical irritation as etiologic factor of cancer: Clinical observation. Am. J. Pathol. 1925, 1, 511-518.
145. Dolberg, D.S.; Hollingsworth, R.; Hertle, M.; Bissell, M.J. Wounding and its role in RSV-mediated tumor formation. Science 1985, 230, 676-678.
146. Takahashi, H.; Ogata, H.; Nishigaki, R.; Broide, D.H.; Karin, M. Tobacco smoke promotes lung tumorigenesis by triggering IKKbeta- and JNK1-dependent inflammation. Cancer Cell 2010, 17, 89-97.
147. Ben-Neriah, Y.; Karin, M. Inflammation meets cancer, with NF-κb as the matchmaker. Nat. Immunol. 2011, 12, 715-723.
148. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646-674.
149. Singer, A.J.; Clark, R.A. Cutaneous wound healing. N. Engl. J. Med. 1999, 341, 738-746.
150. Gurtner, G.C.; Werner, S.; Barrandon, Y.; Longaker, M.T. Wound repair and regeneration. Nature 2008, 453, 314-321.
151. Haddow, A. Molecular repair, wound healing, and carcinogenesis: Tumor production a possible overhealing? Adv. Cancer Res. 1972, 16, 181-234.
152. Dvorak, H.F. Tumors: Wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 1986, 315, 1650-1659.
153. Schauer, I.G.; Rowley, D.R. The functional role of reactive stroma in benign prostatic hyperplasia. Differ. Res. Biol. Divers. 2011, 82, 200-210.
154. Lokmic, Z.; Musyoka, J.; Hewitson, T.D.; Darby, I.A. Hypoxia and hypoxia signaling in tissue repair and fibrosis. Int. Rev. Cell Mol. Biol. 2012, 296, 139-185.
155. Folkman, J. Tumor angiogenesis: Therapeutic implications. N. Engl. J. Med. 1971, 285, 1182-1186.
156. Senger, D.R.; Galli, S.J.; Dvorak, A.M.; Perruzzi, C.A.; Harvey, V.S.; Dvorak, H.F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983, 219, 983-985.
157. Shweiki, D.; Itin, A.; Soffer, D.; Keshet, E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 1992, 359, 843-845.
158. Chan, D.A.; Giaccia, A.J. Hypoxia, gene expression, and metastasis. Cancer Metastasis Rev. 2007, 26, 333-339.
159. Semenza, G.L. Molecular mechanisms mediating metastasis of hypoxic breast cancer cells. Trends Mol. Med. 2012, 18, 534-543.
160. Finger, E.C.; Giaccia, A.J. Hypoxia, inflammation, and the tumor microenvironment in metastatic disease. Cancer Metastasis Rev. 2010, 29, 285-293.
161. Eltzschig, H.K.; Carmeliet, P. Hypoxia and inflammation. N. Engl. J. Med. 2011, 364, 656-665.
162. Mamlouk, S.; Wielockx, B. Hypoxia-inducible factors as key regulators of tumor inflammation. Int. J. Cancer 2013, 132, 2721-2729.
163. Kuraishy, A.; Karin, M.; Grivennikov, S.I. Tumor promotion via injury- and death-induced inflammation. Immunity 2011, 35, 467-477.
164. Grivennikov, S.I.; Karin, M. Inflammation and oncogenesis: A vicious connection. Curr. Opin. Genet. Dev. 2010, 20, 65-71.
165. Mantovani, A.; Allavena, P.; Sica, A.; Balkwill, F. Cancer-related inflammation. Nature 2008, 454, 436-444.
166. Li, N.; Grivennikov, S.I.; Karin, M. The unholy trinity: Inflammation, cytokines, and STAT3 shape the cancer microenvironment. Cancer Cell 2011, 19, 429-431.
167. Hanahan, D.; Coussens, L.M. Accessories to the crime: Functions of cells recruited to the tumor microenvironment. Cancer Cell 2012, 21, 309-322.
168. Barrientos, S.; Stojadinovic, O.; Golinko, M.S.; Brem, H.; Tomic-Canic, M. Growth factors and cytokines in wound healing. Wound Repair Regen. 2008, 16, 585-601.
169. Shaw, T.J.; Martin, P. Wound repair at a glance. J. Cell Sci. 2009, 122, 3209-3213.
170. Sandbo, N.; Dulin, N. Actin cytoskeleton in myofibroblast differentiation: Ultrastructure defining form and driving function. Transl. Res. 2011, 158, 181-196.
