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MUC16 (CA125): tumor biomarker to cancer therapy, a work in progress

Mildred Felder, Arvinder Kapur, Jesus Gonzalez-Bosquet and 9 more

Molecular Cancer · 2014 · Review

doi:10.1186/1476-4598-13-129

Abstract

Over three decades have passed since the first report on the expression of CA125 by ovarian tumors. Since that time our understanding of ovarian cancer biology has changed significantly to the point that these tumors are now classified based on molecular phenotype and not purely on histological attributes. However, CA125 continues to be, with the recent exception of HE4, the only clinically reliable diagnostic marker for ovarian cancer. Many large-scale clinical trials have been conducted or are underway to determine potential use of serum CA125 levels as a screening modality or to distinguish between benign and malignant pelvic masses. CA125 is a peptide epitope of a 3-5 million Da mucin, MUC16. Here we provide an in-depth review of the literature to highlight the importance of CA125 as a prognostic and diagnostic marker for ovarian cancer. We focus on the increasing body of literature describing the biological role of MUC16 in the progression and metastasis of ovarian tumors. Finally, we consider previous and on-going efforts to develop therapeutic approaches to eradicate ovarian tumors by targeting MUC16. Even though CA125 is a crucial marker for ovarian cancer, the exact structural definition of this antigen continues to be elusive. The importance of MUC16/CA125 in the diagnosis, progression and therapy of ovarian cancer warrants the need for in-depth research on the biochemistry and biology of this mucin. A renewed focus on MUC16 is likely to culminate in novel and more efficient strategies for the detection and treatment of ovarian cancer.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

CA125 is best known as a biomarker to monitor epithelial ovarian cancer and for the differential diagnosis of pelvic masses. Serum levels of CA125 are routinely monitored in patients with ovarian cancer, and an increase from an individualized nadir concentration is a prognostic indicator of cancer recurrence. An extensive body of work has been published on the interpretation of CA125 assay results, with particular focus given to CA125 in ovarian cancer patients undergoing therapy. Understanding of the clinical applicability of the CA125 assay has come from basic, translational, and clinical studies conducted since the early 1980’s. However, what remains underappreciated is that the assay to measure CA125 in clinical samples is limited by an incomplete understanding of the biochemical structure of this antigen. Here, we will review the current knowledge of the structure of CA125 and provide critical appraisal of factors that may interfere with accurate and sensitive measurement of this biomarker.

CA125 is a repeating peptide epitope of the mucin MUC16, which promotes cancer cell proliferation and inhibits anti-cancer immune responses. Our discussion of the biological role of MUC16 will focus on its importance in cancer cell signaling, metastasis, regulation of immune responses and on anti-cancer therapeutic strategies that target this mucin. A major goal of this review is to highlight gaps in our knowledge of the biochemistry and biology of MUC16/CA125 to provide a framework of unanswered questions to be addressed in future studies.

CA125 as a clinical biomarker

CA125 has been extensively investigated as a biomarker in three separate clinical scenarios: (1) as a screening test for the early detection of ovarian cancer, (2) to distinguish between benign and malignant disease in pre- and post-menopausal women presenting with pelvic masses, and (3) to monitor response to therapy in women with ovarian cancer.

CA125 as a screening modality for ovarian cancer

An increase (beyond a cut-off of 30–35 U/ml) is generally observed in blood samples that are serially obtained from women with ovarian cancer. Therefore, for screening, longitudinal monitoring of serum CA125 levels is likely to be more useful than a single measurement. The Risk of Ovarian Cancer Algorithm (ROCA) predicts the probability of ovarian cancer based on such longitudinal monitoring of CA125. ROCA allows triaging of patients into groups with low, intermediate and high risk of ovarian cancer.

ROCA was developed after retrospective analysis of serum samples obtained from an ovarian cancer screening trial of 5550 women conducted in Sweden. This trial concluded that serum CA125 monitoring will be most beneficial in post-menopausal women. In this cohort, the serum CA125 test provides sensitivity and specificity of 91 and 94.5%, respectively.

The largest fully reported ovarian cancer screening trial that used CA125 as a biomarker (in combination with ultrasonography) was conducted in the United Kingdom with a cohort of 22,000 women. A total of 41 women tested positive for ovarian cancer based on CA125 and ultrasound. Only eleven of these 41 cases were found to be truly positive for ovarian cancer after subsequent surgical investigation. Eight women who had screened negative for ovarian cancer developed the disease 12–22 months after the initial screen.

Enthusiasm for the success of combination of CA125 assay and transvaginal ultrasound screening is tempered by the negative results from the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) trial. In this randomized control trial of 78,216 subjects, women in the intervention arm were screened for CA125 levels and transvaginal ultrasound. There was no improvement in mortality (the primary endpoint of this study) in this trial. The PLCO trial did not employ ROCA. A retrospective analysis has suggested that the use of ROCA in PLCO would not have led to statistically significant mortality benefit of screening, in part because of the long delay (one year) between screens and the absence of a standardized diagnostic algorithm.

