Modulation of mCRPs for Immunotherapy

Chemo Secrets From a Breast Cancer Survivor

Breast Cancer Survivors

Get Instant Access

Since mCRPs can prevent efficient complement activation, inhibit complement-mediated killing mechanisms such as CDC, ADCC, CR3-DCC, and also down-regulate effector T cell responses, it is therefore hypothesized that blockade or neutralizing mCRPs would significantly improve anti-tumor mAb-based tumor immunotherapy or vaccine-mediated anti-tumor immune responses. These strategies include neutralizing mAbs against mCRPs, small interfering RNAs or anti-sense oligos to knockdown mCRPs, utilization of chemotherapeutic drugs or cytokines to downregulate mCRPs, and a recently proposed new approach for suppression of expression of membrane-bound complement regulator (mCR) genes.

5.1 Neutralizing mAbs

Specific inhibition of mCRP activity has been achieved with blocking mAbs against CD46, CD55, and CD59. In most of in vitro studies, anti-mCRP blocking mAbs have successfully demonstrated the enhancement of susceptibility of tumor cells to complement-mediated killing mechanisms. For example, neutralization of CD55 with blocking mAb in Burkitt lymphoma cells (Kuraya et al. 1992), leukemia cells (Jurianz et al. 2001), melanoma cells (Cheung et al. 1988), and breast cancer cells (Madjd et al. 2004) can significantly increase their sensitivity to complement-mediated killing. Similarly, blockade of CD59 with neutralizing mAb significantly enhances efficiency of complement-mediated lysis to neutroblastoma cells (Chen et al. 2000), leukemia cells (Jurianz et al. 2001), breast (Ellison et al. 2007), ovarian (Donin et al. 2003), renal (Gorter et al. 1996), and prostate carcinoma cells (Jarvis et al. 1997). Blocking mAb for CD46 is controversial in the in vitro studies. In renal carcinoma, blocking CD46 did not significantly affect complement sensitivity (Ajona et al. 2007). This may be related to a particular blocking mAb since inhibition of CD46 mRNA expression significantly increases complement-mediated lysis (Buettner et al. 2007).

Inhibition of mCRPs with neutralizing mAbs may also enhance ADCC effect via iC3b-CR3 interaction. Our recent study indicated that anti-CD55 blocking mAb, but not anti-CD46 blocking mAb, significantly enhanced iC3b deposition on tumors mediated by anti-her-2/neu mAb (Li et al. 2007). Although blocking anti-CD55 itself does not significantly increase the iC3b-CR3-mediated ADCC, enhanced iC3b deposition on tumors synergizes with yeast-derived p-glucan to elicit enhanced CR3-DCC in vitro. More importantly, in vivo administration with anti-CD55 mAb with p-glucan plus anti-her-2/neu mAb elicited tumor regression and long survival in animals bearing the previously resistant SKOV-3 human ovarian carcinoma. In addition, blocking anti-CD55 significantly led to C5a release and massive neutrophil influx within tumors.

However, one concern regarding use of anti-mCRP mAb blockade in vivo is widespread expression of mCRPs on normal tissues or cells such as red blood cells (Lublin and Atkinson 1989). This could potentially lead to hemolytic or vascular disease as a result of increased complement activation on normal cells or targeting by ADCC. This drawback may be overcome by using bi-specific mAb against tumor Ag with higher affinity and CD55 or CD59 with lower affinity (Gelderman et al. 2002a,b; Harris et al. 1997). A previous study has demonstrated that this strategy could specifically target tumor cells with minimally binding to normal cells and increase p-glucan mediated CR3-DCC (Gelderman et al. 2006). Indeed, bi-specific mAb to epithelial cell adhesion molecule (Ep-CAM) and Crry in rat has demonstrated a significant therapeutic efficacy for a rat colorectal cancer lung metastases model in vivo (Gelderman et al. 2004a). Moreover, a recent study showed that CD55 is highly expressed on tumor cells but not on non-neoplastic epithelia, suggesting that it might predominately target the tumor (Ravindranath and Shuler 2006).

5.2 Small Interfering RNAs or Anti-sense Oligos

Since the in vivo utilization of blocking mCRP mAbs could potentially cause undesirable adverse effects, novel strategies to block mCRPs on tumors have been developed. For example, using small interfering RNA (siRNA) technology, CD55 expression levels can be significantly downregulated in prostate cancer cells leading to a profound attenuation of overall tumor burden in vivo (Loberg et al. 2006). Similarly, CD46 siRNA downregulates CD46 expression on prostate cancer resulting in enhanced CDC in vitro (Buettner et al. 2007). Our recent study using CD59 siRNA showed that downregulation of CD59 on human ovarian carcinoma SKOV-3, non-small cell lung carcinoma NCI-H23, and breast carcinoma ZR-75-1 significantly enhanced their susceptibility to anti-tumor mAb and complement-mediated cell lysis (Yan R., et al. unpublished observations).