171. Martins, V.L.; Caley, M.; O'Toole, E.A. Matrix metalloproteinases and epidermal wound repair. Cell Tissue Res. 2013, 351, 255-268.
172. Kalluri, R.; Zeisberg, M. Fibroblasts in cancer. Nat. Rev. Cancer 2006, 6, 392-401.
173. Hinz, B.; Phan, S.H.; Thannickal, V.J.; Galli, A.; Bochaton-Piallat, M.L.; Gabbiani, G. The myofibroblast: One function, multiple origins. Am. J. Pathol. 2007, 170, 1807-1816.
174. Dvorak, H.F. Rous-whipple award lecture. How tumors make bad blood vessels and stroma. Am. J. Pathol. 2003, 162, 1747-1757.
175. Orimo, A.; Gupta, P.B.; Sgroi, D.C.; Arenzana-Seisdedos, F.; Delaunay, T.; Naeem, R.; Carey, V.J.; Richardson, A.L.; Weinberg, R.A. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005, 121, 335-348.
176. Schafer, M.; Werner, S. Cancer as an overhealing wound: An old hypothesis revisited. Nat. Rev. Mol. Cell Biol. 2008, 9, 628-638.
177. Erez, N.; Truitt, M.; Olson, P.; Arron, S.T.; 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, 135-147.
178. Camps, J.L.; Chang, S.M.; Hsu, T.C.; Freeman, M.R.; Hong, S.J.; Zhau, H.E.; von Eschenbach, A.C.; Chung, L.W. Fibroblast-mediated acceleration of human epithelial tumor growth in vivo. Proc. Natl. Acad. Sci. USA 1990, 87, 75-79.
179. Olumi, A.F.; Grossfeld, G.D.; Hayward, S.W.; Carroll, P.R.; Tlsty, T.D.; Cunha, G.R. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 1999, 59, 5002-5011.
180. Bhowmick, N.A.; Neilson, E.G.; Moses, H.L. Stromal fibroblasts in cancer initiation and progression. Nature 2004, 432, 332-337.
181. Valastyan, S.; Weinberg, R.A. Tumor metastasis: Molecular insights and evolving paradigms. Cell 2011, 147, 275-292.
182. Cirri, P.; Chiarugi, P. Cancer-associated-fibroblasts and tumour cells: A diabolic liaison driving cancer progression. Cancer Metastasis Rev. 2012, 31, 195-208.
183. Lund, L.R.; Green, K.A.; Stoop, A.A.; Ploug, M.; Almholt, K.; Lilla, J.; Nielsen, B.S.; Christensen, I.J.; Craik, C.S.; Werb, Z. et al. Plasminogen activation independent of UPA and TPA maintains wound healing in gene-deficient mice. EMBO J. 2006, 25, 2686-2697.
184. Joyce, J.A.; Pollard, J.W. Microenvironmental regulation of metastasis. Nat. Rev. Cancer 2009, 9, 239-252.
185. Nieto, M.A. Epithelial plasticity: A common theme in embryonic and cancer cells. Science 2013, 342, doi:10.1126/science.1234850.
186. Radisky, D.; Hagios, C.; Bissell, M.J. Tumors are unique organs defined by abnormal signaling and context. Semin. Cancer Biol. 2001, 11, 87-95.
187. Franco, O.E.; Shaw, A.K.; Strand, D.W.; Hayward, S.W. Cancer associated fibroblasts in cancer pathogenesis. Semin. Cell Dev. Biol. 2010, 21, 33-39.
188. Tuxhorn, J.A.; Ayala, G.E.; Smith, M.J.; Smith, V.C.; Dang, T.D.; Rowley, D.R. Reactive stroma in human prostate cancer: Induction of myofibroblast phenotype and extracellular matrix remodeling. Clin. Cancer Res. 2002, 8, 2912-2923.
189. Barron, D.A.; Rowley, D.R. The reactive stroma microenvironment and prostate cancer progression. Endocr. Related Cancer 2012, 19, R187-R204.