Given the low prevalence of ovarian cancer in the general population, it is estimated that a good clinical trial to develop a screening paradigm for ovarian cancer would require recruitment of >150,000 women. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) accrued a total of 202,638 post-menopausal women between 2001 and 2005. Subjects were randomized into (1) control, (2) serum CA125 plus transvaginal ultrasound, and (3) transvaginal ultrasound only groups. The ROCA was used to triage women in the second group to low, intermediate and high-risk categories. Subjects in the intermediate-risk category were monitored for CA125 levels every 4 months, and if they continued to show increased risk for ovarian cancer, were monitored by ultrasound scans. The subjects in the high-risk category underwent transvaginal ultrasound scans. Final results from this trial are expected in 2015. Interim analysis from this trial has led to the promising finding that 47.1% of women testing positive after combined assessment with CA125 test and transvaginal ultrasound had stage I or II disease. The combined use of ROCA and ultrasound, strict guidelines for follow up in 3–4 months after elevated CA125 is detected and a well-coordinated plan for screening patients across all participating sites are advantages of the UKCTOCS over the PLCO study design that are expected to contribute to successful identification of a screening strategy for ovarian cancer. Survival data from the UKCTOCS trial is expected in 2015.

CA125 as a diagnostic marker for ovarian cancer

The majority of patients with ovarian cancer are periodically assayed for CA125. An increase in concentration of CA125 above a nadir is an indicator of disease recurrence. Another important potential application of the CA125 assay is in distinguishing benign pelvic masses from ovarian cancer. The Risk of Malignancy Index (RMI) combines serum CA125 concentrations with ultrasound and menopausal status to distinguish between benign disease and cancer. Recent studies suggest that a Risk of Ovarian Malignancy Algorithm (ROMA) incorporating CA125 and HE4 levels in serum is likely to produce a test of high sensitivity and specificity in identifying ovarian cancer patients.

Currently, HE4 is the only biomarker, other than CA125, that has been approved by the U.S. Food and Drug Administration as a diagnostic marker for ovarian cancer. Another algorithm, OVA1, uses CA125, apolipoprotein A1, transthyretin, transferrin and β2-microglobulin and takes into account data from ultrasound imaging and menopausal status of patients.

Mesothelin, osteopontin, CA15.3, CA19.9, AFP, KLK6 and several others have been investigated and suggested as potential biomarkers for ovarian malignancy. A recent multi-center effort to test the sensitivity and specificity of panels of markers conducted using the serum samples obtained from PLCO has been reported. None of the panels of markers tested in this trial improve on the sensitivity and specificity of CA125 in screening or ovarian cancer diagnosis. The conclusion from the important trials and studies described in this section is that CA125 continues to be, and for the foreseeable future will persist as, the predominant and most clinically useful biomarker for ovarian cancer. It is therefore imperative that significant effort be put forth to clearly understand the chemical nature of this antigen with the express intent of improving the widely used CA125 assay.

Biochemistry of CA125

CA125 was first identified in a screen of monoclonal antibodies raised against the ovarian cancer cell line OVCA433. One antibody, OC125, recognized an antigen in ovarian cancer specimens which was designated as CA125. Several antibodies, M11, VK8 and OV197 among them, were subsequently developed against CA125. Based on their binding specificities, CA125-specific antibodies are grouped as belonging to the OC125, M11 or OV197 families.

Initial gel filtration experiments suggested that CA125 had a molecular weight as high as 2 million Da. Hanisch and colleagues demonstrated that CA125 activity was contained in a high molecular weight mucinous fraction isolated from human milk. Isopycnic density gradient centrifugation led to isolation of CA125 activity in a fraction with the buoyant density of 1.41 g/ml, a density that is typically observed for most human mucinous glycoproteins.

A more definitive study on the molecular characterization of CA125 by Davis et al. showed that CA125 isolated from OVCA433 cells had a buoyant density of 1.42 g/ml whereas the antigen in human serum and milk had a density of 1.46 g/ml and 1.39 g/ml, respectively. Davis and co-workers also performed size exclusion chromatography of OVCA433 cell culture supernatant on a Sepharose CL-4B column, a matrix with a size exclusion limit of 6 × 104 – 2 × 107 Da for globular proteins. These chromatography studies demonstrated that CA125 activity was contained in fractions having molecular masses of 200,000-1 million Da.

Importantly, the report by Davis et al. conclusively refuted a previous claim that CA125 was a carbohydrate epitope. Oxidation of the CA125-containing fractions at pH 4.5 with 1 mM and 10 mM sodium periodate—conditions that oxidize vicinal hydroxyls of terminal sialic acid or those present in the entire oligosaccharide chains, respectively—did not result in significant loss of OC125 binding to the antigen. Instead, exposure to heat and low pH (100°C, 3.3 pH), protease digestion, reduction and alkylation in buffer containing 4 M guanidine hydrochloride abrogated binding of OC125 to the antigen. These crucial observations suggested that CA125 was a conformationally dependent peptide epitope present in a high molecular weight mucin. Although some incremental advances in our understanding of the molecule were gained from important fundamental research conducted independently by Lloyd and O’Brien, major advance in our understanding of the biochemistry of CA125 was gained from the identification of MUC16 as the mucin that contained this antigen.

