The Role of Membrane Complement Regulatory Proteins in Cancer Immunotherapy

  • Jun Yan
  • Daniel J. Allendorf
  • Bing Li
  • Ruowan Yan
  • Richard Hansen
  • Rossen Donev
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 632)


Anti-tumor monoclonal antibody therapy represents one of the earliest targeted therapy in clinical cancer care and has achieved a great clinical promise. Complement activation mediated by anti-tumor mAbs can result in direct tumor lysis or enhancement of antibody-dependent cellular cytotoxicy. Chemotaxis of phagocytic cells by complement activation products C5a is also required for certain cancer immunotherapy such as combined β -glucan with anti-tumor mAb therapy. However, high expression levels of membrane-bound complement regulatory proteins (mCRPs) such as CD46, CD55 and CD59 on tumors significantly limit the anti-tumor mAb therapeutic efficacy. In addition, mCRPs have been shown to directly or indirectly down-regulate adaptive T cell responses. Therefore, it is desirable to combine anti-tumor mAb therapy or tumor vaccines with the blockade of mCRPs. Such strategies so far include the utilization of neutralizing mAbs for mCRPs, small interfering RNAs or anti-sense oligos for mCRPs, and chemotherapeutic drugs or cytokines. In vitro studies have demonstrated the feasibility and efficacy of such methods although concerns have been raised about the for utilization of neutralizing mAbs in vivo due to widespread expression of mCRPs on normal cells and tissues. Strategies have been developed to address these issues and more in vivo studies are needed to further validate these combination approaches.


Complement Activation CD46 mRNA Expression Complement Activation Product Protect Host Cell Follicular Dendritic Cell Tumor 
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.



This work was supported by NIH/NCI RO1 CA86412, the Kentucky Lung Cancer Research Board, the James Graham Brown Cancer Center Pilot Project Program to J.Y. and by the MRC New Investigator Grant 81345 to R.D.


  1. Adams, G. P. and Weiner, L. M. (2005). Monoclonal antibody therapy of cancer. Nat Biotechnol 23, 1147–1157PubMedCrossRefGoogle Scholar
  2. Ajona, D., Hsu, Y. F., Corrales, L., Montuenga, L. M., and Pio, R. (2007). Down-regulation of human complement factor H sensitizes non-small cell lung cancer cells to complement attack and reduces in vivo tumor growth. J Immunol 178, 5991–5998PubMedGoogle Scholar
  3. Allendorf, D. J., Yan, J., Ross, G. D., Hansen, R. D., Baran, J. T., Subbarao, K., Wang, L., and Haribabu, B. (2005). C5a-mediated leukotriene B4-amplified neutrophil chemotaxis is essential in tumor immunotherapy facilitated by anti-tumor monoclonal antibody and {beta}-glucan. J Immunol 174, 7050–7056PubMedGoogle Scholar
  4. Babiker, A. A., Nilsson, B., Ronquist, G., Carlsson, L., and Ekdahl, K. N. (2005). Transfer of functional prostasomal CD59 of metastatic prostatic cancer cell origin protects cells against complement attack. Prostate 62, 105–114PubMedCrossRefGoogle Scholar
  5. Bannerji, R., Kitada, S., Flinn, I. W., Pearson, M., Young, D., Reed, J. C., and Byrd, J. C. (2003). Apoptotic-regulatory and complement-protecting protein expression in chronic lymphocytic leukemia: relationship to in vivo rituximab resistance. J Clin Oncol 21, 1466–1471PubMedCrossRefGoogle Scholar
  6. Barchet, W., Price, J. D., Cella, M., Colonna, M., MacMillan, S. K., Cobb, J. P., Thompson, P. A., Murphy, K. M., Atkinson, J. P., and Kemper, C. (2006). Complement-induced regulatory T cells suppress T-cell responses but allow for dendritic-cell maturation. Blood 107, 1497–1504PubMedCrossRefGoogle Scholar
