Abstract
The integrin family of extracellular matrix receptors plays an important role in normal development, epithelial morphogenesis, angiogenesis, and in tumor progression and metastasis. Integrins cooperate with growth factor receptors to control many cellular functions including proliferation and cell survival. Integrin-mediated adhesion regulates many of the cell cycle checkpoints including activation of cyclin D/cdk4/6 complexes, expression of cyclin D genes, and regulation of levels of cyclin-dependent kinase inhibitors. In addition, integrin-mediated cell adhesion regulates apoptosis by modulating the activity of both the mitochondrial pathway and the death receptor pathways. Therefore, integrin-mediated adhesion modulates the decision of life or death. A role for tumor-matrix interactions in the acquisition of drug resistance has been reported for many cancers including breast cancer. Recent evidence suggests that integrin-mediated adhesion to the ECM may undermine the response of tumors to chemotherapeutic agents. Integrins have been shown to be readily accessible drug targets and are therefore attractive potential targets for combined modality chemotherapy.
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Loftus JC, Smith JW, Ginsberg MH. Integrin-mediated cell adhesion: The extracellular face. J Biol Chem 1994; 269(41):25235–25238.
Hood JD, Cheresh DA. Role of integrins in cell invasion and migration. Nat Rev Cancer 2002; 2(2):91–100.
Guo W, Giancotti FG. Integrin signalling during tumour progression. Nat Rev Mol Cell Biol 2000; 5(10):816–826.
Hynes RO. Cell adhesion: Old and new questions. Trends Cell Biol 1999; 9(12):M33–M37.
Gustafsson E, Fassler R. Insights into extracellular matrix functions from mutant mouse models. Exp Cell Res 2000; 261(1):52–68.
Hynes RO. A reevaluation of integrins as regulators of angiogenesis. Nat Med 2002; 8(9):918–921.
Tucker GC. Inhibitors of integrins. Current Opinion in Pharmacology 2002; 2:394–401.
Damiano JS. Integrins as novel drug targets for overcoming innate drug resistance. Curr Cancer Drug Targets 2002; 2(1):37–43.
Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathology 2005; 205:275–292.
Zutter MM, Sun H, Santoro S. Altered integrin expression and the malignant phenotype: The contribution of multiple integrated integrin receptors. J Mammary Gland Biol Neoplasia 1998; 3(2):191–200.
Hynes RO. Integrins: Bidirectional, allosteric signaling machines. Cell 2002; 110(6):673–687.
Hynes RO, Zhao Q. The evolution of cell adhesion. J Cell Biol 2000; 150(2):F89–F96.
Clark EA, Brugge JS. Integrins and signal transduction pathways: The road taken. Science 1995; 268(5208):233–239.
Liddington RC, Ginsberg MH. Integrin activation takes shape. J Cell Biol 2002; 158(5):833–839.
Giancotti FG, Rouslahti E. Integrin signaling. Science 1999; 285:1028–1032.
Wary KK, Mainiero F, Isakoff SJ et al. The adaptor protein She couples a class of integrins to the control of cell cycle progression. Cell 1996; 87(4):733–743.
Wary KK, Mariotti A, Zurzolo C et al. A requirement for caveolin-1 and associated kinase Fyn in integrin signaling and anchorage-dependent cell growth. Cell 1998; 94(5):525–634.
Guan JL, Shalloway D. Regulation of focal adhesion-associated protein tyrosine kinase by both cellular adhesion and oncogenic transformation. Nature 199; 358(6388):690–692.
Schaller MD, Borgman CA, Cobb BS et al. pp 125FAK a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proc Natl Acad Sci USA 1992; 89(11):5192–5196.
Schaller MD, Parsons JT. Focal adhesion kinase and associated proteins. Curr Opin Cell Biol 1994; 6(5):705–710.
Hannigan GE, Leung-Hagesteijn C, Fitz-Gibbon L et al. Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase. Nature 1996; 379(6560):91–96.
Dedhar S, Hannigan GE. Integrin cytoplasmic interactions and bidirectional transmembrane signalling. Curr Opin Cell Biol 1996; 8(5):657–669.
