• Lori A. Hazlehurst
Part of the Cancer Metastasis – Biology and Treatment book series (CMBT, volume 9)


β1 integrin is known to be an important mediator of cell cycle kinetics, survival and differentiation. More recently evidence is accumulating that β1 integrin-mediated adhesion is sufficient to cause resistance to mechanistically distinct cytotoxics. This drug resistant phenotype is commonly referred to as cell adhesion mediated drug resistance or CAM-DR. The CAM-DR phenotype is observed in multiple tumor types that express a diverse array of oncogenes, suggesting that underlying resistant mechanism(s) do not require the expression of a specific oncogene for conferring the drug resistant phenotype. Despite the consistency of the drug resistant phenotype a single CAM-DR pathway has yet to emerge. However, current data suggest that alterations in cell cycle checkpoints and Bcl-2 family members are likely to be critical for conferring the CAM-DR phenotype. This chapter will discuss CAM-DR models and potential targets downstream of β1 integrin ligation that contribute to the drug resistant phenotype.


U937 Cell Minimal Residual Disease Acquire Drug Resistance Drug Resistant Phenotype Confer Drug Resistance 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Dalton, W.S. and Salmon, S.E. Drug resistance in myeloma: mechanisms and approaches to circumvention. Hematol. Oncol. Clin. North Am., 6: 383–393, 1992.PubMedGoogle Scholar
  2. 2.
    Gottesman, M.M., Fojo, T., and Bates, S.E. Multidrug resistance in cancer: role of ATP dependent transporters. Nat.Rev. Cancer, 2: 48–58, 2002.PubMedCrossRefGoogle Scholar
  3. 3.
    Hazlehurst, L.A., Foley, N.E., Gleason-Guzman, M.C., Hacker, M.P., Cress A.E., Greenberger, L.W., De Jong, M.C., and Dalton, W.S. Multiple mechanisms confer drugresistance to mitoxantrone in the human 8226 myeloma cll line. Cancer Research, 59: 1021–1028, 1999.PubMedGoogle Scholar
  4. 4.
    Frisch, S.M. and Francis, H. Disruption of epithelial cell-matrix interactions induces apoptosis. J. Cell Biol., 124: 619-626, 1994.PubMedCrossRefGoogle Scholar
  5. 5.
    Windham, T.C., Parikh, N.U., Siwak, D.R., Summy, J.M., McConkey, D.J., Kraker, A.J., and Gallick, G.E. Src activation regulates anoikis in human colon tumor cell lines. Oncogene, 21: 7797–7807, 2002.PubMedCrossRefGoogle Scholar
  6. 6.
    Rosen, K., Rak, J., Leung, T., Dean, N.M., Kerbel, R.S., and Filmus, J. Activated Ras prevents downregulation of Bcl-X(L) triggered by detachment from the extracellular matrix. A mechanism of Ras-induced resistance to anoikis in intestinal epithelial cells. J.Cell Biol., 149: 447–456, 2000.PubMedCrossRefGoogle Scholar
  7. 7.
    Durand, R.E. and Sutherland, R.M. Effects of intercellular contact on repair of radiation damage. Experimental Cell Research, 71: 75–80, 1972.PubMedCrossRefGoogle Scholar
  8. 8.
    Damiano, J.S., Cress, A.E., Hazlehurst, L.A., Shtil, A.A., and Dalton, W.S. Cell adhesion mediated drug resistance (CAM-DR): Role of integrins and resistance to apoptosis in human myeloma cell lines. Blood, 93: 1658–1667, 1999.PubMedGoogle Scholar
  9. 9.
    Hazlehurst, L.A., Damiano J.S., BuyuksalmI., Pledger W.J., and Dalton W.S. Adhesion to fibronectin regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR). Oncogene, 38: 4319–4327, 2000.CrossRefGoogle Scholar
  10. 10.
    Hazlehurst, L.A., Valkov, N., Wisner, L., Storey, J.A., Boulware, D., Sullivan, D.M., and Dalton, W.S. Reduction in drug-induced DNA double strand-breaks associated with β1 integrin-mediated adhesion correlates with drug resistance in U937 cells. Blood, 98: 1897–1903, 2001.PubMedCrossRefGoogle Scholar
  11. 11.
