Complement has been considered since a long time as an immune surveillance system against cancer, because complement is activated on the surface of tumor cells. Nevertheless, tumor cells develop inhibitory mechanisms for the terminal steps of the complement cascade, thus preventing complement-mediated cytotoxicity. Surprisingly, recent studies demonstrated that complement activation within the tumor microenvironment can promote tumor growth. Complement activation may support chronic inflammation, promote an immunosuppressive microenvironment, induce angiogenesis, and activate cancer-related signaling pathways. The mechanisms of these phenomena are not fully understood. Prolonged complement activation supports chronic inflammation, promotes an immunosuppressive microenvironment, induces angiogenesis, and activates cancer-related signaling pathways.
Several lines of evidence indicate a role for molecules of the complement system in tumor growth and metastasis. C3, C4, or C5aR deficiencies prevent tumor growth in mice, potentially via inhibition of the classical pathway and the generation of C5a, which has a potent inflammatory potential. In mouse models, the presence of C5a in the tumor microenvironment enhances tumor growth by recruitment of myeloid-derived suppressor cell / MDSC and increasing T cell-directed suppressive abilities. In a breast cancer model, C5aR facilitated metastasis in the lungs through different immune mechanisms in the metastatic niche, including the suppression of effector CD8(+) and CD4(+) T cell responses, the recruitment of immature myeloid cells and the generation of Tregs and a Th2-oriented response.
Cancer cells also secrete complement proteins that stimulate tumor growth upon activation via a direct autocrine effect through C3aR and C5aR signaling. In patients with ovarian or lung cancer, higher tumoral C3 or C5aR mRNA levels were associated with decreased overall survival. In addition, patients with non-small cell lung cancer have elevated C5a plasma levels.
C3a and C5a seem to have opposing effects during tumor development and in case of anti-tumor radiotherapy. While C3a and especially C5a promote tumor growth, radiotherapy-induced tumor cell death and transient local complement activation with production of C3a and C5a. The latter appeared crucial to the tumor response to radiotherapy and concomitant stimulation of tumor-specific immunity.
Overexpression of FH has been described in non-small cell lung cancer cell lines and on non-small cell lung cancer biopsies (but not in small cell lung carcinoma and carcinoid cell lines), in bladder tumor cells, in cutaneous squamous cell carcinoma (cSCC) and cell lines, and in hepatocellular carcinoma tumors. Low titer anti-FH antibodies were also found in sera from patients with non-small cell lung cancer. Recent studies demonstrated that FH binds to pentraxin 3 (PTX3) in the tumor microenvironment, thus preventing local complement overactivation and generation of pro-tumorigenic C5a.
These examples clearly indicate that complement is indispensable immunosurveillance system, which needs to function with the right force when and where is needed. Therefore, therapeutic strategies are needed to adjust the level of complement activation in pathological conditions.
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