Lewis JM, Baskaran R, Taagepera S et al. Integrin regulation of c-Abl tyrosine kinase activity and cytoplasmic-nuclear transport. Proc Natl Acad Sci USA 1996; 93(26):15174–15179.
Delcommenne M, Tan C, Gray V et al. Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci USA 1998; 95(19):11211–11216.
Schaller MD, Hildebrand JD, Parsons JT. Complex formation with focal adhesion kinase: A mechanism to regulate activity and subcellular localization of Src kinases. Mol Biol Cell 1999; 10(10):3489–3505.
Schlaepfer DD, Hanks SK, Hunter T et al. Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature 1994; 372(6508):786–791.
Richardson A, Parsons T. A mechanism for regulation of the adhesion-associated proteintyrosine kinase pp 125 FAK. Nature 1996; 380(6574):538–450, (Erratum in Nature 1996; 381 (6585):810).
Vuori K, Hirai H, Aizawa S et al. Introduction of p 130cas signaling complex formation upon integrin-mediated cell adhesion: A role for Src family kinases. Mol Cell Biol 1996; 16(6):2606–2613.
Frisch SM, Vuori K, Ruoslahti E et al. Control of adhesion-dependent cell survival by focal adhesion kinase. J Cell Biol 1996; 134(3):793–799.
Schlaepfer DD, Broome MA, Hunter T. Fibronectin-stimulated signaling from a focal adhesion kinase-c-Src complex: Involement of the Grb2, p130cas, and Nck adaptor proteins. Mol Cell Biol 1997; 17(3):1702–1713.
Oktay M, Wary KK, Dans M et al. Integrin-mediated activation of focal adhesion kinase is required for signaling to Jun NH2-terminal kinase and progression through the G1 phase of the cell cycle. J Cell Biol 1999; 145(7):1461–1469.
Chen HC, Appeddu PA, Parsons JT et al. Interaction of focal adhesion kinase with cytoskeletal protein talin. J Biol Chem 1995; 270(28):16995–16999.
Berditchevski F, Chang S, Bodorova J et al. A novel link between integrins, transmembrane-4 superfamily proteins (CD63 and CD81), and phosphatidylinositol 4-kinase. J Biol Chem 1997; 272(5):2595–2598.
Lindberg FP, Gresham HD, Schwarz E et al. Molecular cloning of integrin-associated protein: An immunoglobulin family member with multiple membrane-spanning domains implicated in alpha v beta 3-dependent ligand binding. J Cell Biol 1993; 123(2):485–496.
Chung J, Gao A, Frazier WA. Thrombspondin acts via integrin-associated protein to activate the platelet integrin alphallbbeta 3. J Biol Chem 1997; 272(23):14740–14746.
Rojiani MV, Finlay BB, Gray V et al. In vitro interaction of a polypeptide homologous to human Ro/SS-A antigen (calreticulin) with a highly conserved amino acid sequence in the cytoplasmic domain of integrin alpha subunits. Biochemistry 1991; 30(41):9859–9866.
Kieffer JD, Plopper G, Ingber DE et al. Direct binding of F actin to the cytoplasmic domain of the alpha 2 integrin chain in vitro. Biochem Biophys Res Commun 1995; 217(2):466–474.
Liu S, Thomas SM, Woodside DG et al. Binding of paxillin to alpha4 integrins modifies integrin-dependent biological responses. Nature 1999; 402(6762):676–681.
Alahari SK, Lee JW, Juliano RL. Nischarin, a novel protein that interacts with the integrin alpha 5 subunit and inhibits cell migration. J Cell Biol 2000; 151(6):1141–1154.
Wixler V, Laplantine E, Geerts D et al. Identification of novel interaction partners for the conserved membrane proximal region of alpha-integrin cytoplasmic domains. FEBS Lett 1999; 445(2–3):351–355.
Hannigan GE, Leung-Hagesteijn C, Fitz-Gibbon L et al. Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase. Nature 1996; 379(6560):91–96.