MUC16, a large molecular weight membrane-spanning mucin

Molecular cloning of MUC16 revealed it to be a mucinous glycoprotein with an average molecular weight between 3–5 million Da. Similar to other membrane-spanning mucins, MUC16 (Figure 1) is composed of a tandem repeat region sandwiched between N-terminal and C-terminal domains. The C-terminal domain is the smallest part of the molecule and is composed of 284 amino acids (Figure 1). While it has been proposed that this C-terminal domain can be phosphorylated under specific conditions, conclusive proof is lacking.

The N-terminal region is composed of 12,068 amino acids. Other than potential sites for both N-linked and O-linked glycosylation, there are no major structural features identified in this domain. The tandem repeat domain is composed of up to 60 repeats (Figure 1). Each repeat has 156 amino acids. The primary amino acid sequence in each repeat is not identical but is homologous. Two conserved cysteines, at positions 59 and 79 of each repeat, are proposed to have structural significance. These cysteines could form intra- as well as inter-molecular disulfide bonds. While the intramolecular disulfide bonds could form loops within each MUC16 molecule, intermolecular disulfide linkages may contribute to formation of an extracellular matrix.

Evidence supporting the location of CA125 antigen in the MUC16 tandem repeat came from two initial studies where the tandem repeats were expressed in E. coli or in human ovarian cancer cell lines. In the first study, the 11th MUC16 tandem repeat (R11) was expressed and isolated from E. coli. This recombinant R11 protein was recognized by the three anti-CA125 antibodies M11, OC125 and OV197. In another study, a recombinant protein containing three of the MUC16 tandem repeats was produced in two cell lines—SW626 and SKOV-3—that do not express MUC16. The recombinant proteins expressed in these cell lines were detected by M11 and OC125 but not by the VK8 antibody. This finding was interesting because VK8 was initially classified as an M11-type antibody, but studies with the recombinant MUC16 fragments demonstrated clear differences in the epitope specificities of M11 and VK8.

Digestion of the recombinant R11 tandem repeat by the endoproteases Lys-C or Asp-D completely destroyed the CA125 epitope as demonstrated by the observation that the resulting fragments were not detected by the OC125 or M11 antibodies. It was primarily this one experiment that led to the prevalent viewpoint that the CA125 epitope is located in the 21-amino acid loop of the tandem repeats formed by disulfide bridging of cysteines located at positions 59 and 79. Recent experiments conducted by us and by Bressan et al. have led us to believe that this model is inaccurate and that the CA125 epitope has not been sufficiently characterized.

In our experiments we did not observe binding of OC125 and M11 antibodies to a synthetic 21-mer peptide sequence (Peptide 1) comprising the loop region shared by eight of the 60 MUC16 tandem repeats. We also investigated OC125 and M11 binding to three variants of Peptide 1 that differ in single amino acids (C21A, Peptide 3; P8S, Peptide 4) or in two amino acids (P8S and C21A, Peptide 5). These variants were selected because their sequences are also found in the MUC16 repeats (Ser appears in position 8 in ~25% of tandem repeats) or they produce specific modifications in the secondary structures of the peptides (replacing Cys with Ala removes the possibility of intramolecular disulfide bonding). In five independent assay protocols—Silicon Photonic Microring Resonator Immunoassay, Surface Plasmon Resonance Immunoassay, ELISA, Competitive ELISA and Affinity Probe Capillary Electrophoresis—none of these four peptides were recognized by OC125 and M11 antibodies.

Not all of the MUC16 repeats are recognized to the same extent by these antibodies. Recombinant proteins containing either R2, R7, R9, R11, R25, or R51 repeats were recognized by M11 in Western blot assays. However, only a subset of these repeats (R9, R11, R25, and R51) were detected strongly by OC125 and a partially overlapping subset (R2, R9, R25, and R51) were detected by OV197 antibodies. Deletion mutants of the 156 amino acid R25 repeat that are missing residues 129–156 from the C-terminal end retain binding by OC125, M11 and OV-197. However, deletion of the amino acids 1–30 from the N-terminal end of this truncated mutant abrogated binding by all three antibodies. Thus the CA125 epitope is likely localized between amino acids 1–128 of the MUC16 repeats. However, any further refined characterization of the CA125 epitope has not been achieved.

Incidentally, the region 1–128 of R25 contains the Sea urchin Enterokinase and Agrin (SEA) domain. In fact BLAST protein homology search shows the presence of SEA domains in each of the MUC16 tandem repeats (Additional file 1). In addition, one SEA domain is also located in the C-terminal region of the mucin. While MUC1 and some other mucins are known to contain a single or limited number of SEA domains, such extensive presentation of these structural units is unique to MUC16 among all of the identified mammalian mucins. One SEA domain from the murine Muc16 ortholog has been structurally characterized. While SEA domains can exhibit autoproteolytic activity, any potential importance of this domain in the shedding of MUC16 is not clear.