  7. Barilla-LaBarca, M. L., Liszewski, M. K., Lambris, J. D., Hourcade, D., and Atkinson, J. P. (2002). Role of membrane cofactor protein (CD46) in regulation of C4b and C3b deposited on cells. J Immunol 168, 6298–6304PubMedGoogle Scholar
  8. Bjorge, L., Hakulinen, J., Wahlstrom, T., Matre, R., and Meri, S. (1997). Complement-regulatory proteins in ovarian malignancies. Int J Cancer 70, 14–25PubMedCrossRefGoogle Scholar
  9. Budzko, D. B., Lachmann, P. J., and McConnell, I. (1976). Activation of the alternative complement pathway by lymphoblastoid cell lines derived from patients with Burkitt’s lymphoma and infectious mononucleosis. Cell Immunol 22, 98–109PubMedCrossRefGoogle Scholar
  10. Buettner, R., Mora, L. B., and Jove, R. (2002). Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res 8, 945–954PubMedGoogle Scholar
  11. Buettner, R., Huang, M., Gritsko, T., Karras, J., Enkemann, S., Mesa, T., Nam, S., Yu, H., and Jove, R. (2007). Activated signal transducers and activators of transcription 3 signaling induces CD46 expression and protects human cancer cells from complement-dependent cytotoxicity. Mol Cancer Res 5, 823–832PubMedCrossRefGoogle Scholar
  12. Chen, S., Caragine, T., Cheung, N. K., and Tomlinson, S. (2000). CD59 expressed on a tumor cell surface modulates decay-accelerating factor expression and enhances tumor growth in a rat model of human neuroblastoma. Cancer Res 60, 3013–3018PubMedGoogle Scholar
  13. Cheung, N. K., Walter, E. I., Smith-Mensah, W. H., Ratnoff, W. D., Tykocinski, M. L., and Medof, M. E. (1988). Decay-accelerating factor protects human tumor cells from complement-mediated cytotoxicity in vitro. J Clin Invest 81, 1122–1128PubMedCrossRefGoogle Scholar
  14. Coulson, J. M., Edgson, J. L., Woll, P. J., and Quinn, J. P. (2000). A splice variant of the neuron-restrictive silencer factor repressor is expressed in small cell lung cancer: a potential role in derepression of neuroendocrine genes and a useful clinical marker. Cancer Res 60, 1840–1844PubMedGoogle Scholar
  15. Di Gaetano, N., Xiao, Y., Erba, E., Bassan, R., Rambaldi, A., Golay, J., and Introna, M. (2001). Synergism between fludarabine and rituximab revealed in a follicular lymphoma cell line resistant to the cytotoxic activity of either drug alone. Br J Haematol 114, 800–809PubMedCrossRefGoogle Scholar
  16. Donev, R. M., Cole, D. S., Sivasankar, B., Hughes, T. R., and Morgan, B. P. (2006). p53 regulates cellular resistance to complement lysis through enhanced expression of CD59. Cancer Res 66, 2451–2458PubMedCrossRefGoogle Scholar
  17. Donin, N., Jurianz, K., Ziporen, L., Schultz, S., Kirschfink, M., and Fishelson, Z. (2003). Complement resistance of human carcinoma cells depends on membrane regulatory proteins, protein kinases and sialic acid. Clin Exp Immunol 131, 254–263PubMedCrossRefGoogle Scholar
  18. Ellison, B. S., Zanin, M. K., and Boackle, R. J. (2007). Complement susceptibility in glutamine deprived breast cancer cells. Cell Div 2, 20PubMedCrossRefGoogle Scholar
  19. Faderl, S., Coutre, S., Byrd, J. C., Dearden, C., Denes, A., Dyer, M. J., Gregory, S. A., Gribben, J. G., Hillmen, P., Keating, M., Rosen, S., Venugopal, P., and Rai, K. (2005). The evolving role of alemtuzumab in management of patients with CLL. Leukemia 19, 2147–2152PubMedCrossRefGoogle Scholar