    Sethi, T., Rintoul, R.C., Moore, S.M., MacKinnon, A.C., Salter, D., Choo, C., Chilvers E.R., Dransfield, I., Donnelly, S.C., Streiter, R., and Haslett, C. Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: A mechanism for small cell lung cancer growth and drug resistance in vivo. Nature Medicine, 5: 662–668, 1999.PubMedCrossRefGoogle Scholar
  12. 12.
    Aoudjit, F. and Vuori, K. Integrin signaling inhibits paclitaxel-induced apoptosis in breast cancer cells. Oncogene, 20: 4995–5004, 2001.PubMedCrossRefGoogle Scholar
  13. 13.
    Cordes, N. and van Beuningen, D. Arrest of human lung fibroblasts in G2 phase after irradiation is regulated by converging phosphatidylinositol-3 kinase and beta1-integrin signaling in vitro. Int. J. Radiat. Oncol. Biol. Phys., 58: 453–462, 2004.PubMedCrossRefGoogle Scholar
  14. 14.
    Damiano, J.S., Hazlehurst, L.A., and Dalton, W.S. Cell adhesion mediated resistance (CAM-DR) protects the K562 chronic myelogenous leukemia cell line from apoptosis induced by BCR/ABL inhibition cyctoxic drugs and γ radiation. Leukemia, 15: 1232–1239, 2001.PubMedCrossRefGoogle Scholar
  15. 15.
    Shain, K.H., Landowski, T.H., and Dalton, W.S. Adhesion-mediated intracellular redistribution of c-Fas-associated death domain-like IL-1-converting enzyme-like inhibitory protein-long confers resistance to CD95-induced apoptosis in hematopoietic cancer cell lines. J.Immunol., 168: 2544–2553, 2002.PubMedGoogle Scholar
  16. 16.
    van der, K.H., Goetz, A.W., Miething, C., Duyster, J., and Aulitzky, W.E. Adhesion to fibronectin selectively protects Bcr-Abl+ cells from DNA damage-induced apoptosis. Blood, 98: 1532–1541, 2001.CrossRefGoogle Scholar
  17. 17.
    Matsunaga, T., Takemoto, N., Sato, T., Takimoto, R., Tanaka, I., Fujimi, A., Akiyama, T., Kuroda, H., Kawano, Y., Kobune, M., Kato, J., Hirayama, Y., Sakamaki, S., Kohda, K., Miyake, K., and Niitsu, Y. Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Nat. Med., 9: 1158–1165, 2003.PubMedCrossRefGoogle Scholar
  18. 18.
    Teicher, B.A., Herman, T.S., Holden, S.A., Wang, Y.Y., Pfeffer, M.R., Crawford, J.W., and Frei, E.I. Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo. Science, 247: 1457–1460, 1990.PubMedCrossRefGoogle Scholar
  19. 19.
    Sherman-Baust, C.A., Weeraratna, A.T., Rangel, L.B., Pizer, E.S., Cho, K.R., Schwartz, D.R., Shock, T., and Morin, P.J. Remodeling of the extracellular matrix through overexpression of collagen VI contributes to cisplatin resistance in ovarian cancer cells. Cancer Cell, 3: 377–386, 2003.PubMedCrossRefGoogle Scholar
  20. 20.
    Hazlehurst, L.A., Argilagos, R.F., Emmons, M., Boulware, D., Beam, C.A., Sullivan D.M. and Dalton, W.S. Cell Adhesion to fibronectin (CAM-DR) influences acquired mitoxantrone resistance in U937 cells. In Press Cancer Research, 2006.Google Scholar
  21. 21.
    Farrelly, N., Lee, Y.J., Oliver, J., Dive, C., and Streuli, C.H. Extracellular matrix regulates apoptosis in mammary epithelium through a control on insulin signaling. J. Cell Biol., 144: 1337–1348, 1999.PubMedCrossRefGoogle Scholar
  22. 22.
    de la Fuente, M.T., Casanova, B., Moyano, J.V., Garcia-Gila, M., Sanz, L., Garcia-Marco, J., Silva, A., and Garcia-Pardo, A. Engagement of alpha4beta1 integrin by fibronectin induces in vitro resistance of B chronic lymphocytic leukemia cells to fludarabine. J. Leukoc. Biol., 71: 495–502, 2002.PubMedGoogle Scholar
  23. 23.