Antibodies that recognize continuous epitopes are likely to bind sequences that are composed of not more than 15–22 amino acids of which 5–6 residues are critical as they provide maximum binding energy. However, deletion of even 30 amino acids from the N- or the C-terminal end of the 128 amino acid recombinant repeat domain abrogates antibody binding. These results have prompted the suggestion that the CA125 epitope is not continuous but is instead a discontinuous epitope that is dependent on the secondary conformational structure of the MUC16 tandem repeat. While this suggestion is consistent with our studies with the C-loop peptides, its acceptance relies on the proposal that detection of the 1–128 deletion mutant by the CA125 antibodies in western blots follows renaturation during transfer to the nitrocellulose membrane. One important conclusion drawn from our studies with the peptides and those reported by Bressan et al. is that the CA125 epitope most likely does not reside in the loop region of the tandem repeat as predicted initially. The implications of this conclusion are serious as it indicates that even though the CA125 assay is routinely used to monitor the vast majority of patients with serous ovarian cancer, the exact molecular nature of the antigen is not accurately characterized.

The CA125 II assay currently used to measure serum concentrations of this biomarker in patients uses M11 as a capture antibody and OC125 as a tracer. Studies with recombinant R11 indicate that binding of OC125 to this antigen is enhanced several-fold after pre-binding of M11. Whether enhancement—or inhibition—of OC125 binding is also observed with other recombinant repeats of MUC16, or the entire molecule in patient sera, needs to be determined. A corollary to this statement is that since OC125 binding is sensitive to the molecular environment of its epitope, other factors such as post-translational modification may influence detection of CA125 in patient sera.

In our experiments with ovarian cancer cell lines, we have observed that OC125 weakly binds to the surface of cells—SKOV-3 and A2780—that are generally considered to be non-expressors of MUC16. However, under the same conditions another anti-CA125 antibody, VK8, which was used in the initial cloning experiments, does not recognize SKOV-3 (Figure 2). The marginal binding of OC125 to SKOV-3 cells corresponds to weak expression of MUC16 as determined by RT-PCR (data not shown).We observe that trypsin digestion significantly reduces VK8 binding to MUC16-expressing cells, but only slightly reduces OC125 binding to cells under the same conditions (Figure 3). We tested the possibility that even after trypsin digestion the OC125 epitopes remain bound to the cell surface via disulfide bridges. Mild treatment of the cells with mercaptoethanol or dithiothreitol to release disulfide-bound moieties did not decrease OC125 binding to the trypsinized OVCAR-3 cells (Figure 3).

If CA125 is indeed a discontinuous epitope, it is not clear if the O- or N-glycosylation of the tandem repeat will influence binding of OC125, M11 or OV197. Most studies characterizing the MUC16 repeats have been conducted with recombinant proteins produced in bacterial cells and therefore lacking native glycosylation. Similarly our 21mer peptides, assembled by solid-phase peptide synthesis, are not glycosylated. After initial characterization of the glycosylation of MUC16, there has not been a robust and systematic characterization of the glycan chains attached to each domain of the mucin or of the glycan site occupancy in mucin molecules produced by tumor versus normal epithelial cells. Attempts to identify disease-specific MUC16 glycoforms by glycomic analysis are producing interesting results that may enhance the diagnostic potential of this mucin. However, with the enormous potential diversity in glycan chains and glycoforms a significant effort will be required to fully understand the post-translational status of this mucin and its effect on detection in the CA125 assay and systemic half-life of the MUC16 glycoforms.

Mucins in systemic circulation are rapidly processed by the reticulo-endothelial cells, leaving behind only a fraction of the mucins in circulation to be detected in clinical assays such as the CA125 test. The combined effects of MUC16 clearance—reducing the amount of circulating MUC16 to miniscule levels—and the inability of the antibodies to uniformly bind all tandem repeats and isoforms—undercounting circulating MUC16—suggests that the CA125 assay significantly underestimates the concentration of this biomarker. New generation of reagents and assay protocols that can capture and more accurately quantify a larger cohort of the MUC16 molecules will likely add to the clinical significance of this biomarker.

To date, the majority of the anti-MUC16 antibodies raised against full-length mucin recognize regions within the tandem repeat domains. An explanation for the bias toward antibodies that recognize the tandem repeat region of MUC16 is not available but is likely due to higher immunogenicity of these epitopes. Antibodies against defined epitopes that are outside of the tandem repeat region (against peptides from the carboxy terminal end, for example) will serve an important purpose in modifying the CA125 assays and also in attempts to understand the biology of this mucin.

Biological role of MUC16

MUC16 is expressed by normal bronchial, endometrial, ovarian and corneal epithelial cells and has evolved from the proteoglycan, agrin. A transmembrane region anchors the mucin in the cell membrane and as a result the mucin can be detected on the cell surface (Figure 4).