Nikolopoulos SN, Turner CE. Molecular dissection of actopaxin-integrin-linked kinase-paxillin interactions and their role in subcellular localization. J Biol Chem 2002; 277:1568–1575.
Nikolopoulos SN, Turner CE. Integrin-linked kinase (ILK) binding to paxillin LD1 motif regulates ILK localization to focal adhesions. J Biol Chem 2001; 276(26):23499–23505.
Olski TM, Noegel AA, Korenbaum E. Parvin: A 42-kDa focal adhesion protein, related to the alpha-actinin superfamily. J Cell Sci 2001; 114:525–538.
Tu Y, Huang Y, Zhang Z et al. A new focal adhesion protein that interacts with integrin-linked kinase and regulates cell adhesion and spreading. J Cell Biol 2001; 153:585–598.
Dedhar S. Cell-substrate interactions and signaling through ILK. Curr Opin Cell Biol 2000; 12:250–256.
Radeva G, Petrocelli T, Behrend E et al. Overexpression of the integrin-linked kinase promotes anchorage-independent cell cycle progression. J Biol Chem 1997; 272:13937–13944.
Attwell S, Roskelley C, Dedhar S. The integrin-linked kinase (ILK) suppresses anoikis. Oncogene 2000; 19:3811–3815.
Bottazzi MC, Assoian RK. The extracellular matrix and mitogenic growth factors control G1 phase cyclins and cyclin-dependent kinsae inhibitors. Trends Cell Biol 1997; 7:348–352.
Albanese C, Johnson J, Watanabe G et al. Transforming p21 ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. J Biol Chem 1995; 270(40):23589–23597.
Aplin AE, Howe AK, Juliano RL. Cell adhesion molecules, signal transduction and cell growth. Curr Opin Cell Biol 1999; 11(6):737–744.
Howe AK, Aplin AE, Juliano RL. Anchorage-dependent ERK signaling-mechanisms and consequences. Curr Opin Genet Dev 2000; 12(1):30–35.
Koyama H, Raines EW, Bornfeldt KE et al. Fibrillar collagen inhibits arterial smooth muscle proliferation through regulation of Cdk2 inhibitors. Cell 1996; 87(6):1069–1078.
Fang F, Orend G, Watanabe N et al. Dependence of cyclin E-CDK2 kinase activity on cell anchorage. Science 1996; 271(5248):499–502.
Zhu X, Ohtsubo M, Bohmer RM et al. Adhesion-dependent cell cycle progression linked to the expression of cyclin D1, activation of cyclin E-cdk2, and phosphorylation of the retinoblastoma protein. J Cell Biol 1996; 133(2):391–403.
Assoian RK. Anchorage-dependent cell cycle progression. J Cell Biol 1997; 136(1):1–4.
Assoian RK. Common sense signalling. Nat Cell Biol 2002; 4(8):E187–E188.
Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 1995; 9(10):1149–1163.
Frisch SM, Francis H. Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol 1994; 124(4):619–626.
Meredith Jr JE, Fazeli B, Schwartz MA. The extracellular matrix as a cell survival factor. Mol Biol Cell 1993; 4(9):953–961.
Lewis JM, Truong TN, Schwartz MA. Integrins regulate the apoptotic response to DNA damage through modulation of p53. Proc Natl Acad Sci USA 2002; 99(6):3627–3632.
Yawata A, Adachi M, Okuda H et al. Prolonged cell survival enhances peritoneal dissemination of gastric cancer cells. Oncogene 1999; 16:2681–2686.
Streuli CH, Gilmore AP. Adhesion-mediated signaling in the regulation of mammary epithelial cell survival. J Mammary Gland Biol Neoplasia 1999; 4:183–191.
Shanmugathasan M, Jothy S. Apoptosis, anoikis and their relevance to the pathobiology of colon cancer. Pathol Int 2000; 50:273–279.
Wei L, Yang Y, Yu Q. Tyrosine kinase-dependent P13-kinase and mitogen-activated protein-kinase-independent signaling pathways prevent lung adenocarcinoma anoikis. Cancer Res 2001; 61:2439–2444.