  20. Fang, C., Miwa, T., Shen, H., and Song, W. C. (2007). Complement-dependent enhancement of CD8+ T cell immunity to lymphocytic choriomeningitis virus infection in decay-accelerating factor-deficient mice. J Immunol 179, 3178–3186PubMedGoogle Scholar
  21. Fishelson, Z., Donin, N., Zell, S., Schultz, S., and Kirschfink, M. (2003). Obstacles to cancer immunotherapy: expression of membrane complement regulatory proteins (mCRPs) in tumors. Mol Immunol 40, 109–123PubMedCrossRefGoogle Scholar
  22. Fonsatti, E., Altomonte, M., Coral, S., De Nardo, C., Lamaj, E., Sigalotti, L., Natali, P. G., and Maio, M. (2000). Emerging role of protectin (CD59) in humoral immunotherapy of solid malignancies. Clin Ter 151, 187–193PubMedGoogle Scholar
  23. Gelderman, K. A., Blok, V. T., Fleuren, G. J., and Gorter, A. (2002a). The inhibitory effect of CD46, CD55, and CD59 on complement activation after immunotherapeutic treatment of cervical carcinoma cells with monoclonal antibodies or bispecific monoclonal antibodies. Lab Invest 82, 483–493CrossRefGoogle Scholar
  24. Gelderman, K. A., Kuppen, P. J., Bruin, W., Fleuren, G. J., and Gorter, A. (2002b). Enhancement of the complement activating capacity of 17-1A mAb to overcome the effect of membrane-bound complement regulatory proteins on colorectal carcinoma. Eur J Immunol 32, 128–135CrossRefGoogle Scholar
  25. Gelderman, K. A., Kuppen, P. J., Okada, N., Fleuren, G. J., and Gorter, A. (2004a). Tumor-specific inhibition of membrane-bound complement regulatory protein Crry with bispecific monoclonal antibodies prevents tumor outgrowth in a rat colorectal cancer lung metastases model. Cancer Res 64, 4366–4372CrossRefGoogle Scholar
  26. Gelderman, K. A., Tomlinson, S., Ross, G. D., and Gorter, A. (2004b). Complement function in mAb-mediated cancer immunotherapy. Trends Immunol 25, 158–164CrossRefGoogle Scholar
  27. Gelderman, K. A., Lam, S., Sier, C. F., and Gorter, A. (2006). Cross-linking tumor cells with effector cells via CD55 with a bispecific mAb induces beta-glucan-dependent CR3-dependent cellular cytotoxicity. Eur J Immunol 36, 977–984PubMedCrossRefGoogle Scholar
  28. Gorter, A., Blok, V. T., Haasnoot, W. H., Ensink, N. G., Daha, M. R., and Fleuren, G. J. (1996). Expression of CD46, CD55, and CD59 on renal tumor cell lines and their role in preventing complement-mediated tumor cell lysis. Lab Invest 74, 1039–1049PubMedGoogle Scholar
  29. Greenblatt, M. S., Bennett, W. P., Hollstein, M., and Harris, C. C. (1994). Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54, 4855–4878PubMedGoogle Scholar
  30. Harris, C. L., Kan, K. S., Stevenson, G. T., and Morgan, B. P. (1997). Tumour cell killing using chemically engineered antibody constructs specific for tumour cells and the complement inhibitor CD59. Clin Exp Immunol 107, 364–371PubMedCrossRefGoogle Scholar
  31. Heeger, P. S., Lalli, P. N., Lin, F., Valujskikh, A., Liu, J., Muqim, N., Xu, Y., and Medof, M. E. (2005). Decay-accelerating factor modulates induction of T cell immunity. J Exp Med 201, 1523–1530PubMedCrossRefGoogle Scholar
  32. Holla, V. R., Wang, D., Brown, J. R., Mann, J. R., Katkuri, S., and DuBois, R. N. (2005). Prostaglandin E2 regulates the complement inhibitor CD55/decay-accelerating factor in colorectal cancer. J Biol Chem 280, 476–483PubMedGoogle Scholar
  33. Hong, F., Hansen, R. D., Yan, J., Allendorf, D. J., Baran, J. T., Ostroff, G. R., and Ross, G. D. (2003). Beta-glucan functions as an adjuvant for monoclonal antibody immunotherapy by recruiting tumoricidal granulocytes as killer cells. Cancer Res 63, 9023–9031PubMedGoogle Scholar
