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* Division of Oncology, Center for Applied Medical Research,
Department of Histology and Pathology, and
Department of Biochemistry, School of Medicine, University of Navarra, Pamplona, Spain
Malignant cells are often resistant to complement activation through the enhanced expression of complement inhibitors. In this work, we examined the protective role of factor H, CD46, CD55, and CD59 in two non-small cell lung cancer cell lines, H1264 and A549, upon activation of the classical pathway of complement. Complement was activated with polyclonal Abs raised against each cell line. After blocking factor H activity with a neutralizing Ab, C3 deposition and C5a release were more efficient. Besides, a combined inhibition of factor H and CD59 significantly increased complement-mediated lysis. CD46 and CD55 did not show any effect in the control of complement activation. Factor H expression was knockdown on A549 cells using small interfering RNA. In vivo growth of factor H-deficient cells in athymic mice was significantly reduced. C3 immunocytochemistry on explanted xenografts showed an enhanced activation of complement in these cells. Besides, when mice were depleted of complement with cobra venom factor, growth was recovered, providing further evidence that complement was important in the reduction of in vivo growth. In conclusion, we show that expression of the complement inhibitor factor H by lung cancer cells can prevent complement activation and improve tumor development in vivo. This may have important consequences in the efficiency of complement-mediated immunotherapies.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was funded through the UTE Project CIMA, Instituto de Salud Carlos III: Red Temática de Investigación Cooperativa en Cáncer (C03/10), the 2004–2006 American Association for Cancer Research-Cancer Research and Prevention Foundation Career Development Award in Translational Lung Cancer Research, and Ministerio de Educación y Ciencia (SAF-2005-01302).
2 Address correspondence and reprint requests to Dr. Ruben Pio or Dr. Luis M Montuenga, Oncology Division, CIMA Building, Pio XII, 55, Pamplona 31008, Spain. E-mail address: rpio{at}unav.es or lmontuenga{at}unav.es
3 Abbreviations used in this paper: MAC, membrane attack complex; mCRP, membrane-bound complement regulatory protein; FHL-1, factor H-like protein 1; NSCLC, non-small cell lung cancer; NHS, normal human serum; HI-NHS, heat-inactivated NHS; siRNA, small interfering RNA; CVF, cobra venom factor.
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