190. Saadi, A.; Shannon, N.B.; Lao-Sirieix, P.; O'Donovan, M.; Walker, E.; Clemons, N.J.; Hardwick, J.S.; Zhang, C.; Das, M.; Save, V. et al. Stromal genes discriminate preinvasive from invasive disease, predict outcome, and highlight inflammatory pathways in digestive cancers. Proc. Natl. Acad. Sci. USA 2010, 107, 2177-2182.
191. Chang, H.Y.; Sneddon, J.B.; Alizadeh, A.A.; Sood, R.; West, R.B.; Montgomery, K.; Chi, J.T.; van de Rijn, M.; Botstein, D.; Brown, P.O. Gene expression signature of fibroblast serum response predicts human cancer progression: Similarities between tumors and wounds. PLoS Biol. 2004, 2, doi:10.1371/journal.pbio.0020007.
192. Defee, M.R.; Qin, Z.; Dai, L.; Toole, B.P.; Isaacs, J.S.; Parsons, C.H. Extracellular Hsp90 serves as a co-factor for NF-κb activation and cellular pathogenesis induced by an oncogenic herpesvirus. Am. J. Cancer Res. 2011, 1, 687-700.
193. Triantafilou, K.; Triantafilou, M.; Dedrick, R.L. A CD14-independent lps receptor cluster. Nat. Immunol. 2001, 2, 338-345.
194. Qin, S.; Ni, M.; Wang, X.; Maurier-Mahe, F.; Shurland, D.L.; Rodrigues, G.A. Inhibition of rpe cell sterile inflammatory responses and endotoxin-induced uveitis by a cell-impermeable Hsp90 inhibitor. Exp. Eye Res. 2011, 93, 889-897.
195. Chung, S.W.; Lee, J.H.; Choi, K.H.; Park, Y.C.; Eo, S.K.; Rhim, B.Y.; Kim, K. Extracellular heat shock protein 90 induces interleukin-8 in vascular smooth muscle cells. Biochem. Biophys. Res. Commun. 2009, 378, 444-449.
196. Grivennikov, S.I.; Greten, F.R.; Karin, M. Immunity, inflammation, and cancer. Cell 2010, 140, 883-899.
197. Kluwe, J.; Mencin, A.; Schwabe, R.F. Toll-like receptors, wound healing, and carcinogenesis. J. Mol. Med. 2009, 87, 125-138.
198. Rose, W.A., 2nd; Sakamoto, K.; Leifer, C.A. TLR9 is important for protection against intestinal damage and for intestinal repair. Sci. Rep. 2012, 2, doi:10.1038/srep00574.
199. Triantafilou, M.; Triantafilou, K. Heat-shock protein 70 and heat-shock protein 90 associate with toll-like receptor 4 in response to bacterial lipopolysaccharide. Biochem. Soc. Trans. 2004, 32, 636-639.
200. Basseres, D.S.; Baldwin, A.S. Nuclear factor-kappab and inhibitor of kappab kinase pathways in oncogenic initiation and progression. Oncogene 2006, 25, 6817-6830.
201. Chen, W.S.; Chen, C.C.; Chen, L.L.; Lee, C.C.; Huang, T.S. Secreted heat shock protein 90α (Hsp90α) induces nuclear factor-κb-mediated TCF12 protein expression to down-regulate E-cadherin and to enhance colorectal cancer cell migration and invasion. J. Biol. Chem. 2013, 288, 9001-9010.
202. Hiratsuka, S.; Watanabe, A.; Sakurai, Y.; Akashi-Takamura, S.; Ishibashi, S.; Miyake, K.; Shibuya, M.; Akira, S.; Aburatani, H.; Maru, Y. The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat. Cell Biol. 2008, 10, 1349-1355.
203. Gatti, G.; Quintar, A.A.; Andreani, V.; Nicola, J.P.; Maldonado, C.A.; Masini-Repiso, A.M.; Rivero, V.E.; Maccioni, M. Expression of toll-like receptor 4 in the prostate gland and its association with the severity of prostate cancer. Prostate 2009, 69, 1387-1397.
204. Lillis, A.P.; van Duyn, L.B.; Murphy-Ullrich, J.E.; Strickland, D.K. LDL receptor-related protein 1: Unique tissue-specific functions revealed by selective gene knockout studies. Physiol. Rev. 2008, 88, 887-918.