  34. Huber-Lang, M., Sarma, J. V., Zetoune, F. S., Rittirsch, D., Neff, T. A., McGuire, S. R., Lambris, J. D., Warner, R. L., Flierl, M. A., Hoesel, L. M., Gebhard, F., Younger, J. G., Drouin, S. M., Wetsel, R. A., and Ward, P. A. (2006). Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 12, 682–687PubMedCrossRefGoogle Scholar
  35. Inoue, H., Mizuno, M., Uesu, T., Ueki, T., and Tsuji, T. (1994). Distribution of complement regulatory proteins, decay-accelerating factor, CD59/homologous restriction factor 20 and membrane cofactor protein in human colorectal adenoma and cancer. Acta Med Okayama 48, 271–277PubMedGoogle Scholar
  36. Jarvis, G. A., Li, J., Hakulinen, J., Brady, K. A., Nordling, S., Dahiya, R., and Meri, S. (1997). Expression and function of the complement membrane attack complex inhibitor protectin (CD59) in human prostate cancer. Int J Cancer 71, 1049–1055PubMedCrossRefGoogle Scholar
  37. Junnikkala, S., Jokiranta, T. S., Friese, M. A., Jarva, H., Zipfel, P. F., and Meri, S. (2000). Exceptional resistance of human H2 glioblastoma cells to complement-mediated killing by expression and utilization of factor H and factor H-like protein 1. J Immunol 164, 6075–6081PubMedGoogle Scholar
  38. Jurianz, K., Maslak, S., Garcia-Schuler, H., Fishelson, Z., and Kirschfink, M. (1999). Neutralization of complement regulatory proteins augments lysis of breast carcinoma cells targeted with rhumAb anti-HER2. Immunopharmacology 42, 209–218PubMedCrossRefGoogle Scholar
  39. Jurianz, K., Ziegler, S., Donin, N., Reiter, Y., Fishelson, Z., and Kirschfink, M. (2001). K562 erythroleukemic cells are equipped with multiple mechanisms of resistance to lysis by complement. Int J Cancer 93, 848–854PubMedCrossRefGoogle Scholar
  40. Kemper, C., Chan, A. C., Green, J. M., Brett, K. A., Murphy, K. M., and Atkinson, J. P. (2003). Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature 421, 388–392PubMedCrossRefGoogle Scholar
  41. Kiso, T., Mizuno, M., Nasu, J., Shimo, K., Uesu, T., Yamamoto, K., Okada, H., Fujita, T., and Tsuji, T. (2002). Enhanced expression of decay-accelerating factor and CD59/homologous restriction factor 20 in intestinal metaplasia, gastric adenomas and intestinal-type gastric carcinomas but not in diffuse-type carcinomas. Histopathology 40, 339–347PubMedCrossRefGoogle Scholar
  42. Koretz, K., Bruderlein, S., Henne, C., and Moller,. P. (1992)Decay-accelerating factor (DAF, CD55) in normal colorectal mucosa, adenomas and carcinomas. Br J Cancer 66, 810–814PubMedCrossRefGoogle Scholar
  43. Kuraya, M., Yefenof, E., Klein, G., and Klein,. E. (1992)Expression of the complement regulatory proteins CD21, CD55 and CD59 on Burkitt lymphoma lines: their role in sensitivity to human serum-mediated lysis. Eur J Immunol 22, 1871–1876PubMedCrossRefGoogle Scholar
  44. Lalli, P. N., Strainic, M. G., Lin, F., Medof, M. E., and Heeger, P. S. (2007). Decay accelerating factor can control T cell differentiation into IFN-{gamma}-producing effector cells via regulating local C5a-induced IL-12 production. J Immunol 179, 5793–5802PubMedGoogle Scholar
  45. Leyland-Jones, B. (2002). Trastuzumab: hopes and realities. Lancet Oncol 3, 137–144PubMedCrossRefGoogle Scholar
  46. Li, B., Allendorf, D. J., Hansen, R., Marroquin, J., Ding, C., Cramer, D. E., and Yan, J. (2006). Yeast beta-glucan amplifies phagocyte killing of iC3b-opsonized tumor cells via complement receptor 3-Syk-phosphatidylinositol 3-kinase pathway. J Immunol 177, 1661–1669PubMedGoogle Scholar