    Matter, M.L. and Ruoslahti, E.A signaling pathway from the alpha5beta1 and alpha(v)beta3 integrins that elevates bcl-2 transcription. J. Biol. Chem., 276: 27757–27763, 2001.PubMedCrossRefGoogle Scholar
  24. 24.
    Gilmore, A.P., Metcalfe, A.D., Romer, L.H., and Streuli, C.H. Integrin-mediated survival signals regulate the apoptotic function of Bax through its conformation and subcellular localization. J. Cell Biol., 149: 431–446, 2000.PubMedCrossRefGoogle Scholar
  25. 25.
    Hazlehurst, L.A., Enkemann, S., Beam, C., Argilagos, R.F., Painter, J., Shain, K., Saporta, S., Boulware, D., Mosciniski, M., Alsina, M., and Dalton, W.S. Genotypic and phenotypic comparisons of de novo and acquired melphalan resistance in an isogenic multiple myeloma cell line model. Cancer Research, 56: 660–670, 2003.Google Scholar
  26. 26.
    Bouillet, P., Metcalf, D., Huang, D.C., Tarlinton, D.M., Kay, T.W., Kontgen, F., Adams, J.M., and Strasser, A. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science, 286: 1735–1738, 1999.PubMedCrossRefGoogle Scholar
  27. 27.
    Lei, K. and Davis, R.J. JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc. Natl. Acad. Sci. USA, 100: 2432–2437, 2003.PubMedCrossRefGoogle Scholar
  28. 28.
    Marani, M., Tenev, T., Hancock, D., Downward, J., and Lemoine, N.R. Identification of novel isoforms of the BH3 domain protein Bim which directly activate Bax to trigger apoptosis. Mol. Cell Biol., 22: 3577–3589, 2002.PubMedCrossRefGoogle Scholar
  29. 29.
    Ley, R., Balmanno, K., Hadfield, K., Weston, C., and Cook, S.J. Activation of the ERK1/2 signaling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein, Bim. J. Biol. Chem., 278: 18811–18816, 2003.PubMedCrossRefGoogle Scholar
  30. 30.
    Akiyama, T., Bouillet, P., Miyazaki, T., Kadono, Y., Chikuda, H., Chung, U.I., Fukuda, A., Hikita, A., Seto, H., Okada, T., Inaba, T., Sanjay, A., Baron, R., Kawaguchi, H., Oda, H., Nakamura, K., Strasser, A., and Tanaka, S. Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3-only Bcl-2 family member Bim. EMBO J., 22: 6653–6664, 2003.PubMedCrossRefGoogle Scholar
  31. 31.
    Tsygankov, A.Y., Teckchandani, A.M., Feshchenko, E.A., and Swaminathan, G. Beyond the RING: CBL proteins as multivalent adapters. Oncogene, 20: 6382–6402, 2001.PubMedCrossRefGoogle Scholar
  32. 32.
    Teckchandani, A.M., Birukova, A.A., Tar, K., Verin, A.D., and Tsygankov, A.Y. The multidomain protooncogenic protein c-Cbl binds to tubulin and stabilizes microtubules. Exp. Cell Res., 306: 114–127, 2005.PubMedCrossRefGoogle Scholar
  33. 33.
    Puthalakath, H., Huang, D.C., O'Reilly, L.A., King, S.M., and Strasser, A. The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol. Cell, 3: 287–296, 1999.PubMedCrossRefGoogle Scholar
  34. 34.
    Zhu, Y., Swanson, B.J., Wang, M., Hildeman, D.A., Schaefer, B.C., Liu, X., Suzuki, H., Mihara, K., Kappler, J., and Marrack, P. Constitutive association of the proapoptotic protein Bim with Bcl-2-related proteins on mitochondria in T cells. Proc. Natl. Acad. Sci. USA, 101: 7681–7686, 2004.PubMedCrossRefGoogle Scholar
  35. 35.
    Essafi, A., Fernandez, D.M., Hassen, Y.A., Soeiro, I., Mufti, G.J., Thomas, N.S., Medema, R.H., and Lam, E.W. Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells. Oncogene, 2005.Google Scholar
  36. 36.
    Brunet, A., Park, J., Tran, H., Hu, L.S., Hemmings, B.A., and Greenberg, M.E. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol. Cell Biol., 21: 952–965, 2001.PubMedCrossRefGoogle Scholar
  37. 37.