205. Staudt, N.D.; Jo, M.; Hu, J.; Bristow, J.M.; Pizzo, D.P.; Gaultier, A.; VandenBerg, S.R.; Gonias, S.L. Myeloid cell receptor LRP1/CD91 regulates monocyte recruitment and angiogenesis in tumors. Cancer Res. 2013, 73, 3902-3912.
206. Ffrench-Constant, C.; van de Water, L.; Dvorak, H.F.; Hynes, R.O. Reappearance of an embryonic pattern of fibronectin splicing during wound healing in the adult rat. J. Cell Biol. 1989, 109, 903-914.
207. Clark, R.A.; Lanigan, J.M.; DellaPelle, P.; Manseau, E.; Dvorak, H.F.; Colvin, R.B. Fibronectin and fibrin provide a provisional matrix for epidermal cell migration during wound reepithelialization. J. Investig. Dermatol. 1982, 79, 264-269.
208. Stupack, D.G.; Cheresh, D.A. ECM remodeling regulates angiogenesis: Endothelial integrins look for new ligands. Sci. STKE 2002, 2002, doi:10.1126/stke.2002.119.pe7.
209. Hunter, M.C.; O'Hagan, K.L.; Kenyon, A.; Dhanani, K.C.; Prinsloo, E.; Edkins, A.L. Hsp90 binds directly to fibronectin (FN) and inhibition reduces the extracellular fibronectin matrix in breast cancer cells. PLoS One 2014, 9, e86842.
210. Hynes, R.O. The extracellular matrix: Not just pretty fibrils. Science 2009, 326, 1216-1219.
211. Liotta, L.A.; Tryggvason, K.; Garbisa, S.; Hart, I.; Foltz, C.M.; Shafie, S. Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature 1980, 284, 67-68.
212. Parks, W.C.; Wilson, C.L.; Lopez-Boado, Y.S. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat. Rev. Immunol. 2004, 4, 617-629.
213. Jodele, S.; Blavier, L.; Yoon, J.M.; DeClerck, Y.A. Modifying the soil to affect the seed: Role of stromal-derived matrix metalloproteinases in cancer progression. Cancer Metastasis Rev. 2006, 25, 35-43.
214. Lu, P.; Takai, K.; Weaver, V.M.; Werb, Z. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb. Perspect. Biol. 2011, 3, doi:10.1101/cshperspect.a005058.
215. Bissell, M.J.; Hines, W.C. Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat. Med. 2011, 17, 320-329.
216. Tsen, F.; Bhatia, A.; O'Brien, K.; Cheng, C.F.; Chen, M.; Hay, N.; Stiles, B.; Woodley, D.T.; Li, W. Extracellular heat shock protein 90 signals through subdomain II and the NPVY motif of LRP-1 receptor to Akt1 and Akt2: A circuit essential for promoting skin cell migration in vitro and wound healing in vivo. Mol. Cell. Biol. 2013, 33, 4947-4959.
217. Wykosky, J.; Debinski, W. The EphA2 receptor and ephrinA1 ligand in solid tumors: Function and therapeutic targeting. Mol. Cancer Res. MCR 2008, 6, 1795-1806.
218. Vaught, D.; Brantley-Sieders, D.M.; Chen, J. Eph receptors in breast cancer: Roles in tumor promotion and tumor suppression. Breast Cancer Res. 2008, 10, doi:10.1186/bcr2207.
219. Parrinello, S.; Napoli, I.; Ribeiro, S.; Wingfield Digby, P.; Fedorova, M.; Parkinson, D.B.; Doddrell, R.D.; Nakayama, M.; Adams, R.H.; Lloyd, A.C. Ephb signaling directs peripheral nerve regeneration through sox2-dependent schwann cell sorting. Cell 2010, 143, 145-155.
220. Coulthard, M.G.; Morgan, M.; Woodruff, T.M.; Arumugam, T.V.; Taylor, S.M.; Carpenter, T.C.; Lackmann, M.; Boyd, A.W. Eph/ephrin signaling in injury and inflammation. Am. J. Pathol. 2012, 181, 1493-1503.
221. Ling, S.; Chang, X.; Schultz, L.; Lee, T.K.; Chaux, A.; Marchionni, L.; Netto, G.J.; Sidransky, D.; Berman, D.M. An EGFR-ERK-SOX9 signaling cascade links urothelial development and regeneration to cancer. Cancer Res. 2011, 71, 3812-3821.