Frisch SM, Screaton RA. Anoikis mechanisms. Curr Opin Cell Biol 2001; 13(5):555–562.
Martin SS, Vuori K. Regulation of Bcl-2 proteins during anoikis and amorphosis. Biochim Biophys Acta 2004; 1692(2–3):145–157.
Matter ML, Ruoslahti E. A signaling pathway from the alpha5betal and alpha(v)beta3 integrins that elevates bcl-2 transcription. J Biol Chem 2001; 276:27757–27763.
Zhang Z, Vuori K, Reed JC et al. The alpha 5 beta 1 integrin supports survival of cells on fibronectin and up-regulates Bcl-2 expression. Proc Natl Acad Sci USA 1995; 92:6161–6165.
Scheid MP, Duronio V. Dissociation of cytokine-induced phosphorylation of Bad and activation of PKB/ akt: Involvement of MEK upstream of Bad phosphorylation. Proc Natl Acad Sci USA 1998; 95:7439–7444.
Scheid MP, Schubert KM, Duronio V. Regulation of bad phosphorylation and association with Bcl-x(L) by the MAPK/Erk kinase. J Biol Chem 1999; 274:31108–31113.
Breitschopf K, Haendeler J, Malchow P et al. Posttranslational modification of Bcl-2 facilitates its proteasome-dependent degradation: Molecular characterization of the involved signaling pathway. Mol Cell Biol 2000; 20:1886–1896.
Rytomaa M, Martins LM, Downward J. Involvement of FADD and caspase-8 signalling in detachment-induced apoptosis. Curr Biol 1999; 9:1043–1046.
Coll ML, Rosen K, Ladeda V et al. Increased Bcl-xL expression mediates v-Src-induced resistance to anoikis in intestinal epithelial cells. Oncogene 2002; 21:2908–2913.
Tiberio R, Marconi A, Fila C et al. Keratinocytes enriched for stem cells are protected from anoikis via an integrin signaling pathway in a Bcl-2 dependent manner. FEBS Lett 2002; 524:139–144.
Stromblad S, Becker JC, Yebra M et al. Suppression of p53 activity and p21 WAF1/CIP1 expression by vascular cell integrin alphaVbeta3 during angiogenesis. J Clin Invest 1996; 98:426–433.
Miyashita T, Krajewski S, Krajewska et al. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene 1994; 9:1799–1805.
Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 1995; 80:293–299.
Valentijn AJ, Gilmore AP. Translocation of full-length Bid to mitochondria during anoikis. J Biol Chem 2004; 279(31):32848–32857.
Reginato MJ, Mills KR, Paulus JK et al. Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis. Nat Cell Biol 2003; 5(8):733–740.
Wang P, Gilmore AP, Streuli CH. Bim is an apoptosis sensor that responds to loss of survival signals delivered by epidermal growth factor but not those provided by integrins. J Biol Chem 2004; 279(40):41280–41285.
Hazlehurst LA, Landowski TH, Dalton WS. Role of the tumor microenvironment in mediating de novo resistance to drugs and physiological mediators of cell death. Oncogene 2003; 23(47):7396–7402.
Puthalakath H, Huang DC, O’Reilly LA et al. The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol Cell 1999; 3:287–296.
Puthalakath H, Villunger A, O’Reilly LA et al. Bmf: A proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science 2001; 293:1829–1832.
Bouillet P, Strasser A. BH3-only proteins—evolutionarily conserved proapoptotic Bcl-2 family members essential for initiating programmed cell death. J Cell Sci 2002; 115:1567–1574.
Bouillet P, Purton JF, Godfrey DI et al. BH3-only Bcl-2 family member Bim is required for apoptosis of auto reactive thymocytes. Nature 2002; 415:922–926.
Frisch SM, Vuori K, Ruoslahti E et al. Control of adhesion-dependent cell survival by focal adhesion kinase. J Cell Biol 1996; 134(3):793–799.