    Lin, T.H., Aplin, A.E., Shen, Y., Chen, Q., Schaller, M., Romer, L., Aukhil, I., and Juliano, R.L. Integrin-mediated activation of MAP kinase is independent of FAK:evidence for dual integrin signaling pathways in fibroblasts. Journal of Cell Biology, 136: 1385–1395, 1997.PubMedCrossRefGoogle Scholar
  38. 38.
    Chen, Q., Lin, T.H., Der, C.J., and Juliano, R.L. Integrin-mediated activation of MEK and mitogen-activated protein kinase is independent of Ras [corrected]. J. Biol. Chem., 271: 18122–18127, 1996.PubMedCrossRefGoogle Scholar
  39. 39.
    Lee J.W. and Juliano R.L. Alpha 5 beta 1 integrin protects intestinal epithelial cells from apoptosis through a phosphatidylinositol 3-kinase and protein kinase B-dependent pathway. Molecular Biology of the Cell, 11: 1973–1987, 2000.PubMedGoogle Scholar
  40. 40.
    Shelly, C. and Herrera, R. Activation of SGK1 by HGF, Rac1 and integrin-mediated cell adhesion in MDCK cells: PI-3K-dependent and -independent pathways. J. Cell Sci., 115: 1985–1993, 2002.PubMedGoogle Scholar
  41. 41.
    Manie, S.N., Sattler, M., Astier, A., Phifer, J.S., Canty, T., Morimoto, C., Druker, B.J., Salgia, R., Griffin, J.D., and Freedman, A.S. Tyrosine phosphorylation of the product of the c-cbl protooncogene is [corrected] induced after integrin stimulation. Exp. Hematol., 25: 45–50, 1997.PubMedGoogle Scholar
  42. 42.
    Solary, E., Bertrand R., Kohn, K.W., and Pommier, Y. Differential induction of apoptosis in undifferentiated and differentiated HL-60 cells by DNA toposiomerase I and II inhibitors. Blood, 81: 1359–1368, 1993.PubMedGoogle Scholar
  43. 43.
    Ruan, S., Okcu, F.M., Ren, J.P., Chiao, P., Andreeff, M., Levin, V., and Zhang, W. Overexpressed WAF1/CIP1 renders glioblastoma cells resistant to chemotherapy agents 1,3-Bis(2-chloroethyl)-1-nitrosurea and cisplatin. Cancer Research, 58: 1538–1543, 1998.PubMedGoogle Scholar
  44. 44.
    Eymin B., Haugg, M., Droin, N., Sordet, O., Dimanche-Boitrel, M.T., and Solary, E. p27Kip1 induces drug resistance by preventing apoptosis upstream of cytochrome c release and procaspase-3 activation in leukemic cells. Oncogene, 18: 1411–1418, 1999.PubMedCrossRefGoogle Scholar
  45. 45.
    Fornaro, M. and Languino, L.R. Alternatively spliced variants:A new veiw of the integrin cytoplasmic domain. Matrix Biology, 16: 185–193, 1997.PubMedCrossRefGoogle Scholar
  46. 46.
    Fornaro, M., Steger, C.A., Bennett, A.M., Wu, J.J., and Languino, L.R. Differential role of beta(1C) and beta(1A) integrin cytoplasmic variants in modulating focal adhesion kinase, protein kinase B/AKT, and Ras/Mitogen-activated protein kinase pathways. Mol.Biol.Cell, 11: 2235–2249, 2000.PubMedGoogle Scholar
  47. 47.
    Zhao, J.H., Reiske, H., and Guan, J.L. Regulation of the cell cycle by focal adhesion kinase. Journal of Cell Biology, 143: 1997–2008, 1997.CrossRefGoogle Scholar
  48. 48.
    Belkin, A.M. and Retta, S.F. β1D integrin inhibits cell cycle progression in normal myoblasts and fibroblasts. Journal of Biological Chemistry, 273: 15234–15240, 1998.PubMedCrossRefGoogle Scholar
  49. 49.
    Meredith, J., Takada Y., Fornaro, M., Languino, L.R., and Schwartz, M.A. Inhibition of the cell cycle progression by the alternatively spliced integrin β1c. Science, 269: 1570–1572, 1995.PubMedCrossRefGoogle Scholar
  50. 50.