MUC16 is released from the cell surface following proteolytic cleavage at a site presumably 50 amino acids upstream of its transmembrane segment. As a result the proteolytically released ectodomain of MUC16 is not significantly different in molecular weight than the cell surface-bound intact mucin.

Neutrophil elastase, MMP-7, MMP-9 and bacterial metalloprotease (ZmpC) can release the ectodomain of MUC16. Post-translational modifications (especially glycosylation) around the site of cleavage are thought to regulate the release of the ectodomains of these mucins. Post-translational modifications around the cleavage site may be a variable that impacts the sensitivity of the CA125 assay.

In corneal epithelial cells, MUC16-Galectin-3 interaction has been shown to serve as a barrier for bacterial and viral infections in ocular epithelia. These are the first studies to show a potential biological role for MUC16 in non-cancer cells. However, knockdown of murine Muc16 does not result in any obvious functional deficit. Since these knockout mice were maintained in a pathogen free environment and were not otherwise challenged with chemical or biological agents, the potential impact of Muc16 knockdown in specific pathological states remains unknown. Further exploration into the normal physiologic role(s) of human and murine MUC16 is warranted.

Immunoprotection of cancer cell cells

Innate immune cells, Natural Killer (NK) cells and monocytes are unable to attack tumor cells expressing high levels of MUC16. Knockdown of MUC16 results in increased lysis of the ovarian cancer cells by the cytolytic NK cells. The mechanism by which MUC16 inhibits NK cell-mediated killing of cancer cells is under investigation. One proposal is that MUC16 acts as a barrier that prevents interaction between the NK cells and their targets. NK cells require physical contact with the target cells for cytolysis to occur. NK cell immunologic synapse is defined by polarization of cytoskeletal and cell signaling molecules along with cytolytic granules of the effector cells to the site of contact. The NK cell cytolytic granules are released into the target cells, triggering cell death via apoptosis. MUC16 with its ~5 million Da molecular size is expected to have a linear length of 1–5 μm. Due to its extended structure and overall negative charge (due to the presence of terminal sialic acid residues), MUC16 may inhibit intimate interactions between NK and cancer cells. This situation is analogous to the mechanism of immuneprotection demonstrated for MUC4.

Imunoprotective effect by MUC16 may also arise from its interaction with the NK cell inhibitory receptor, Siglec-9 (Figure 5). NK cells express both activating (NKG2D, CD16, DNAM-1, for example) and inhibitory receptors (Killer Immunoglobulin-like Receptors (KIR’s), Siglec-9, and Siglec-7, for example) on their cell surface. Interaction of activating and inhibiting receptors with their corresponding ligands on target cells leads to either activation or inhibition of the NK cell cytolytic response (reviewed in and other articles). The interplay between the activating and inhibitory receptors controls the cytolytic activity of NK cells.

Siglecs are a class of inhibitory receptors that bind to negatively charged sialic acid ligands. MUC16 oligosaccharides carry sialic acid in a terminal α2-3 linkage. Oligosaccharides terminated with α2-3-linked sialic acids are recognized as ligands by the inhibitory Siglec-9 receptor. Our work demonstrates that MUC16-Siglec-9 interaction protects cancer cells from NK cell attack. Siglec-9 is also expressed on monocytes and MUC16 promotes binding of monocytes to cancer cells. Upon binding to its ligand, Siglec-9 is phosphorylated on its Immunoreceptor Tyrosine-based Inhibition Motif (ITIM) tail, triggering an inhibitory signaling cascade that results in inhibition of the NK cell response. Ovarian cancer cells are therefore likely to be protected from NK cell and monocyte attack due to the negative signaling induced via MUC16-Siglec-9 interaction (Figure 5). This type of protection can occur from interaction of the NK and monocyte Siglec-9 with MUC16 on the surface of cancer cells and also from circulating MUC16 molecules cleaved from the cancer cells via proteolysis.

MUC16 protects ovarian cancer cells from naïve unstimulated NK cells as well as IL-2 stimulated NK cells. A recent study has implicated MUC16 in inhibiting target cell killing via Antibody-dependent Cell-Mediated Cytotoxicity (ADCC), suggesting that the mucin may dampen the response of immunotherapeutic antibodies.

NK cells preferentially target ovarian tumor cells that express low levels of MUC16 on their cell surface. As a result, tumor cells surviving NK cell attack are high expressors of MUC16 that are more resistant to immune attack. We have proposed that NK cells contribute to immune editing by selectively lysing cancer cells expressing lower levels of MUC16. As a result, those cancer cells with high levels of MUC16, the subset that is most likely to resist immune attack, survive.