Hungerford JE, Compton MT, Matter ML et al. Inhibition of pp125FAK in cultured fibroblasts results in apoptosis. J Cell Biol 1996; 135(5):1383–1390.
Ilic D, Almeida EA, Schlaepfer DD et al. Extracellular matrix survival signals transduced by focal adhesion kinase suppress p53-mediated apoptosis. J Cell Biol 1998; 143:547–560.
Almeida EA, Ilic D, Han Q et al. Matrix survival signaling: From fibronectin via focal adhesion kinase to c-Jun NH(2)-terminal kinase. J Cell Biol 2000; 149:741–754.
Khwaja A, Downward J. Lack of correlation between activation of Jun-NH2-terminal kinase and induction of apoptosis after detachment of epithelial cells. J Cell Biol 1997; 139(4):1017–1023.
Kiyokawa E, Hashimoto Y, Kurata T et al. Evidence that DOCK180 up-regulates signals from the Crkll-p130(Cas) complex. J Biol Chem 1998; 273:24479–24484.
Aoudjit F, Vuori K. Engagement of the alpha2beta1 integrin inhibits Fas ligand expression and activation-induced cell death in T cells in a focal adhesion kinase-dependent manner. Blood 2000; 95:2044–2051.
Gilmore AP, Metcalfe AD, Romer LH et al. Integrin-mediated survival signals regulate the apoptotic function of Bax through its conformation and subcellular localization. J Cell Biol 2000; 149:431–446.
Khwaja A, Rodriguez-Viciana P, Wennstrom S et al. Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J 1997; 16(10):2783–2793.
Datta SR, Dudek H, Tao X et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997; 91(2):231–241.
Cardone MH, Roy N, Stennicke HR et al. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998; 282(5392):1318–1321.
Sonoda Y, Matsumoto Y, Funakoshi M et al. Anti-apoptotic role of FAK: Induction of inhibitor of apoptosis proteins and apoptosis suppression by the overexpression of FAK in a human leukemic cell line, HL-60. J Biol Chem 2000; 275:16309–16315.
Hannigan G, Troussard AA, Dedhar S. Integrin-linked kinase: A cancer therapeutic target unique among its ILK. Nature Reviews Cancer 2005; 5:51–63.
Persad S, Attwell S, Gray V et al. Inhibition of integrin-linked kinase (ILK) suppresses activation of protein kinase B/Akt and induces cell cycle arrest and apoptosis of PTEN-mutant prostate cancer cells. Proc Natl Acad Sci USA 2000; 97:3207–3212.
Attwell S, Roskelle C, Dedhar S. The integrin-linked kinase (ILK) suppresses anoikis. Oncogene 2000; 19:3811–3815.
Plantefaber LC, Hynes RO. Changes in integrin receptors on oncogenically transformed cells. Cell 1989; 56(2):281–290.
Dedhar S, Saulnier R. Alterations in integrin receptor expression on chemically transformed human cells: Specific enhancement of laminin and collagen receptor complexes. J Cell Biol 1990; 110(2):481–489.
Sainsbury JR, Nicholson S, Angus B et al. Epidermal growth factor receptor status of histological sub-types of breast cancer. Br J Cancer 1988; 58(4):458–460.
Slamon DJ, Clark GM, Wong SG et al. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987; 235(4785):177–182.
Slamon DJ, Godolphin W, Jones LA et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989; 244(4905):707–712.
Liu E, Thor A, He M et al. The HER2 (c-erb B-2) oncogene is frequently amplified in in situ carcinomas of the breast. Oncogene 1992; 7(5):1027–1032.
Berdichevsky F, Gilbert C, Shearer M et al. Collagen-induced rapid morphogenesis of human mammary epithelial cells: The role of the alpha 2 beta 1 integrin. J Cell Sci 1992; 102(Pt 3):437–446.
D’Souza B, Berdichevsky F, Kyprianou N et al. Collagen-induced morphogenesis and expression of the alpha 2-integrin subunit is inhibited in c-erb B2-transfected human mammary epithelial cells. Oncogene 1993; 8(7):1797–1806.
