Complement-regulatory proteins in ovarian malignancies

Bjørge, Line; Hakulinen, Juha; Wahlström, Torsten; Matre, R.; Meri, Seppo

doi:10.1002/(sici)1097-0215(19970106)70:1<14::aid-ijc3>3.0.co;2-9

Cited by 105 publications

(84 citation statements)

References 19 publications

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“…This latter finding was in accordance with prior data suggesting that CD46 is mainly involved in regulation of the alternative pathway (Devaux et al, 1999). However, protection of classical pathway activation by CD46 expression on tumor cell lines has been shown previously (Azuma et al, 1995), although mainly CD55 and CD59 have been implicated as being important for classical pathway activation (Bjørge et al, 1997;Brasoveanu et al, 1996;Cheung et al, 1988); Gorter et al, 1996;Venneker et al, 1998). We propose, in view of our present results, that CD46 is able to regulate the amplification loop of the classical pathway when the expression of CD55 is low or absent.…”

Section: Discussionsupporting

confidence: 93%

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: Discussionsupporting

confidence: 93%

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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“…3 Extensive clinical and experimental evidence indicates that CD59 is highly effective at protecting NHL and CLL cells from Ab (rituximab or ofatumumab)-mediated CDC. [7][8][9][10][11][12][13][14][15][16][17][18][19] Many in vivo and in vitro studies indicate that CDC plays a critical role and also interacts synergistically with Ab-dependent cell cytotoxicity in rituximab therapy. 3 To further enhance CDC activity, the human IgG1 anti-CD20 mAb ofatumumab has been developed as another new mAb therapeutic.…”

Section: Introductionmentioning

confidence: 99%

“…22 Thus, there remains a need for more effective therapies in both the upfront and the relapsed settings. Since upregulation of human CD59 (hCD59) is an important determinant of sensitivity to Ab (rituximab and ofatumumab) treatment for NHL and CLL, [7][8][9][10][11][12][13][14][15][16][17][18] it is imperative for us to develop a molecule capable of abrogating CD59 function in cancer cells and facilitating Ab-mediated cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Application of a novel inhibitor of human CD59 for the enhancement of complement-dependent cytolysis on cancer cells

You

et al. 2011

Cell Mol Immunol

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Many monoclonal antibodies (mAbs) have been extensively used in the clinic, such as rituximab to treat lymphoma. However, resistance and non-responsiveness to mAb treatment have been challenging for this line of therapy. Complement is one of the main mediators of antibody-based cancer therapy via the complement-dependent cytolysis (CDC) effect. CD59 plays a critical role in resistance to mAbs through the CDC effect. In this paper, we attempted to investigate whether the novel CD59 inhibitor, recombinant ILYd4, was effective in enhancing the rituximab-mediated CDC effect on rituximab-sensitive RL-7 lymphoma cells and rituximab-induced resistant RR51.2 cells. Meanwhile, the CDC effects, which were mediated by rituximab and anti-CD24 mAb, on the refractory multiple myeloma (MM) cell line ARH-77 and the solid tumor osteosarcoma cell line Saos-2, were respectively investigated. We found that rILYd4 rendered the refractory cells sensitive to the mAb-mediated CDC effect and that rILYd4 exhibited a synergistic effect with the mAb that resulted in tumor cells lysis. This effect on tumor cell lysis was apparent on both hematological tumors and solid tumors. Therefore, rILYd4 may serve as an adjuvant for mAb mediated-tumor immunotherapy. Keywords: CD59; complement; lymphoma; multiple myeloma; rituximab INTRODUCTIONMonoclonal antibody (mAb) therapy is becoming a powerful approach and is increasingly used in the clinic for the treatment of different types of cancer through targeting specific cancer antigens. Rituximab, the first mAb approved for cancer therapy by the Food and Drug Administration, has been successfully used in the treatment of B-cell non-Hodgkin's B-lymphoma (NHL) via specifically targeting the CD20 molecule on the B lymphocyte membrane. Treatment with rituximab has lead to greatly improved clinical outcomes. 1 Trastuzumab (Herceptin) is used to treat HER2-positive breast cancer. Other new mAbs are actively being developed. Once the antibodies (Abs) are given, they can then recruit other parts of the immune system to destroy the cancer cells or to enhance the immune response against the cancer. The mechanism of action of these Abs and the host and cellular factors that influence the immune response following Ab treatment are not completely known. The induction of apoptosis, Abdependent cell cytotoxicity and complement-mediated cell death (CDC) are the proposed mechanisms of action of these Abs. 2 Complement is one of the main mediators of Ab-based cancer therapy via the CDC effect. When cancer therapeutic Abs activate the so-called classical complement pathway, they trigger the formation of the membrane attack complex on cancer cells, leading to the killing of cancer cells through CDC. 3 CD59, a critical membrane complement regulator, inhibits membrane attack complex formation by binding to

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“…14 MV-CEA targets and causes extensive fusion in ovarian cancer cells through the CD46 receptor, which is expressed at high levels by many tumor types, including ovarian cancer. [15][16][17][18] MV-CEA is derived from an attenuated strain of measles virus belonging to the Edmonston vaccine lineage (MV-Edm), and its inserted transgene codes for the soluble extracellular domain of human CEA, which serves as an inert soluble marker to facilitate noninvasive monitoring of virus spread in vivo. 19 MV-CEA-infected cells release CEA into body fluids, and the circulating level of CEA, which can be easily measured, provides a convenient readout to determine if the number of virus-infected cells in the body is increasing or decreasing over time.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of oncolytic measles virotherapy: eventual equilibrium between virus and tumor in an ovarian cancer xenograft model

Hadac

et al. 2006

Cancer Gene Ther

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Because of their ability to replicate, the dose-response relationships of oncolytic viruses cannot easily be predicted. To better understand the pharmacokinetics of virotherapy in relation to viral dose and schedule, we administered MV-CEA intraperitoneally in an orthotopic mouse model of ovarian cancer. MV-CEA is an attenuated oncolytic measles virus engineered to express soluble human carcinoembryonic antigen (CEA), and the virus is currently undergoing phase I clinical testing in patients with ovarian cancer. Plasma CEA levels correlate with numbers of virus-infected tumor cells at a given time, and were used as a surrogate to monitor the profiles of viral gene expression over time. The antineoplastic activity of single-or multiple-dose MV-CEA was apparent over a wide range of virus doses (10 3 -10 8 TCID 50 ), with little reduction in observed antitumor efficacy, even at the lowest tested dose. However, analysis of CEA profiles of treated mice was highly informative, illustrating the variability in virus kinetics at different dose levels. The highest doses of virus were associated with higher initial levels of tumor cell killing, but the final outcome of MV-CEA therapy at all dose levels was a partial equilibrium between virus and tumor, resulting in significant slowing of tumor growth and enhanced survival of the mice.

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Complement-regulatory proteins in ovarian malignancies

Cited by 105 publications

References 19 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

Application of a novel inhibitor of human CD59 for the enhancement of complement-dependent cytolysis on cancer cells

Pharmacokinetics of oncolytic measles virotherapy: eventual equilibrium between virus and tumor in an ovarian cancer xenograft model

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