Pro-metastasis role of MUC16

Immune editing in favor of cancer cells expressing higher levels of MUC16 may also increase peritoneal metastasis of ovarian tumors. MUC16 binds to mesothelin, a GPI-anchored glycoprotein found on the surface of mesothelial cells and also overexpressed by ovarian tumors, with an apparent Kd of 5 nM. MUC16-mesothelin interaction allows tumor cells to bind to themselves (likely increasing tumor mass at metastatic sites) and also allows attachment of ovarian cancer cells to the mesothelial lining. Removal of N-glycans from MUC16 attenuates its interaction with mesothelin. Mesothelin, similar to other members of its superfamily, contains superhelical ARM-type repeats that could potentially recognize carbohydrate ligands presented by MUC16.

MUC16, via its sialofucosylated oligosaccharides, binds to both E- and L-selectin even under shear stress conditions. Contribution of MUC16-selectin interaction to ovarian cancer progression or metastasis is not known. Even after MUC16 knockdown, E- and L-selectin binding is observed to cancer cells, presumably via other glycolipid, mucin, or glycoprotein ligands. Therefore, interpretation of results MUC16-selectin interactions and their possible roles in metastasis are complicated by presence of such redundant binding mechanisms.

MUC16 associated cell signaling

MUC1 and MUC4 undergo auto-cleavage during their synthesis to generate α- and β-subunits. The β-subunit of MUC1 and MUC4 is involved in intracellular signaling. For example, EGF stimulation causes the MUC1 β-subunit to signal via PI3K and MAPK MUC1 β-subunit also interacts with p53, NF-κB, β-catenin and STAT1.

Phosphorylation of the cytoplasmic portion of C-terminal domain of MUC16 increases shedding of the ectodomain of this mucin. Specific serine, threonine and tyrosine residues in the cytoplasmic tail of MUC16 have been proposed as likely candidates for phosphorylation.

Knockdown of MUC16 inhibits in vitro and in vivo proliferation of cancer cells MUC16-triggered activation of STAT3 via JAK2 results in increasing cancer cell proliferation. On the other hand, knockdown of MUC16 causes cell cycle arrest (either in G2/M or G1 phase) and apoptosis.

Expression of the C-terminal domain of the mucin in the MUC16neg SKOV-3 cells increases their proliferation with 2–3 fold increase in tumor weight and a significant decrease in survival of tumor-bearing mice. MUC16 knockdown causes a decrease in the expression of matrix metalloproteases (MMP-2), a class of proteolytic enzymes that plays a crucial role in cancer cell metastasis. A recent report suggests that the cytoplasmic tail of MUC16 interacts with Src-family kinases and induces E-cadherin-mediated cell invasion and migration.

MUC16 is overexpressed but not associated with decreased survival or chemoresistance

Silencing of MUC16 increased the sensitivity of OVCAR-3 cells to cisplatin and doxorubicin but not to paclitaxel. However, bioinformatics analysis of MUC16 expression and mutations available through The Cancer Genome Atlas (TCGA) does not support a major effect of MUC16 on overall survival in ovarian cancer patients (Figure 6). No correlation is observed between MUC16 expression and resistance to chemotherapy in the ovarian cancer cohorts. Of the patients on whom MUC16 data has been deposited in TCGA, mutations in the mucin were identified in fifteen of 196 patients (Additional file 2). Patients with mutated MUC16 had a slightly lower survival than patients with wild-type MUC16; however the difference was not statistically significant (Figure 6).

MUC16 as a target for therapy

The lack of significant effect of MUC16 observed in our analysis of TCGA data is inconsistent with the effect of MUC16 observed in in vitro and in vivo studies with ovarian and breast cancer cells, described above, where the expression of this mucin was attenuated. This dichotomy may potentially arise from the fact that only eight healthy donor samples are reported in the TCGA database for ovarian cancer. We estimate that data from 40 individuals each in the healthy control and ovarian cancer group will be required to attain 90% power to demonstrate the effect of differential MUC16 gene expression on patient survival. If no correlation between MUC16 expression and survival is demonstrated in a larger study, an intriguing possibility that will have to be considered is that MUC16 may be a factor whose presence (in terms of biological significance) is felt only by its absence (as shown by the knockdown experiments). If true, this model suggests that significant effect on ovarian tumors may be achieved by the application of small molecule agents and other strategies for in vivo knockdown of MUC16 or inhibition of its biological function. In this scenario, tumors will be subject to increased apoptosis, decreased proliferation, increased sensitivity to chemotherapy, and reduced efficiency in subverting innate immune responses and immunotherapeutic agents. In this context it is interesting to note that microRNA-200c regulates expression of both MUC4 and MUC16.

MUC16 as a target for immunotherapy

Anti-mesothelin antibodies that interfere with mesothelin-MUC16 binding have been developed as immunotherapeutic agents. A novel immunoadhesin, HN125, contains the MUC16 binding epitope of mesothelin fused to the Fc portion of human IgG1 antibody has been developed. However, additional work is required to increase the potency of HN125 to produce a stronger anti-cancer response.