222. Mace, K.A.; Pearson, J.C.; McGinnis, W. An epidermal barrier wound repair pathway in Drosophila is mediated by grainy head. Science 2005, 308, 381-385.
223. Wong, V.W.; Rustad, K.C.; Akaishi, S.; Sorkin, M.; Glotzbach, J.P.; Januszyk, M.; Nelson, E.R.; Levi, K.; Paterno, J.; Vial, I.N. et al. Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling. Nat. Med. 2012, 18, 148-152.
224. Chang, L.; Karin, M. Mammalian map kinase signalling cascades. Nature 2001, 410, 37-40.
225. Polyak, K.; Weinberg, R.A. Transitions between epithelial and mesenchymal states: Acquisition of malignant and stem cell traits. Nat. Rev. Cancer 2009, 9, 265-273.
226. Lim, J.; Thiery, J.P. Epithelial-mesenchymal transitions: Insights from development. Development 2012, 139, 3471-3486.
227. Leopold, P.L.; Vincent, J.; Wang, H. A comparison of epithelial-to-mesenchymal transition and re-epithelialization. Semin. Cancer Biol. 2012, 22, 471-483.
228. Peinado, H.; Olmeda, D.; Cano, A. Snail, Zeb and bHLH factors in tumour progression: An alliance against the epithelial phenotype? Nat. Rev. Cancer 2007, 7, 415-428.
229. Chaffer, C.L.; Weinberg, R.A. A perspective on cancer cell metastasis. Science 2011, 331, 1559-1564.
230. Zheng, H.; Kang, Y. Multilayer control of the EMT master regulators. Oncogene 2013, doi:10.1038/onc.2013.128.
231. Jing, Y.Y.; Han, Z.P.; Sun, K.; Zhang, S.S.; Hou, J.; Liu, Y.; Li, R.; Gao, L.; Zhao, X.; Zhao, Q.D. et al. Toll-like receptor 4 signaling promotes epithelial-mesenchymal transition in human hepatocellular carcinoma induced by lipopolysaccharide. BMC Med. 2012, 10, e98.
232. Huang, J.; Xiao, D.; Li, G.; Ma, J.; Chen, P.; Yuan, W.; Hou, F.; Ge, J.; Zhong, M.; Tang, Y. et al. Epha2 promotes epithelial-mesenchymal transition through the Wnt/beta-catenin pathway in gastric cancer cells. Oncogene 2013, doi: 10.1038/onc.2013.238.
233. Barr, S.; Thomson, S.; Buck, E.; Russo, S.; Petti, F.; Sujka-Kwok, I.; Eyzaguirre, A.; Rosenfeld-Franklin, M.; Gibson, N.W.; Miglarese, M. et al. Bypassing cellular EGF receptor dependence through epithelial-to-mesenchymal-like transitions. Clin. Exp. Metastasis 2008, 25, 685-693.
234. Arnoux, V.; Nassour, M.; L'Helgoualc'h, A.; Hipskind, R.A.; Savagner, P. Erk5 controls slug expression and keratinocyte activation during wound healing. Mol. Biol. Cell 2008, 19, 4738-4749.
235. Hardy, K.M.; Booth, B.W.; Hendrix, M.J.; Salomon, D.S.; Strizzi, L. ErbB/EGF signaling and emt in mammary development and breast cancer. J. Mammary Gland Biol. Neoplasia 2010, 15, 191-199.
236. Radisky, D.C.; Levy, D.D.; Littlepage, L.E.; Liu, H.; Nelson, C.M.; Fata, J.E.; Leake, D.; Godden, E.L.; Albertson, D.G.; Nieto, M.A. et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 2005, 436, 123-127.
237. Nistico, P.; Bissell, M.J.; Radisky, D.C. Epithelial-mesenchymal transition: General principles and pathological relevance with special emphasis on the role of matrix metalloproteinases. Cold Spring Harb. Perspect. Biol. 2012, 4, doi:10.1101/cshperspect.a011908.
238. Ota, I.; Li, X.Y.; Hu, Y.; Weiss, S.J. Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by snail1. Proc. Natl. Acad. Sci. USA 2009, 106, 20318-20323.
239. Eckert, M.A.; Lwin, T.M.; Chang, A.T.; Kim, J.; Danis, E.; Ohno-Machado, L.; Yang, J. Twist1-induced invadopodia formation promotes tumor metastasis. Cancer Cell 2011, 19, 372-386.