  47. Li, B., Allendorf, D. J., Hansen, R., Marroquin, J., Cramer, D. E., Harris, C. L., and Yan, J. (2007). Combined yeast {beta}-glucan and antitumor monoclonal antibody therapy requires C5a-mediated neutrophil chemotaxis via regulation of decay-accelerating factor CD55. Cancer Res 67, 7421–7430PubMedCrossRefGoogle Scholar
  48. Liljefors, M., Nilsson, B., Fagerberg, J., Ragnhammar, P., Mellstedt, H., and Frodin, J. E. (2005). Clinical effects of a chimeric anti-EpCAM monoclonal antibody in combination with granulocyte-macrophage colony-stimulating factor in patients with metastatic colorectal carcinoma. Int J Oncol 26, 1581–1589PubMedGoogle Scholar
  49. Linton, S. M. and Morgan, B. P. (1999). Complement activation and inhibition in experimental models of arthritis. Mol Immunol 36, 905–914PubMedCrossRefGoogle Scholar
  50. Liu, J., Miwa, T., Hilliard, B., Chen, Y., Lambris, J. D., Wells, A. D., and Song, W. C. (2005). The complement inhibitory protein DAF (CD55) suppresses T cell immunity in vivo. J Exp Med 201, 567–577PubMedCrossRefGoogle Scholar
  51. Loberg, R. D., Day, L. L., Dunn, R., Kalikin, L. M., and Pienta, K. J. (2006). Inhibition of decay-accelerating factor (CD55) attenuates prostate cancer growth and survival in vivo. Neoplasia 8, 69–78PubMedCrossRefGoogle Scholar
  52. Longhi, M. P., Sivasankar, B., Omidvar, N., Morgan, B. P., and Gallimore, A. (2005). Cutting edge: murine CD59a modulates antiviral CD4+ T cell activity in a complement-independent manner. J Immunol 175, 7098–7102PubMedGoogle Scholar
  53. Longhi, M. P., Harris, C. L., Morgan, B. P., and Gallimore,. A. (2006)Holding T cells in check – a new role for complement regulators?, Trends Immunol 27102–108PubMedCrossRefGoogle Scholar
  54. Lublin, D. M. and Atkinson, J. P. (1989). Decay-accelerating factor: biochemistry, molecular biology, and function. Annu Rev Immunol 7, 35–58PubMedCrossRefGoogle Scholar
  55. Lucas, S. D., Karlsson-Parra, A., Nilsson, B., Grimelius, L., Akerstrom, G., Rastad, J., and Juhlin, C. (1996). Tumor-specific deposition of immunoglobulin G and complement in papillary thyroid carcinoma. Hum Pathol 27, 1329–1335PubMedCrossRefGoogle Scholar
  56. Ma, Y., Uemura, K., Oka, S., Kozutsumi, Y., Kawasaki, N., and Kawasaki, T. (1999). Antitumor activity of mannan-binding protein in vivo as revealed by a virus expression system: mannan-binding proteindependent cell-mediated cytotoxicity. Proc Natl Acad Sci U S A 96, 371–375PubMedCrossRefGoogle Scholar
  57. Macor, P. and Tedesco, F. (2007). Complement as effector system in cancer immunotherapy. Immunol Lett 111, 6–13PubMedCrossRefGoogle Scholar
  58. Madjd, Z., Durrant, L. G., Bradley, R., Spendlove, I., Ellis, I. O., and Pinder, S. E. (2004). Loss of CD55 is associated with aggressive breast tumors. Clin Cancer Res 10, 2797–2803PubMedCrossRefGoogle Scholar
  59. Magyarlaki, T., Mosolits, S., Baranyay, F., and Buzogany, I. (1996). Immunohistochemistry of complement response on human renal cell carcinoma biopsies. Tumori 82, 473–479PubMedGoogle Scholar
  60. Manderson, A. P., Botto, M., and Walport, M. J. (2004). The role of complement in the development of systemic lupus erythematosus. Annu Rev Immunol 22, 431–456PubMedCrossRefGoogle Scholar
  61. Marie, J. C., Astier, A. L., Rivailler, P., Rabourdin-Combe, C., Wild, T. F., and Horvat, B. (2002). Linking innate and acquired immunity: divergent role of CD46 cytoplasmic domains in T cell induced inflammation. Nat Immunol 3, 659–666PubMedGoogle Scholar