Oregovomab and Abgovomab are two antibodies developed for ovarian cancer immunotherapy. Oregovomab, (B43.13, OVAREX) is a mouse anti-MUC16 antibody developed for the in vivo detection of ovarian tumors. A retrospective analysis of results trials designed to test the use of B43.13 as an imaging agent suggested increased survival in patients developing a human anti-mouse antibody (HAMA) response. Repeated administration of the anti-CA125 antibodies results in increased anti-tumor T cell responses and the generation of anti-idiotypic antibodies. These positive results led to the testing of Oregovomab in larger clinical trials in ovarian cancer patients. Overall the results of these trials were disappointing as no benefit of Oregovomab was observed.

Abgovomab has met a similar fate in clinical trials. Abgovomab is an anti-idiotype antibody that was developed as a targeting agent against MUC16. Here again, clinical trials showed no difference in the overall survival of ovarian cancer patients as compared to patients in the control arm of the study.

One potential reason for Oregovomab and Abgovomab being unsuccessful in inhibiting tumor growth is that these antibodies may conjugate with the circulating ectodomain of MUC16 reducing the amount of antibody available to target the cancer cells. Additionally, shedding of the ectodomain may release the antibodies bound to the cell surface associated mucin. The rate at which the ectodomain is shed and the factors controlling the proteolysis of MUC16 are not clearly defined. It will be interesting to determine the efficacy of treatment regimens that combine anti-MUC16 antibodies with agents that can inhibit MUC16 release in controlling the growth of ovarian tumors.

Targeting MUC16 with antibody-drug conjugates

Two anti-MUC16 antibodies, 3A5 and 11D10, were developed and conjugated to the cytotoxic drug Monomethyl auristatin E (MMAE). 3A5 targets MUC16 tandem repeats and is more effective than 11D10 in delivering MMAE to cancer cells and inducing cell death. The 3A5-MMAE conjugate (now referred to as DMUC5754A) is being tested in a Phase I clinical trial. Twenty two of the 44 patients recruited in this trial received DMUC5754A. The antibody drug conjugate produced minimal toxicity and, importantly, one patient showed complete response and five patients experienced a reduction in tumor. These results are encouraging and support further development of MUC16-targeted therapies for cancer.

Conclusion

Recent studies on MUC16 indicate that this mucin is not only important because it contains the biomarker CA125 but also for its role in contributing to ovarian tumor growth and metastasis. The complex biochemical structure of this mucin continues to provide major challenges to efforts being undertaken to make improvements to the CA125 assay and to understand the biological role of MUC16. The complexity of this antigen however also provides multiple opportunities that can be exploited to develop a test that can monitor this mucin even at low concentrations and, as the encouraging results with DMUC5754A suggest, developing novel anti-cancer therapeutic strategies. A sustained and systematic effort will be required to fully understand and exploit MUC16 to realize a benefit for patients with ovarian and other malignancies.

Abbreviations

CA125: Cancer Antigen 125; MMAE: Monomethyl Auristatin E; MUC16: Mucin 16; NK: Natural killer cells; PLCO: Prostate, lung, colorectal and ovarian cancer; RMI: Risk of malignancy index; ROCA: Risk of ovarian cancer algorithm; ROMA: Risk of ovarian malignancy algorithm; SEA: Sea urchin Enterokinase and Agrin; TCGA: The cancer genome atlas; UKCTOCS: United Kingdom Collaborative Trial of Ovarian Cancer Screening.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

MF conducted the flow cytometry experiments; AK conducted flow cytometry experiments and MUC16 mutation analysis; JGB conducted the TCGA data analysis and helped with writing of the manuscript; SH, JH and RA helped with obtaining the electron microscopy data; LF and JK conducted MUC16 mutation analysis; KH helped with the analysis of antibody binding to CA125 peptides; HS assisted in the writing of the manuscript; RJW and MSP conceptualized the idea for this review and wrote the manuscript. All authors read and approved the final manuscript.

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  2. 2.

    Sturgeon CM Duffy MJ Stenman UH Lilja H Brunner N Chan DW Babaian R Bast RC Jr Dowell B Esteva FJ Haglund C Harbeck N Hayes DF Holten-Andersen M Klee GG Lamerz R Looijenga LH Molina R Nielsen HJ Rittenhouse H Semjonow A Shih Ie M Sibley P Soletormos G Stephan C Sokoll L Hoffman BR Diamandis EP National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancersClin Chem2008 54e11e79

    Not in our library10.1373/clinchem.2008.105601

  3. 3.

    Seltzer V Drukker BH Gillespie BW Gossfeld LM Grigsby PW Harvey HA Hendricks CB Hummel S Makuch RW Monaco GP Parham GP Sawyers CL West RJ Alberts DS Anderson B Averette HE Bast RC Christian MC Colombo N Creasman WT John P Curtin JP Gershenson DM Hoskins WJ Karlan BY Kramer BS Markman M McGuire WP Ozols RF Pecorelli S NIH consensus conference: ovarian cancer: screening, treatment, and follow-up. NIH consensus development panel on ovarian cancerJAMA1995 273491497

    Not in our library10.1001/jama.1995.03520300065039

  4. 4.