Ye J, Xu RH, Taylor-Papadimitriou J et al. Sp1 binding plays a critical role in Erb-B2-and v-ras-mediated downregulation of alpha2-integrin expression in human mammary epithelial cells. Mol Cell Biol 1996; 16(11):6178–6189.
Zutter MM, Mazoujian G, Santoro SA. Decreased expression of integrin adhesive protein receptors in adenocarcinoma of the breast. Am J Pathol 1990; 137(4):863–870.
Koukoulis GK, Virtanen I, Korhonen M et al. Immunohistochemical localization of integrins in the normal, hyperplastic, and neoplastic breast. Correlations with their functions as receptors and cell adhesion molecules. Am J Pathol 1991; 139(4):787–799.
Pignatelli M, Cardillo MR, Hanby A et al. Integrins and their accessory adhesion molecules in mammary carcinomas: Loss of polarization in poorly-differentiated tumors. Hum Pathol 1992; 23(10):1159–1166.
Pignatelli M, Hanby AM, Stamp GW. Low expression of beta 1, alpha 2 and alpha 3 subunits of VLA integrins in malignant mammary tumours. J Pathol 1991; 165(1):25–32.
Pignatelli M, Smith MEF, Bodmer WF. Low expression of collagen receptors in moderate and poorly-differentiated colorectal adenocarcinomas. Brit J Cancer 1991; 61:636–638.
Stallmach A, von Lampe B, Matthes H et al. Diminished expression of integrin adhesion molecules on human colonic epithelial cells during the benign to malign tumour transformation. Gut 1992; 33(3):342–346.
Bonkhoff H, Stein U, Remberger K. Differential expression of alpha 6 and alpha 2 very late antigen integrins in the normal, hyperplastic, and neoplastic prostate: Simultaneous demonstration of cell surface receptors and their extracellular ligands. Hum Pathol 1993; 24(3):243–248.
Fridman R, Giaccone G, Kanemoto T et al. Reconstituted basement membrane (matrigel) and laminin can enhance the tumorigenicity and the drug resistance of small cell lung cancer cell lines. Proc Natl Acad Sci USA 1990; 87(17):6698–6702.
Kraus AC, Ferber I, Bachmann SO et al. In vitro chemo-and radio-resistance in small cell lung cancer correlates with cell adhesion and constitutive activation of AKT and MAP kinase pathways. Oncogene 2002; 21(57):8683–8695.
Sethi T, Rintoul RC, Moore SM et al. Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: A mechanism for small cell lung cancer growth and drug resistance in vivo. Nat Med 1999; 5(6):662–668.
Buttery RC, Rintoul RC, Sethi T. Small cell lung cancer: The importance of the extracellular matrix. Int J Biochem Cell Biol 2004; 36(7):1154–1160.
Hartmann TN, Burger M, Burger JA. The role of adhesion molecules and chemokine receptor CXCR4 (CD184) in small cell lung cancer. J Biol Regul Homeost Agents 2004; 18:126–130.
Cordes N, Beinke C, Plasswilm L et al. Trradiation and various cytotoxic drugs enhance tyrosine phosphorylation and beta (1)-integrin clustering in human A549 lung cancer cells in a substratum-dependent manner in vitro. Strahlenther Onkol 2004; 180(3):157–164.
Oshita F, Kameda Y, Hamanaka N et al. High expression of integrin β1 and p53 is a greater poor prognostic factor than clinical stage in small-cell lung cancer. Am J Clin Oncol 2000; 27:215–219.
Holcik M, Yeh C, Korneluk RG et al. Translational upregulation of X-linked inhibitor of apoptosis (XIAP) increases resistance to radiation induced cell death. Oncogene 2000; 19:4174–4177.
Rodel C, Haas J, Groth A et al. Spontaneous and radiation-induced apoptosis in colorectal carcinoma cells with different intrinsic radiosensitivities: Survivin as a radioresistance factor. Int J Radiat Oncol Biol Phys 2003; 55:1341–1347.
