1. ¹Department of Bacteriology and Immunology, Haartman Institute, University Central Hospital, FIN-0014 Helsinki, Finland
2. ²Helsinki University Central Hospital, FIN-00014 Helsinki, Finland
3. ³Department of Microbiology and Immunology, The Gade Institute, Haukeland Hospital, N-5021 Bergen, Norway
4. ⁴Department of Obstetrics and Gynaecology, Haukeland Hospital, N-5021 Bergen, Norway
5. ⁵Department of Infectious Biology, Hans-Knoell-Institute, 07745 Jena, Germany
6. ⁶Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, FIN-00014 Helsinki, Finland

Correspondence: S Meri, Department of Bacteriology and Immunology, Haartman Institute, P.O. Box 21, FIN-00014 University of Helsinki, Finland. E-mail: Seppo.Meri@helsinki.fi

Received 28 January 2002; Revised 26 July 2002; Accepted 4 September 2002.

Abstract

We observed that the soluble complement regulators factor H and factor H-like protein were abundantly present in ascites samples as well as in primary tumours of patients with ovarian cancer. RT–PCR and immunoblotting analyses showed that the two complement inhibitors were constitutively produced by the ovarian tumour cell lines SK-OV-3 and Caov-3, but not PA-1 or SW626 cells. The amounts of factor H-like protein secreted were equal to those of factor H. This is exceptional, because e.g. in normal human serum the concentration of factor H-like protein is below 1/10th of that of factor H. In ascites samples the mean level of factor H-like protein (13055 g ml^-1) was 5.5-fold higher than in normal human serum (243 g ml^-1). Ovarian tumour cells thus preferentially synthesise factor H-like protein, the alternatively spliced short variant of factor H. The tumour cells were found to bind both ¹²⁵I-labelled factor H and recombinant factor H-like protein to their surfaces. Surprisingly, the culture supernatants of all of the ovarian tumour cell lines studied, including those of PA-1 and SW626 that did not produce factor H/factor H-like protein, promoted factor I-mediated cleavage of C3b to inactive iC3b. Subsequently, the PA-1 and SW626 cell lines were found to secrete a soluble form of the membrane cofactor protein (CD46). Thus, our studies reveal two novel complement resistance mechanisms of ovarian tumour cells: (i) production of factor H-like protein and factor H and (ii) secretion of soluble membrane cofactor protein. Secretion of soluble complement inhibitors could protect ovarian tumour cells against humoral immune attack and pose an obstacle for therapy with monoclonal antibodies.