Expression of CD59, a complement regulator protein and a second ligand of the CD2 molecule, and CD46 in normal and neoplastic colorectal epithelium

Abstract

SummaryCD59 (protectin) and CD46 (membrane cofactor protein, MCP) are membrane-bound complement regulator proteins which inhibit complement-mediated cytolysis of autologous cells. CD59, a phosphatidyl-inositol-anchored glycoprotein, inhibits the formation of the terminal membrane attack complex (MAC) of complement and was found to be a second ligand for CD2 contributing to T-cell activation. In 20 colorectal normal mucosa samples, in ten adenomas, 71 carcinomas and in ten liver metastases derived thereof, CD59 was inconsistently expressed in the epithelial compartment. In carcinomas CD59 expression in the whole neoplastic compartment was more often found in well-and moderately differentiated tumours. By contrast, focal expression or even complete lack of CD59 was more often found in poorly differentiated tumours (P = 0.021). In addition, carcinomas without metastases at the time of operation (Dukes A/B) more often expressed CD59 in the entire neoplastic population compared to those carcinomas which had already metastasised (P = 0.018). There was no correlation between the mode of CD59 expression in colorectal carcinomas and the tumour type or location. CD46 has C3b/C4b binding and factor-I dependent cofactor activity and is broadly expressed in various cells and tissues. In the epithelial compartment of normal colorectal mucosa, of all adenomas, carcinomas and their liver metastases, CD46 was expressed throughout the epithelial compartment.Since CD46 was consistently expressed in colorectal carcinomas the low expression or even lack of CD59 in a subset of tumours might not lead to critical complement-mediated attack of CD59-negative tumour cells. Regarding CD59 as a natural T-cell ligand involved in cognate T-cell -target-cell interaction, however, loss of CD59 might well be a selection advantage, provided that tumour antigen-mediated T-cell toxicity in colorectal carcinoma exists.Membrane-bound regulatory proteins protect autologous cells from complement mediated cytotoxicity when fragments of the complement cascade are deposited on host cells which are not the desired target (Davitz, 1986). These proteins regulate the coordinating points in the classic and alternative pathways, the formation of the C3 convertases and the assembly of the terminal membrane attack complex (MAC) (Kinoshita, 1991). One of these proteins which aids in regulating the latter is protectin or CD59 (Hadam, 1989a), an 18-20 kD phosphatidyl-inositol anchored glycoprotein (Meri et al., 1990;Ratnoff et al., 1992). CD59 restricts homologous lysis by binding to the C8 and C9 molecules during the MAC formation, thus disturbing the C8: C9 ratio in the MAC complex (Meri et al., 1990;Lachmann, 1991 Asghar, 1992) where it functions as a second ligand for CD2 (Hahn et al., 1992). One protein which helps regulate the formation of the C3 convertases on autologous cells (Kinoshita, 1991) and the C5 convertase of the alternative complement pathway (Seya et al., 1991) is the 45-70 kD membrane cofactor protein (MCP) (Lublin & Atkinson, 1989) or CD46 (H...

Cellular and complement-dependent cytotoxicity of Ep-CAM-specific monoclonal antibody MT201 against breast cancer cell lines

“…We have here observed a high expression level of complement resistance factors CD46, CD55 and CD59 on almost all cell lines. IHC studies of tumour samples from various stages of colorectal cancer, however, showed that CD59 and CD55 expression is far less frequent than seen with our tumour cell lines (Koretz et al, 1993;Hosch et al, 2001). As CD59 can interact with CD2 on T cells, there may even be a selective pressure against CD59 expression on tumour cells to avoid interaction with T cells (Hahn et al, 1992;Koretz et al, 1993).…”

K562 erythroleukemic cells are equipped with multiple mechanisms of resistance to lysis by complement

“…29 CD59 prevents cytolysis by binding to C8 and C9 and by inhibition of the C9-polymerization process. 30 Expression of these membrane complement regulators has been described for many tumors as well as for tumor cell lines of different origin, e.g., colon carcinoma, 31,32 melanoma, 33 breast carcinoma, 25 ovarian carcinoma 34 and tumors of the hematopoietic system. 35,36 Cumulative evidence supports the notion that membrane complement regulatory proteins are expressed in higher quantities in malignant tissue than in normal tissue.…”

“…35,36 Cumulative evidence supports the notion that membrane complement regulatory proteins are expressed in higher quantities in malignant tissue than in normal tissue. 32,37,38 CD59 is considered as the main membrane complement regulatory protein restricting complement-mediated lysis of tumor cells. 39 K562 cells express high levels of CD59Ͼ CD46ϾCD55 (Fig.…”

Systematic Immunohistochemical Analysis of the Expression of CD46, CD55, and CD59 in Colon Cancer

“…The study also reported increased CD55 expression in colon cancer tissues compared with normal tissues, which is consistent with our observations, although their study also found that low expression or even a lack of CD59 expression was a characteristic feature in colon cancer. 17,18 However, Thorsteinsson and colleagues 14 found that CD46 and CD59 (but not CD55) were highly expressed in the epithelium of colorectal cancer tissues. In addition, mCRPs have been shown to be localized only at the membrane.…”

“…These results were notable because they differed from findings in previous studies. For example, Koretz and colleagues 17,18 investigated the expression of mCRPs in normal and cancerous colon tissues and found homogeneous, strong staining for CD46 in both types of tissues. The study also reported increased CD55 expression in colon cancer tissues compared with normal tissues, which is consistent with our observations, although their study also found that low expression or even a lack of CD59 expression was a characteristic feature in colon cancer.…”