Monzo M, Rosell R, Felip E et al. A novel anti-apoptosis gene: Reexpression of survivin messenger RNA as a prognosis marker in nonsmall-cell lung cancers. J Clin Oncol 1999; 17:2100–2104.
Ikehara M, Oshita F, Kameda Y et al. Expression of survivin correlated with vessel invasion is a marker of poor prognosis in small adenocarcinoma of the lung. Oncol Rep 2002; 9:835–838.
Cao C, Mu Y, Hallahan DE et al. XIAP and survivin as therapeutic targets for radiation sensitization in preclinical models of lung cancer. Oncogene 2004; 23(42):7047–7052.
Fornaro M, Plescia J, Chheang S et al. Fibronectin protects prostate cancer cells from tumor necrosis factor-alpha-induced apoptosis via the AKT/survivin pathway. J Biol Chem 2003; 278(50):50402–50411.
Uhm JH, Dooley NP, Kyritsis AP et al. Vitronectin, a glioma-derived extracellular matrix protein, protects tumor cells from apoptotic death. Clin Cancer Res 1999; 5:1578–1594.
Miyamoto H, Murakami T, Tsuchida K et al. Tumor-stroma interaction of human pancreatic cancer: Acquired resistance to anticancer drugs and proliferation regulation is dependent on extracellular matrix proteins. Pancreas 2004; 28(1):38–44.
Burbridge MF, Venot V, Casara PJ et al. Decrease in survival threshold of quiescent colon carcinoma cells in the presence of a small molecule integrin antagonist. Mol Pharmacol 2003; 63(6):1281–1288.
Maubant S, Cruet-Hennequart S, Poulain L et al. Altered adhesion properties and alphav integrin expression in a cisplatin-resistant human ovarian carcinoma cell line. Int J Cancer 2002; 97(2):186–194.
Cruet-Hennequart S, Maubant S, Luis J et al. alpha(v) integrins regulate cell proliferation through integrin-linked kinase (ILK) in ovarian cancer cells. Oncogene 2003; 22(11):1688–1702.
Nista A, Leonetti C, Bernardini G et al. Functional role of alpha4betal and alpha5betal integrin fibronectin receptors expressed on adriamycin-resistant MCF-7 human mammary carcinoma cells. Int J Cancer 1997; 72:133–141.
Narita T, Kimura N, Sato M et al. Altered expression of integrins in adriamycin-resistant human breast cancer cells. Anticancer Res 1998; 18(1A):257–262.
Wewer UM, Shaw LM, Albrechtsen R et al. The integrin alpha 6 beta 1 promotes the survival of metastatic human breast carcinoma cells in mice. Am J Pathol 1997; 151:1191–1198.
Aoudjit F, Vuori K. Integrin signaling inhibits paclitaxel-induced apoptosis in breast cancer cells. Oncogene 2001; 20(36):4995–5004.
Menendez JA, Vellon L, Mehmi I et al. A novel CYR61-triggered ‘CYR61-alphavbeta3 integrin loop’ regulates breast cancer cell survival and chemosensitivity through activation of ERK1/ERK2 MAPK signaling pathway. Oncogene 2005; 24(5):761–779.
Tsai M-S, Hornby AE, Lakins J et al. Expression and function of CYR61, an angiogenic factor, in breast cancer cell lines and tumor biopsies. Cancer Res 2000; 60:5603–5607.
Brigstock DR. The connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed (CCN) family. Endocr Rev 1999; 20:189–206.
Brigstock DR, Goldschmeding R, Katsube KI et al. Proposal for a unified CCN nomenclature. Mol Pathol 2003; 56:127–128.
Lester FL, Stephen C-TL. The CCN family of angiogenic regulators: The integrin connection. Exp Cell Res 1999; 248:44–57.
Perbal B. The CCN family of genes: A brief history. Mol Pathol 2001; 54:103–104.
Perbal B. CCN proteins: Multifunctional signalling regulators. Lancet 2004; 363:62–64.
