Introduction Complement And Cancer

Although complement provides a rapid and efficient mean to protect the host from invasive microorganisms (for review see: Walport, 2001a, b) its role in anti-cancer immune response remains vague and has even been questioned.

Treatment of cancer patients with microbial vaccines, dating back to the 19th century, was attempted in a hope to stimulate the immune system to arrest the malignant process. The anti-cancer effect of Corynebacterium parvum and Staphylococcus aureus protein A could be correlated with the activation of the alternative complement pathway and with macrophage infiltration (reviewed in Cooper, 1985). Although complement activation with subsequent deposition of complement components in tumor tissue has frequently been demonstrated in cancer patients (Lukas et al., 1996; Niculescu et al., 1992; Yamakawa et al., 1994; Bernet-Camard et al., 1996; Niehans et al., 1996), its role as the principal factor behind positive anticancer effects was not clearly shown. In clinical studies, complement levels were often found normal or even elevated in patients with various hematological neoplasia (Southam et al., 1966; Batlle Fonrodona et al., 1979; Minh et al., 1983), with neuroblastoma (Carli et al., 1979) or lung (Nishioka et al., 1976; Gminski et al., 1992), digestive tract (Maness and Orengo, 1977) and brain (Matsutani et al., 1984) tumors. Reduced CH50 and C3 (but not C4) were observed in individuals suffering from breast, gastric and colon-rectum carcinomas (Mangano et al., 1984). Classical pathway activation was assumed to be involved in the immune response against chronic lymphatic leukemia (CLL) in patients presenting low serum levels of several complement proteins and increased concentrations of circulating C1r-C1s-C1inhibitor complexes (Füst et al 1987; Hidvegi et al., 1989; Schlesinger et al., 1996). It can not be excluded that the complement system in those cancer patients was activated indirectly by immune complexes, infectious agents or substances generated within a tumor mass.

Certain tumor cell lines can activate, to some degree, complement in vitro. Oat cell carcinoma (Okada and Baba, 1974), EBV-transformed B cell lymphoma (Mc Connell et al., 1978) and Raji B lymphoblastoid cells (Budzko et al., 1976; Theofilopoulos and Perrin, 1976) are capable of activating the alternative human complement pathway in the absence of antibodies. Treatment with or led to increased C3 deposition on

B lymphoblastoid cells (Yefenof et al., 1991). Pretreatment with the metabolic inhibitor puromycin accelerated Raji cell lysis (Baker et al., 1977; Schreiber et al., 1980).

Complement activation and lysis of tumor cells by homologous complement gets more effective after sensitization with potent complement-fixing antibodies and by inhibiting various metabolic processes within the tumor cells. Complement-associated anti-tumor effects of mouse monoclonal antibodies (mAb) have been observed in nude mice growing human tumors (Capone et al., 1983; Chapman et al., 1990).

As transformation to malignancy may be accompanied by an increased capacity of the cells to activate complement, it is conceivable, that cancer cells have developed means to resist complement attack in order to survive in vivo. Most of the resistant mechanisms are probably also utilized by normal tissues to resist accidental cell damage following local activation of complement.

There is a growing body of evidence indicating that resistance of tumor cells to complement-mediated lysis depends on extracellular as well as on intracellular factors (reviewed in Jurianz et al., 1999b, Fishelson et al., 2003). Extracellular protection, interfering with the cascade of complement activation at specific points or directly affecting activated complement proteins limits the quantity of components deposited on the surface of target cells. However, as we now begin to understand, resistance mechanisms also extend to intracellular pathways, which lead to the reduction of MAC-induced damage, eliminate the MAC from the cell surface and facilitate repair processes. Perhaps the best example is the elimination of the MAC from the plasma membrane by endocytosis and by vesiculation, a phenomenon which was observed in neutrophils (Campbell and Morgan, 1985), oligodendrocytes (Scolding et al., 1989) and platelets (Sims and Wiedmer, 1986), but also in Ehrlich ascites tumor cells (Carney et al., 1985), U937 and K562 cells (Morgan, 1992).

Finally, additional resistance mechanisms are induced upon stimulation of cells with cytokines, hormones, drugs, or even with sublytic doses of C5b-9 complexes and other pore-formers. As will be discussed below, blocking one or more of the protective mechanisms is required to amplify a weak spontaneous process of complement activation into an efficient lytic complement attack on homologous tumor cells.

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