The possible role of factor H in colon cancer resistance to complement attack

Abstract

A soluble complement inhibitor factor H (FH) and its splice variant factor H-like protein (FHL) have been recently discovered to play a major role in malignant cell escape from complement-mediated cytotoxicity in lung-, ovarian-and glia-derived neoplasms. The role of FH in colon cancer has not yet been examined. Here, we studied immunocytochemically FH/FHL expression in tumor samples derived from 40 patients, with both primary colon adenocarcinoma and metastatic foci in the liver. FH/FHL immunoreactivity was present in stroma of both primary and metastatic tumors, in virtually all patients. The cellular immunoreactivity was observed infrequently. Importantly, when analyzed quantitatively, FH/FHL immunoreactivity was significantly increased in liver metastases when compared with the primary sites. In addition, we have analyzed FH and FHL expression in 5 colon cancer cell lines: SW480, SW620, HCT116, HT-29 and Lovo. FH mRNA and FH secretion were observed in SW620 and HT-29 cells, whereas FHL was produced only by HT-29 cell-line. By confocal and electron microscopy, FH immunoreactivity was associated with the plasma membrane and intracellular vesicular structures. Finally, we have analyzed the role of FH in the susceptibility of SW620 colon cancer cells to complement-mediated damage. When FH function was blocked, using specific antibody, the cells became more susceptible to lysis. Taken together, our results suggest an important role of FH/FHL in colon cancer cells defense against complement-mediated cytotoxicity, and in metastatic process. ' 2008 Wiley-Liss, Inc.Key words: factor H; colon cancer; metastasis; immunotherapy; complement Although recent years have brought many advances in clinical oncology, colon cancer is still a serious problem. Surgical resection remains as the most efficient treatment, but its results are often not satisfactory. Sixty percent of patients with colon cancer develop liver metastases, which, for a third of those, is the main and only metastatic site. About 25% of the patients have potentially resectable hepatic metastases, but at least half of them have recurrence after surgery. 1 Unfortunately, for a large group of patients, radical surgery is impossible. For about 60% of such patients, advanced chemo-and radiotherapy allows for a 5-year survival, however a major objection to this kind of treatment is severe side effects. 2 To improve disease-free survival, overall survival and to prevent formation of metastases, new strategies for effective treatment should be considered.

The dual role of complement in cancer and its implication in anti-tumor therapy

“…It binds to C3b, thereby preventing subsequent formation of the lytic components at the cell surface. Resistance to factor H-mediated complement attack was found to be significant in ovarian cancer cells, lung cancer and glioblastoma cells (106,(120)(121)(122). Moreover, the monoclonal antibody cetuximab had significantly higher activity on A549 cells, in which factor H was genetically downregulated with siRNA (122,123).…”

Regulation of complement and modulation of its activity in monoclonal antibody therapy of cancer

“…Secretion of the sCRP Factor H and its splice variant FHL-1 was shown for primary tumor cells and cancer cell lines, including ovarian cancer cells, 24 lung tumor cells, 25 and colon cancer cells. 26 High levels of the sCRP clusterin are found in several human cancers [27][28][29][30] compared with normal tissues with some exceptions. 30,31 Upregulation of clusterin was reported in cases of in vivo breast cancer progression and tumor formation.…”

“…Neutralization of fH with a specific antibody resulted in an increased C3 deposition 25 and increased CDC of colorectal cancer cells by the anti-CEA mAb up to 3-fold. 26 It was recently shown that the abrogation of fH function by using short-consensus repeat 18-20, representing the C-terminal ligand binding domain, in combination with ofatumumab or rituximab resulted in an increased susceptibility of primary CLL cells to CDC. 91,92 A further synergistic effect was seen upon blockage of fH and CD55/CD59.…”

Human Serum Proteins Recognized by CA215 and Cancerous Immunoglobulins and Implications in Cancer Immunology

“…Specifically, complement factor H protects host cells and tissues from complement activation by acting as a cofactor for serine protease factor I to induce cleavage and inactivation of C3b and C4b, as well as to accelerate the degradation of C3 convertase (Jozsi & Zipfel, 2008). Complement factor H has been found to be expressed and secreted by many primary tumors and cancer cell lines, including glioblastomas, myoblastomas, and carcinomas of the bladder, ovary, and lung (Ajona et al, 2007;Holmberg et al, 2001;Junnikkala et al, 2000;Junnikkala et al, 2002;Wilczek et al, 2008). In addition, it has been found that these cancer cells are resistant to complement-mediated cytolysis.…”

“…In addition, it has been found that these cancer cells are resistant to complement-mediated cytolysis. Downregulation of complement factor H has been found to sensitize cancer cells to complement attack and reduce tumor growth, and therefore it has been hypothesized that complement factor H acts to protect cancer cells from complement activation (Ajona et al, 2004;Ajona et al, 2007;Junnikkala et al, 2000;Wilczek et al, 2008).…”