In addition to siRNAs, anti-sense phosphorothioate oligonucleotides (S-ODNs) are also used to knockdown mCRP expression on tumor cells (Zell et al. 2007). Using S-ODNs for CD46 and CD55, the expression levels of these two molecules were significantly decreased in breast, lung, and prostate carcinoma. The inhibition of mCRPs on tumors led to enhanced CDC both for CD46 and CD55. In addition, C3 opsonization on CD46/CD55-deficient tumor cells was also significantly enhanced. Further in vivo study is needed to test the efficiency and potency of this strategy.

RNA interference (RNAi) can be induced by synthetic siRNA or by vector-driven expression of shRNA. Vectors are usually delivered by viruses resulting in incorporation of the vector into the host genome and a long-term gene silencing. However, this induces unwanted immune response and possible toxic effects. In contrast, siRNA provides a transient gene silencing solving the drawbacks with possible insertional mutagenesis and immune response induction. However, the major challenge is its delivery into cells in vivo and the faded silencing effect due to the high proliferation rate of tumors.

5.3 Chemotherapeutic Drugs

Interestingly, the chemotherapeutic drug fludarabine down-regulates CD55 expression on tumor cells (Di Gaetano et al. 2001). This may well explain the synergistic cytotoxicity of fludarabine and anti-CD20 mAb (rituximab) in a follicular lymphoma cell line (Di Gaetano et al. 2001). We also showed that Paclitaxel could significantly downregulate CD59 on human ovarian carcinoma and synergize with anti-her-2/neu mAb for tumor cytotoxicity (Yan et al. unpublished observation). Study with other chemodrugs is underway. This may be very important since many anti-tumor mAbs are used in combination with chemotherapeutic drugs. The right combination may lead to the maximum therapeutic outcomes.

5.4 Peptide Inhibitors of mCR Gene Expression

Recently we have proposed a new strategy for decreasing expression of mCRPs on tumor surface by downmodulating mCR gene expression (Donev et al. 2006). This can be achieved by targeting transcriptional regulators of the mCR genes. We showed that p53 is a potential target for modulation of expression of CD59 in neuroblastoma (Donev et al. 2006), a tumor type in which mutations in p53 are rare (Valsesia-Wittmann et al. 2004). However, in most other tumors, the DNA-binding domain of p53 is usually mutated (Greenblatt et al. 1994). Hence, p53 is unlikely to be involved in regulation of CD59 expression. Recently we identified another transcription factor involved in overexpression of CD59 in neuroblastoma. This is the neural-restrictive silencer factor (NRSF, REST), which is expressed as a truncated protein not only in neuroblastoma (Palm et al. 1999), but also in small cell lung carcinoma (Coulson et al. 2000) and colorectal cancer (Westbrook et al. 2005). We showed that the expression of this truncated isoform of REST is related to everexpression of CD59 in neuroblastoma and it can be targeted with peptides to sensitize tumor to CDC killing (Donev et al. unpublished data).

We believe that targeting both the mCR gene expression and the stability of synthesized RNA with peptide inhibitors and RNAi, respectively, will significantly decrease the number of mCRPs on tumor surface, resulting in effective CDC killing.

6 Concluding Remarks

It is becoming clear that the evolutionarily ancient complement system can be manipulated to substantially contribute to our current state of the art oncology treatment, particularly to anti-tumor mAb therapy. However, upregulation of mCRPs on tumors imposes an obstacle to maximize the therapeutic efficacy mediated by anti-tumor mAbs or tumor vaccines. Such obstacles may be overcome by the co-administration of neutralizing anti-mCRP mAbs or siRNAs or antisense Oliges to achieve this goal. Indeed, many in vitro studies have demonstrated the synergistic effect when anti-tumor mAb is used in combination with blocking mAbs for mCRPs or other approaches. However, their in vivo efficacy needs to be further investigated.


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.