  62. Mason, J. C., Steinberg, R., Lidington, E. A., Kinderlerer, A. R., Ohba, M., and Haskard, D. O. (2004). Decay-accelerating factor induction on vascular endothelium by vascular endothelial growth factor (VEGF) is mediated via a VEGF receptor-2 (VEGF-R2)- and protein kinase C-alpha/epsilon (PKCalpha/epsilon)-dependent cytoprotective signaling pathway and is inhibited by cyclosporin A. J Biol Chem, 27941611–41618PubMedCrossRefGoogle Scholar
  63. Mastellos, D. and Lambris, J. D. (2002). Complement: more than a ‘guard’ against invading pathogens?, Trends Immunol23485–491PubMedCrossRefGoogle Scholar
  64. Matsumoto, M., Takeda, J., Inoue, N., Hara, T., Hatanaka, M., Takahashi, K., Nagasawa, S., Akedo, H., and Seya, T. (1997). A novel protein that participates in nonself discrimination of malignant cells by homologous complement. Nat Med 3, 1266–1270PubMedCrossRefGoogle Scholar
  65. Medof, M. E., Iida, K., Mold, C., and Nussenzweig,. V. (1982)Unique role of the complement receptor CR1 in the degradation of C3b associated with immune complexes. J Exp Med 156, 1739–1754PubMedCrossRefGoogle Scholar
  66. Morgan, B. P. (2000). The complement system: an overview. Methods Mol Biol 150, 1–13PubMedGoogle Scholar
  67. Muller-Eberhard, H. J. (1986). The membrane attack complex of complement. Annu Rev Immunol 4, 503–528PubMedCrossRefGoogle Scholar
  68. Murray, K. P., Mathure, S., Kaul, R., Khan, S., Carson, L. F., Twiggs, L. B., Martens, M. G., and Kaul, A. (2000). Expression of complement regulatory proteins-CD 35, CD 46, CD 55, and CD 59-in benign and malignant endometrial tissue. Gynecol Oncol 76, 176–182PubMedCrossRefGoogle Scholar
  69. Niculescu, F., Rus, H. G., Retegan, M., and Vlaicu, R. (1992). Persistent complement activation on tumor cells in breast cancer. Am J Pathol 140, 1039–1043PubMedGoogle Scholar
  70. Niehans, G. A., Cherwitz, D. L., Staley, N. A., Knapp, D. J., and Dalmasso, A. P. (1996). Human carcinomas variably express the complement inhibitory proteins CD46 (membrane cofactor protein), CD55 (decay-accelerating factor), and CD59 (protectin). Am J Pathol 149, 129–142PubMedGoogle Scholar
  71. Palm, K., Metsis, M., and Timmusk, T.. (1999)Neuron-specific splicing of zinc finger transcription factor REST/NRSF/XBR is frequent in neuroblastomas and conserved in human, mouse and rat. Brain Res Mol Brain, Res7230–39CrossRefGoogle Scholar
  72. Price, J. D., Schaumburg, J., Sandin, C., Atkinson, J. P., Lindahl, G., and Kemper, C. (2005). Induction of a regulatory phenotype in human CD4+ T cells by streptococcal M protein. Journal of Immunology 175, 677–684Google Scholar
  73. Pritchard-Jones, K., Spendlove, I., Wilton, C., Whelan, J., Weeden, S., Lewis, I., Hale, J., Douglas, C., Pagonis, C., Campbell, B., Alvarez, P., Halbert, G., and Durrant, L. G. (2005). Immune responses to the 105AD7 human anti-idiotypic vaccine after intensive chemotherapy, for osteosarcoma. Br J Cancer 92, 1358–1365PubMedCrossRefGoogle Scholar
  74. Ravindranath, N. M., and Shuler, C. (2006). Expression of complement restriction factors (CD46, CD55 & CD59) in head and neck squamous cell carcinomas. J Oral Pathol Med 35, 560–567PubMedCrossRefGoogle Scholar
  75. Ross, G. D. (2000). Regulation of the adhesion versus cytotoxic functions of the Mac-1/CR3/alphaMbeta2-integrin glycoprotein. Crit Rev Immunol 20, 197–222PubMedGoogle Scholar
  76. Ross, J. S., Schenkein, D. P., Pietrusko, R., Rolfe, M., Linette, G. P., Stec, J., Stagliano, N. E., Ginsburg, G. S., Symmans, W. F., Pusztai, L., and Hortobagyi, G. N. (2004). Targeted therapies for cancer 2004. Am J Clin Pathol, 122598–609PubMedCrossRefGoogle Scholar