Planque N, Perbal B. A structural approach to the role of CCN (CYR61/CTGF/NOV) proteins in tumourigenesis. Cancer Cell Int 2003; 3:15.
Menendez JA, Mehmi I, Griggs DW et al. The angiogenic factor CYR61 in breast cancer: Molecular pathology and therapeutic perspectives. Endocrine Rel Cancer 2003; 10:141–152.
Lupu R, Cardillo M, Cho C et al. The significance of heregulin in breast cancer tumor progression and drug resistance. Breast Cancer Res Treat 1996; 38:57–66.
Tsai M-S, Bogart DF, Castaneda JM et al. Cyr61 promotes breast tumorigenesis and cancer progression. Oncogene 2002; 21:8178–8185.
Tsai MS, Shamon-Taylor LA, Mehmi I et al. Blockage of heregulin expression inhibits tumorigenicity and metastasis of breast cancer. Oncogene 2003; 22:761–768.
Atlas E, Mehmi I, Cardilla M et al. Heregulin is sufficient for the promotion of tumorigenicity and metastasis of breast cancer cells in vivo. Mol Cancer Res 2003; 1:165–175.
Kayaselcuk F, Nursal TZ, Polat A et al. Expression of survivin, bcl-2, P53 and bax in breast carcinoma and ductal intraepithelial neoplasia (DIN 1a) J Exp Clin Cancer Res 2004; 23(1):105–112.
Chu JS, Shew JY, Huang CS. Immunohistochemical analysis of survivin expression in primary breast cancers. J Formos Med Assoc 2004; 103(12):925–931.
Tsuji N, Furuse K, Asanuma K et al. Mutations of the p53 gene and loss of heterozygosity at chromosome 17p13.1 are associated with increased survivin expression in breast cancer. Breast Cancer Res Treat 2004; 87(1):23–31.
Zahir N, Weaver VM. Death in the third dimension: Apoptosis regulation and tissue architecture. Curr Opin Genet Dev 2004; 14(1):71–80.
Teicher BA, Herman TS, Holden SA et al. Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo. Science 1990; 247(4949 Pt 1):1457–1461.
Kerbel RS, Rak J, Kobayashi H et al. Multicellular resistance: A new paradigm to explain aspects of acquired drug resistance of solid tumors. Cold Spring Harbor Symp Quant Biol 1994; 59:661–672.
Kobayashi HS, Man SJ, Kapitain BA et al. Acquired multicellular-mediated resistance to alkylating agents in cancer. Proc Natl Acad Sci USA 1993; 90:3294–3298.
Santini MT, Rainaldi G, Indovina Pl. Apoptosis, cell adhesion and the extracellular matrix in the three-dimensional growth of multicellular tumor spheroids. Crit Rev Oncol Hematol 2000; 36(2–3):75–87.
Green SK, Francia G, Isidoro C et al. Antiadhesive antibodies targeting E-cadherin sensitize multicellular tumor spheroids to chemotherapy in vitro. Mol Cancer Ther 2004; 3(2):149–159.
Boudreau N, Werb Z, Bissell MJ. Suppression of apoptosis by basement membrane requires three-dimensional tissue organization and withdrawal from the cell cycle. Proc Natl Acad Sci USA 1996; 93(8):3509–3513.
Weaver VM, Lelievre S, Lakins JN et al. beta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium. Cancer Cell 2002; 2(3):205–16.
Zahir N, Lakins JN, Russell A et al. Autocrine laminin-5 ligates alpha6beta4 integrin and activates RAC and NFkappaB to mediate anchorage-independent survival of mammary tumors. J Cell Biol 2003; 163(6):1397–1407.
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© 2007 Landes Bioscience and Springer Science+Business Media
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Zutter, M.M. (2007). Integrin-Mediated Adhesion: Tipping the Balance between Chemosensitivity and Chemoresistance. In: Yu, D., Hung, MC. (eds) Breast Cancer Chemosensitivity. Advances in Experimental Medicine and Biology, vol 608. Springer, New York, NY. https://doi.org/10.1007/978-0-387-74039-3_6
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