Expression of protectin (CD59) in human melanoma and its functional role in cell‐ and complement‐mediated cytotoxicity

Braşoveanu, Lorelei Irina; Altomonte, Maresa; Gloghini, Annunziata; Fonsatti, Ester; Coral, Sandra; Gasparollo, Aldo; Montagner, R.; Cattarossi, Ilaria; Simonelli, Cecilia; Cattelan, Anna María; Attadia, Vincenza; Carbone, Antonino; Malo, Michele

doi:10.1002/ijc.2910610420

Cited by 33 publications

(27 citation statements)

References 23 publications

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“…The expression of CD55 and CD59 was enhanced on renal clear cell carcinomas as compared with their expression on PTEC. Also other studies on RCC (Niehans et al, 1996), melanoma (Brasoveanu et al, 1995), and lung cancer (Varsano et al, 1995) observed an enhanced expression of CD55 and/or CD59. In contrast to the results of the study of Niehans et al (1996), who detected a focal moderate expression of CD55 on the interface between tumor cell nests and stroma, we were able to detect weak homogeneous membrane expression on CD55-positive renal tumor cells by immunohistochemistry.…”

Section: Discussionmentioning

confidence: 72%

A Possible Role of CD46 for the Protection In Vivo of Human Renal Tumor Cells from Complement-Mediated Damage

et al. 2000

Laboratory Investigation

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SUMMARY:It is still unclear which membrane-bound regulatory proteins (mCRP) are important in vivo to protect tumor cells from complement-mediated damage. To address this question, the expression levels of CD46, CD55, and CD59 were measured semi-quantitatively in situ on renal cell carcinomas and compared with the expression level and cellular distribution of these mCRP in proximal tubuli within each patient (n ϭ 31). It was also determined whether the expression of mCRP on tumor cells is associated with deposition of C3d and C5b-9. CD46 expression was decreased on tumor cells; in contrast, CD55 was expressed on tumor cells (12 out of 31 samples), while it was not detected on proximal tubular epithelial cells (PTEC). Also, expression of CD59 on tumor cells was increased as compared with its expression on PTEC. Furthermore, the localization on the cell surface of mCRP as observed on PTEC was altered on tumor cells. Because expression of mCRP may limit a complement-mediated anti-tumor response, we determined whether complement deposition was associated with the expression level of CD46, CD55, and CD59. The presence of C3d on tumor cells was associated with a low expression level of CD46 (p Ͻ 0.02). The expression level of CD46 was also associated with a low tumor stage (p Ͻ 0.04). The results suggest that in vivo CD46 plays a role in the protection of human renal tumor cells from complement-mediated injury. (Lab Invest 2000, 80:335-344).

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Section: Discussionmentioning

confidence: 72%

A Possible Role of CD46 for the Protection In Vivo of Human Renal Tumor Cells from Complement-Mediated Damage

et al. 2000

Laboratory Investigation

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2001

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Resistance of tumor cells to lysis by complement is generally attributed to several protective mechanisms. The relative impact of these mechanisms in the same tumor cell, however, has not been assessed yet. We have analyzed the interaction of the human erythroleukemia tumor cell line K562 with human complement. K562 cells express the membrane complement regulatory proteins CD59, CD55 and CD46. As shown here for the first time, K562 also spontaneously release the soluble regulators C1 inhibitor, factor H, and soluble CD59. Complement resistance of K562 cells is augmented upon treatment with PMA, TNF or even with sublytic complement. Unlike TNF and sublytic complement, PMA enhanced the expression of membrane-bound CD55 and CD59 and led to increased secretion of soluble CD59. In addition, we show that complement-resistant K562 cells express a membrane-associated proteolytic activity, higher than the complement-sensitive K562/S cells. Treatment of complement-resistant K562 cells with serine protease inhibitors enhance their sensitivity to complement-mediated lysis. Inhibitors of protein kinase C (PKC) also sensitize K562 cells to complement lysis, implicating PKC-mediated signaling in cell resistance to complement. Neutralization of the CD55 and CD59 but not of CD46 regulatory activity with specific antibodies significantly increases complement-mediated K562 cell lysis. Treatment of K562 cells with a mixture of inhibitory reagents results in a significant additive enhancing effect on complement-mediated lysis of K562. In conclusion, K562 cells resist a complement attack by concomitantly using multiple molecular evasion strategies. Future attempts in antibody-based tumor therapy should include strategies to interfere with those resistance mechanisms.

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“…Barriers for free access of MAbs and C to the tumour cells and the existence of C resistance mechanisms may limit the success rate (Riethmuller et al, 1993). However, in vitro tests have shown that it is possible to kill tumour cells in suspension using appropriate MAbs and C in combination with targeted neutralization of membrane regulators of complement (Cheung et al, 1988;Bj0rge et al, 1994;Hakulinen and Meri, 1994;Junnikkala et al, 1994;Brasoveanu et al, 1995;Maenpaa et al, 1996). The in vivo protocols for this type of immunotherapeutic analysis therefore have to be refined for effective destruction of tumour cells in three-dimensional structures.…”

Section: Sensitivity Of Pa-1 Cells and Spheroids To C-mediated Cytotomentioning

confidence: 99%

“…Most in vitro studies on the expression and function of C regulators on malignant cells have used cell suspensions and/or monolayer cell cultures (Cheung et al, 1988;Bj0rge et al, 1994;Hakulinen and Meri, 1994;Junnikkala et al, 1994;Brasoveanu et al, 1995;Maenpaa et al, 1996). In many respects, these systems are markedly different from the actual conditions in solid tumours in vivo (Miiller-Klieser, 1987).…”

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confidence: 99%

Resistance of ovarian teratocarcinoma cell spheroids to complement-mediated lysis

Bjørge

Junnikkala²,

Kristoffersen³

et al. 1997

Br J Cancer

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Summary We have shown previously that it is possible to target complement-mediated killing against cultured ovarian tumour cells in vitro. As malignant ovarian cells usually grow in solid nodules in vivo, we have in the present study examined the effectiveness of complement killing against ovarian teratocarcinoma cells (PA-1) growing in three-dimensional tumour microspheroids (TMSs). Our study shows that PA-1 cells growing in TMSs are less susceptible to complement-mediated killing than cells growing in monolayer cultures, even after neutralization of protectin (CD59), the main inhibitor of complement lysis. Cells in suspension and cells growing in TMSs showed a similar expression of membrane co-factor protein (MCP, CD46) and CD59. Decay-accelerating factor (DAF, CD55) was not detected on the surface of cells in suspension, but appeared focally on the outermost cell layers of the TMSs. Complement-activating antibodies bound to all PA-1 cells in suspension but only to the most peripherally located cells in TMSs, even though the target antigens were similarly expressed in the two systems. Antibody-induced complement activation on PA-1 cells in suspension led to C3 and C5b-9 deposition on most cells, while C3 and C5b-9 were only found on the outermost layers of the TMSs. The increased complement resistance of tumour cells growing in threedimensional spheroids is partly because of an insufficient penetration of antibodies and complement into the TMSs. TMSs are a useful model for the development of more efficient ways to kill malignant cells in micrometastases with monoclonal antibodies and complement.

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Expression of protectin (CD59) in human melanoma and its functional role in cell‐ and complement‐mediated cytotoxicity

Cited by 33 publications

References 23 publications

A Possible Role of CD46 for the Protection In Vivo of Human Renal Tumor Cells from Complement-Mediated Damage

A Possible Role of CD46 for the Protection In Vivo of Human Renal Tumor Cells from Complement-Mediated Damage

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

Resistance of ovarian teratocarcinoma cell spheroids to complement-mediated lysis

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