  77. Ruf, P., Gires, O., Jager, M., Fellinger, K., Atz, J., and Lindhofer, H. (2007). Characterisation of the new EpCAM-specific antibody HO-3: implications for trifunctional antibody immunotherapy of cancer. Br J Cancer 97, 315–321PubMedCrossRefGoogle Scholar
  78. Ruiz-Arguelles, A. and Llorente, L. (2007). The role of complement regulatory proteins (CD55 and CD59) in the pathogenesis of autoimmune hemocytopenias. Autoimmun Rev 6, 155–161PubMedCrossRefGoogle Scholar
  79. Sakuma, T., Kodama, K., Hara, T., Eshita, Y., Shibata, N., Matsumoto, M., Seya, T., and Mori, Y. (1993). Levels of complement regulatory molecules in lung cancer: disappearance of the D17 epitope of CD55 in small-cell carcinoma. Jpn J Cancer Res 84, 753–759PubMedCrossRefGoogle Scholar
  80. Schmitt, C. A., Schwaeble, W., Wittig, B. M., Meyer zum Buschenfelde, K. H., and Dippold, W. G. (1999). Expression and regulation by interferon-gamma of the membrane-bound complement regulators CD46 (MCP), CD55 (DAF) and CD59 in gastrointestinal tumours. Eur J Cancer 35, 117–124PubMedCrossRefGoogle Scholar
  81. Seya, T., Turner, J. R., and Atkinson, J. P. (1986). Purification and characterization of a membrane protein (gp45-70) that is a cofactor for cleavage of C3b and C4b. J Exp Med 163, 837–855PubMedCrossRefGoogle Scholar
  82. Seya, T., Matsumoto, M., Hara, T., Hatanaka, M., Masaoka, T., and Akedo, H. (1994). Distribution of C3-step regulatory proteins of the complement system, CD35 (CR1), CD46 (MCP), and CD55 (DAF), in hematological malignancies. Leuk Lymphoma 12, 395–400PubMedCrossRefGoogle Scholar
  83. Shinoura, N., Heffelfinger, S. C., Miller, M., Shamraj, O. I., Miura, N. H., Larson, J. J., DeTribolet, N., Warnick, R. E., Tew, J. J., and Menon, A. G. (1994). RNA expression of complement regulatory proteins in human brain tumors. Cancer Lett 86, 143–149PubMedCrossRefGoogle Scholar
  84. Simpson, K. L., Jones, A., Norman, S., and Holmes, C. H. (1997). Expression of the complement regulatory proteins decay accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46) and CD59 in the normal human uterine cervix and in premalignant and malignant cervical disease. Am J Pathol 151, 1455–1467PubMedGoogle Scholar
  85. Sohn, J. H., Bora, P. S., Jha, P., Tezel, T. H., Kaplan, H. J., and Bora, N. S. (2007). Complement, innate immunity and ocular disease. Chem Immunol Allergy 92, 105–114PubMedCrossRefGoogle Scholar
  86. Song, W. C. (2006). Complement regulatory proteins and autoimmunity. Autoimmunity 39, 403–410PubMedCrossRefGoogle Scholar
  87. Spendlove, I., Ramage, J. M., Bradley, R., Harris, C., and Durrant, L. G. (2006). Complement decay accelerating factor (DAF)/CD55 in cancer. Cancer Immunol Immunother 55, 987–995PubMedCrossRefGoogle Scholar
  88. Spiller, O. B., Criado-Garcia, O., Rodriguez De Cordoba, S., and Morgan, B. P. (2000). Cytokine-mediated up-regulation of CD55 and CD59 protects human hepatoma cells from complement attack. Clin Exp Immunol 121, 234–241PubMedCrossRefGoogle Scholar
  89. Stein, R., Govindan, S. V., Hayes, M., Griffiths, G. L., Hansen, H. J., Horak, I. D., and Goldenberg, D. M. (2005). Advantage of a residualizing iodine radiolabel in the therapy of a colon cancer xenograft targeted with an anticarcinoembryonic antigen monoclonal antibody. Clin Cancer Res 11, 2727–2734PubMedCrossRefGoogle Scholar