240. Weiss, M.B.; Abel, E.V.; Mayberry, M.M.; Basile, K.J.; Berger, A.C.; Aplin, A.E. Twist1 is an ERK1/2 effector that promotes invasion and regulates MMP-1 expression in human melanoma cells. Cancer Res. 2012, 72, 6382-6392.
241. Lue, H.W.; Yang, X.; Wang, R.; Qian, W.; Xu, R.Z.; Lyles, R.; Osunkoya, A.O.; Zhou, B.P.; Vessella, R.L.; Zayzafoon, M. et al. LIV-1 promotes prostate cancer epithelial-to-mesenchymal transition and metastasis through HB-EGF shedding and egfr-mediated erk signaling. PLoS One 2011, 6, e27720.
242. Thiery, J.P.; Sleeman, J.P. Complex networks orchestrate epithelial-mesenchymal transitions. Nat. Rev. Mol. Cell Biol. 2006, 7, 131-142.
243. Chua, H.L.; Bhat-Nakshatri, P.; Clare, S.E.; Morimiya, A.; Badve, S.; Nakshatri, H. NF-κb represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: Potential involvement of Zeb-1 and Zeb-2. Oncogene 2007, 26, 711-724.
244. Kim, H.J.; Litzenburger, B.C.; Cui, X.; Delgado, D.A.; Grabiner, B.C.; Lin, X.; Lewis, M.T.; Gottardis, M.M.; Wong, T.W.; Attar, R.M. et al. Constitutively active type I insulin-like growth factor receptor causes transformation and xenograft growth of immortalized mammary epithelial cells and is accompanied by an epithelial-to-mesenchymal transition mediated by NF-κb and snail. Mol. Cell. Biol. 2007, 27, 3165-3175.
245. Min, C.; Eddy, S.F.; Sherr, D.H.; Sonenshein, G.E. NF-κb and epithelial to mesenchymal transition of cancer. J. Cell. Biochem. 2008, 104, 733-744.
246. Xue, G.; Restuccia, D.F.; Lan, Q.; Hynx, D.; Dirnhofer, S.; Hess, D.; Ruegg, C.; Hemmings, B.A. AKT/PKB-mediated phosphorylation of twist1 promotes tumor metastasis via mediating cross-talk between PI3K/AKT and TGF-beta signaling axes. Cancer Discov. 2012, 2, 248-259.
247. Shin, S.; Dimitri, C.A.; Yoon, S.O.; Dowdle, W.; Blenis, J. ERK2 but not ERK1 induces epithelial-to-mesenchymal transformation via DEF motif-dependent signaling events. Mol. Cell 2010, 38, 114-127.
248. Shin, S.Y.; Rath, O.; Zebisch, A.; Choo, S.M.; Kolch, W.; Cho, K.H. Functional roles of multiple feedback loops in extracellular signal-regulated kinase and Wnt signaling pathways that regulate epithelial-mesenchymal transition. Cancer Res. 2010, 70, 6715-6724.
249. Caramel, J.; Papadogeorgakis, E.; Hill, L.; Browne, G.J.; Richard, G.; Wierinckx, A.; Saldanha, G.; Osborne, J.; Hutchinson, P.; Tse, G. et al. A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma. Cancer Cell 2013, 24, 466-480.
250. Buonato, J.M.; Lazzara, M.J. ERK1/2 blockade prevents epithelial-mesenchymal transition in lung cancer cells and promotes their sensitivity to egfr inhibition. Cancer Res. 2014, 74, 309-319.
251. Deschenes-Simard, X.; Kottakis, F.; Meloche, S.; Ferbeyre, G. ERKs in cancer: Friends or foes? Cancer Res. 2014, 74, 412-419.
252. Yang, M.H.; Wu, M.Z.; Chiou, S.H.; Chen, P.M.; Chang, S.Y.; Liu, C.J.; Teng, S.C.; Wu, K.J. Direct regulation of twist by HIF-1α promotes metastasis. Nat. Cell Biol. 2008, 10, 295-305.
253. Zou, W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat. Rev. Cancer 2005, 5, 263-274.
254. De Visser, K.E.; Eichten, A.; Coussens, L.M. Paradoxical roles of the immune system during cancer development. Nat. Rev. Cancer 2006, 6, 24-37.