    Balzac, F., Retta, S.F., Albini, A., Melchiorri, A., Koteliansky, V.E., Geuna, M., Silengo, L., and Tarone, G. Expression of β1B integrin isoform in CHO cells results in a dominant negative effect on cell adhesion and motility. Journal Cell Biology, 127: 557–565: 1994.CrossRefGoogle Scholar
  51. 51.
    Languino, L. and Ruoslahti, E. An alternative form of the integrin β1 subunit with a variant cytoplasmic domain. Journal of Biological Chemistry, 267: 7116–7120, 1992.PubMedGoogle Scholar
  52. 52.
    Belkin, A.M., Zhidkova, N.I., Balzac, F., Altruda, F., Tomats, D., Maier, A., Tarone, G., Koteliansky, V.A., and Burridge, K. β1D integrin displaces the β1A isoform in striated muscles:Localization at junctional structures and signaling potential in nonmuscle cells. Journal Cell Biology, 132: 211–226, 1996.CrossRefGoogle Scholar
  53. 53.
    Fornaro, M., Tallini, G., Zheng, D.Q., Flanagan, W.M., Manzotti, M., and Languino, L.R. p27(kip1) acts as a downstream effector of and is coexpressed with the beta1C integrin in prostatic adenocarcinoma. J. Clin. Invest, 103: 321–329, 1999.PubMedGoogle Scholar
  54. 54.
    Wang, M.W., Consoli, U., Lane, C.M., Durett, A., Lauppe, M.J., Champlin, R., Andreeff, M., and Deisseroth, A.B. Rescue from apoptosis in early (CD34-selected) versus late (non-CD34-selected) human hematopoietic cells by very late antigen 4- and vascular cell adhesion molecule (VCAM) 1-dependent adhesion to bone marrow stromal cells. Cell Growth Differ., 9: 105–112, 1998.PubMedGoogle Scholar
  55. 55.
    Hurley, R.W., McCarthy, J.B., and Verfaille, C.M. Direct adhesion to bone marrow stroma via fibronectin receptors inhibits hematopoietic progenitor proliferation. Journal Clinical Investigations, 96: 511–519, 1995.CrossRefGoogle Scholar
  56. 56.
    Hurley, R.W., McCarthy, J.B., Wayner, E.A., and Verfaille, C.M. Monoclonal antibody crosslinking of the α4 or β1 integrin inhibits committed clonogenic hematopoietic progenitor proliferation. Experimental Hematology, 25: 321–328, 1997.PubMedGoogle Scholar
  57. 57.
    Kremer, C.L., Schmelz, M., and Cress, A.E. Integrin-dependent amplification of the G2 arrest induced by ionizing radiation. Prostate, 2005.Google Scholar
  58. 58.
    Jones, C.B., McIntosh, J., Huang, H., Graytock, A., Hoyt, D.G. Regulation of bleomycin-induced DNA breakage and chromatin structure in lung endothelial cells by integrins and poly(ADP-ribose)polymerase. Mol Pharmacol. 59: 69–75, 2001.PubMedGoogle Scholar
  59. 59.
    Rose, J.L., Huang, H., Wray, S.F., and Hoyt, D.G. Integrin engagement increases histone H3 acetylation and reduces histone H1 association with DNA in murine lung endothelial cells. Mol. Pharmacol., 68: 439–446, 2005.PubMedCrossRefGoogle Scholar
  60. 60.
    Tsai, S., Valkov, N., Yang, W., Gunp, J., Sullivan, D., and Seto E. Histone deactylase interacts directly with DNA toposiomerase II. Nature Genetics, 26: 349–353, 2000.PubMedCrossRefGoogle Scholar
  61. 61.
    Matsunaga, T., Takemoto, N., Sato, T., Takimoto, R., Tanaka, I., Fujimi, A., Akiyama, T., Kuroda, H., Kawano, Y., Kobune, M., Kato, J., Hirayama, Y., Sakamaki, S., Kohda, K., Miyake, K., and Niitsu, Y. Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Nat. Med., 9: 1158–1165, 2003.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2006

Authors and Affiliations

  • Lori A. Hazlehurst
    • 1
  1. 1.Experimental Therapeutics Section, H. Lee Moffitt Cancer CenterTampaUSA

Personalised recommendations