  90. Takei, K., Yamazaki, T., Sawada, U., Ishizuka, H., and Aizawa, S. (2006). Analysis of changes in CD20, CD55, and CD59 expression on established rituximab-resistant B-lymphoma cell lines. Leuk Res 30, 625–631PubMedCrossRefGoogle Scholar
  91. Treon, S. P., Mitsiades, C., Mitsiades, N., Young, G., Doss, D., Schlossman, R., and Anderson, K. C. (2001). Tumor cell expression of CD59 is associated with resistance to CD20 serotherapy in patients with B-cell malignancies. J Immunother 24, 263–271CrossRefGoogle Scholar
  92. Valsesia-Wittmann, S., Magdeleine, M., Dupasquier, S., Garin, E., Jallas, A. C., Combaret, V., Krause, A., Leissner, P., and Puisieux, A. (2004). Oncogenic cooperation between H-Twist and N-Myc overrides failsafe programs in cancer cells. Cancer Cell 6, 625–630PubMedCrossRefGoogle Scholar
  93. Vetvicka, V., Thornton, B. P., Wieman, T. J., and Ross, G. D. (1997). Targeting of natural killer cells to mammary carcinoma via naturally occurring tumor cell-bound iC3b and beta-glucan-primed CR3 (CD11b/CD18). J Immunol 159, 599–605PubMedGoogle Scholar
  94. Walport, M. J. (2001a). Complement. First of two parts. N Engl J Med 344, 1058–1066CrossRefGoogle Scholar
  95. Walport, M. J. (2001b). Complement. Second of two parts. N Engl J Med 344, 1140–1144CrossRefGoogle Scholar
  96. Weichenthal, M., Siemann, U., Neuber, K., and Breitbart, E. W. (1999). Expression of complement regulator proteins in primary and metastatic malignant melanoma. J Cutan Pathol 26, 217–221PubMedCrossRefGoogle Scholar
  97. Weiner, G. J., and Link, B. K. (2004). Monoclonal antibody therapy of B cell lymphoma. Expert Opin Biol Ther 4, 375–385PubMedCrossRefGoogle Scholar
  98. Westbrook, T. F., Martin, E. S., Schlabach, M. R., Leng, Y., Liang, A. C., Feng, B., Zhao, J. J., Roberts, T. M., Mandel, G., Hannon, G. J., Depinho, R. A., Chin, L., and Elledge, S. J. (2005). A genetic screen for candidate tumor suppressors identifies REST. Cell, 121837–848PubMedCrossRefGoogle Scholar
  99. Yamakawa, M., Yamada, K., Tsuge, T., Ohrui, H., Ogata, T., Dobashi, M., and Imai, Y. (1994). Protection of thyroid cancer cells by complement-regulatory factors. Cancer 73, 2808–2817PubMedCrossRefGoogle Scholar
  100. Yan, J., Allendorf, D. J., and Brandley, B. (2005). Yeast whole glucan particle (WGP) beta-glucan in conjunction with antitumour monoclonal antibodies to treat cancer. Expert Opin Biol Ther 5, 691–702PubMedCrossRefGoogle Scholar
  101. Yu, H. and Jove, R. (2004). The STATs of cancer – new molecular targets come of age. Nat Rev Cancer 4, 97–105PubMedCrossRefGoogle Scholar
  102. Zell, S., Geis, N., Rutz, R., Schultz, S., Giese, T., and Kirschfink, M. (2007). Down-regulation of CD55 and CD46 expression by anti-sense phosphorothioate oligonucleotides (S-ODNs) sensitizes tumour cells to complement attack. Clin Exp Immunol 150, 576–584PubMedCrossRefGoogle Scholar
  103. Zwart, B., Ciurana, C., Rensink, I., Manoe, R., Hack, C. E., and Aarden, L. A. (2004). Complement activation by apoptotic cells occurs pred et al. ominantly via IgM and is limited to late apoptotic (secondary necrotic) cells. Autoimmunity 37, 95–102PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Jun Yan
    • 1
  • Daniel J. Allendorf
  • Bing Li
  • Ruowan Yan
  • Richard Hansen
  • Rossen Donev
    • 2
  1. 1.Tumor Immunobiology Program of the James Graham Brown Cancer Center, Department of MedicineUniversity of Louisville School of MedicineLouisvilleUSA
  2. 2.Complement Biology Group, Department of Medical Biochemistry and Immunologychool of MedicineCardiff UniversityUK

Personalised recommendations