Adams, G. P. and Weiner, L. M. (2005). Monoclonal antibody therapy of cancer. Nat

Biotechnol 23, 1147-1157 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, 5991-5998 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, 7050-7056 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, 105-114 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, 1466-1471

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, 1497-1504

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, 6298-6304 Bjorge, L., Hakulinen, J., Wahlstrom, T., Matre, R., and Meri, S. (1997). Complement-

regulatory proteins in ovarian malignancies. Int J Cancer 70, 14-25 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, 98-109 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, 945954

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, 823-832 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, 3013-3018 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, 1122-1128 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, 1840-1844 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, 800-809 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, 2451-2458 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, 254-263 Ellison, B. S., Zanin, M. K., and Boackle, R. J. (2007). Complement susceptibility in glutamine deprived breast cancer cells. Cell Div 2, 20

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, 2147-2152

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, 3178-3186 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, 109-123 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, 187-193 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, 483-493 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, 128-135 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, 4366-4372 Gelderman, K. A., Tomlinson, S., Ross, G. D., and Gorter, A. (2004b). Complement function in mAb-mediated cancer immunotherapy. Trends Immunol 25, 158-164 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, 977-984 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, 1039-1049 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, 4855-4878 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, 364-371 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, 1523-1530

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, 476-483 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, 9023-9031

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, 682-687 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, 271-277

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, 1049-1055 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, 6075-6081

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, 209-218 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, 848-854 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, 388-392 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, 339-347

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, 810-814

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, 1871-1876 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, 57935802

Leyland-Jones, B. (2002). Trastuzumab: hopes and realities. Lancet Oncol 3, 137-144 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, 1661-1669

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, 7421-7430

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, 1581-1589 Linton, S. M. and Morgan, B. P. (1999). Complement activation and inhibition in experimental models of arthritis. Mol Immunol 36, 905-914 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, 567-577 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, 69-78 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, 7098-7102 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 27, 102-108 Lublin, D. M. and Atkinson, J. P. (1989). Decay-accelerating factor: biochemistry, molecular biology, and function. Annu Rev Immunol 7, 35-58 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, 1329-1335 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, 371-375

Macor, P. and Tedesco, F. (2007). Complement as effector system in cancer immunotherapy.

Immunol Lett 111, 6-13 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, 27972803

Magyarlaki, T., Mosolits, S., Baranyay, F., and Buzogany, I. (1996). Immunohistochemistry of complement response on human renal cell carcinoma biopsies. Tumori 82, 473-479 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, 431-456 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, 659-666 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 279, 41611-41618 Mastellos, D. and Lambris, J. D. (2002). Complement: more than a 'guard' against invading pathogens? Trends Immunol 23, 485-491 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, 1266-1270 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, 1739-1754 Morgan, B. P. (2000). The complement system: an overview. Methods Mol Biol 150, 1-13

Muller-Eberhard, H. J. (1986). The membrane attack complex of complement. Annu Rev Immunol 4, 503-528

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, 176-182 Niculescu, F., Rus, H. G., Retegan, M., and Vlaicu, R. (1992). Persistent complement activation on tumor cells in breast cancer. Am J Pathol 140, 1039-1043 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, 129-142 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 Res 72, 30-39 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, 677-684 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, 1358-1365 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, 560-567

Ross, G. D. (2000). Regulation of the adhesion versus cytotoxic functions of the Mac-

1/CR3/alphaMbeta2-integrin glycoprotein. Crit Rev Immunol 20, 197-222 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 122, 598-609 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, 315-321 Ruiz-Arguelles, A. and Llorente, L. (2007). The role of complement regulatory proteins (CD55 and CD59) in the pathogenesis of autoimmune hemocytopenias. Autoimmun Rev 6,155-161

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, 753-759

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, 117-124 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, 837-855

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, 395-400

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, 143-149 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, 1455-1467 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, 105-114 Song, W. C. (2006). Complement regulatory proteins and autoimmunity. Autoimmunity 39, 403-410

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, 987-995 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, 234-241 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, 2727-2734 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, 625-631 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, 263-271 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, 625630

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, 599-605 Walport, M. J. (2001a). Complement. First of two parts. N Engl J Med 344, 1058-1066 Walport, M. J. (2001b). Complement. Second of two parts. NEngl JMed 344, 1140-1144 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, 217-221

Weiner, G. J., and Link, B. K. (2004). Monoclonal antibody therapy of B cell lymphoma.

Expert Opin Biol Ther 4, 375-385 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 121, 837-848

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, 2808-2817

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, 691-702

Yu, H. and Jove, R. (2004). The STATs of cancer - new molecular targets come of age. Nat Rev Cancer 4, 97-105

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, 576-584

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, 95-102

Was this article helpful?

0 0
How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book

Post a comment