    Rustin GJ Quinn M Thigpen T du Bois A Pujade-Lauraine E Jakobsen A Eisenhauer E Sagae S Greven K Vergote I Cervantes A Vermorken J Re: new guidelines to evaluate the response to treatment in solid tumors (ovarian cancer)J Natl Cancer Inst2004 96487488

    Not in our library10.1093/jnci/djh081

  5. 5.

    Vasudev NS Trigonis I Cairns DA Hall GD Jackson DP Broadhead T Buxton J Hutson R Nugent D Perren TJ The prognostic and predictive value of CA-125 regression during neoadjuvant chemotherapy for advanced ovarian or primary peritoneal carcinomaArch Gynecol Obstet2011 284221227

    Not in our library10.1007/s00404-010-1655-2

  6. 6.

    Rustin GJ Follow-up with CA125 after primary therapy of advanced ovarian cancer has major implications for treatment outcome and trial performances and should not be routinely performedAnn Oncol2011 22Suppl 8viii45viii48

    Not in our library10.1093/annonc/mdr471

  7. 7.

    Herzog TJ Vermorken JB Pujade-Lauraine E Provencher DM Jagiello-Gruszfeld A Kong B Boman K Park YC Parekh T Lebedinsky C Gomez J Monk BJ Correlation between CA-125 serum level and response by RECIST in a phase III recurrent ovarian cancer studyGynecol Oncol2011 122350355

    Not in our library10.1016/j.ygyno.2011.04.005

  8. 8.

    Miller RE Rustin GJ How to follow-up patients with epithelial ovarian cancerCurr Opin Oncol2010 22498502

    Not in our library10.1097/cco.0b013e32833ae8b6

  9. 9.

    Gossner G Coleman RL Mutch DG Horowitz NS Rader JS Gibb RK Powell MA Herzog TJ CA-125 response in patients with recurrent ovarian or primary peritoneal cancer treated with pegylated liposomal doxorubicin or topotecanGynecol Oncol2006 103212218

    Not in our library10.1016/j.ygyno.2006.02.026

  10. 10.

    Guppy AE Nathan PD Rustin GJ Epithelial ovarian cancer: a review of current managementClin Oncol (R Coll Radiol)2005 17399411

    Not in our library10.1016/j.clon.2005.05.009

  11. 11.

    Bridgewater JA Nelstrop AE Rustin GJ Gore ME McGuire WP Hoskins WJ Comparison of standard and CA-125 response criteria in patients with epithelial ovarian cancer treated with platinum or paclitaxelJ Clin Oncol1999 17501508

    Not in our library10.1200/jco.1999.17.2.501

  12. 12.

    Rustin G Tuxen M Use of CA 125 in follow-up of ovarian cancerLancet1996 348191192

    Not in our library10.1016/s0140-6736(05)66133-8

  13. 13.

    Bast RC Jr Feeney M Lazarus H Nadler LM Colvin RB Knapp RC Reactivity of a monoclonal antibody with human ovarian carcinomaJ Clin Invest1981 6813311337

    Not in our library10.1172/jci110380

  14. 14.

    Bast RC Jr Klug TL St John E Jenison E Niloff JM Lazarus H Berkowitz RS Leavitt T Griffiths CT Parker L Zurawski VR Jr Knapp RC A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancerN Engl J Med1983 309883887

    Not in our library10.1056/nejm198310133091503

  15. 15.

    Kabawat SE Bast RC Jr Bhan AK Welch WR Knapp RC Colvin RB Tissue distribution of a coelomic-epithelium-related antigen recognized by the monoclonal antibody OC125Int J Gynecol Pathol1983 2275285

    Not in our library10.1097/00004347-198303000-00005

  16. 16.

    Kabawat SE Bast RC Welch WR Knapp RC Colvin RB Immunopathologic characterization of a monoclonal antibody that recognizes common surface antigens of human ovarian tumors of serous, endometrioid, and clear cell typesAm J Clin Pathol1983 7998104

    Not in our library10.1093/ajcp/79.1.98

  17. 17.

    Niloff JM Knapp RC Schaetzl E Reynolds C Bast RC Jr CA125 antigen levels in obstetric and gynecologic patientsObstet Gynecol1984 64703707

    Not in our library

  18. 18.

    Bast RC Jr Xu FJ Yu YH Barnhill S Zhang Z Mills GB CA 125: the past and the futureInt J Biol Markers1998 13179187

    Not in our library10.1177/172460089801300402

  19. 19.

    Fritsche HA Bast RC CA 125 in ovarian cancer: advances and controversyClin Chem1998 4413791380

    Not in our library

  20. 20.

    O'Brien TJ Tanimoto H Konishi I Gee M More than 15 years of CA 125: what is known about the antigen, its structure and its functionInt J Biol Markers1998 13188195

    Not in our library10.1177/172460089801300403

  21. 21.

    O'Brien TJ Beard JB Underwood LJ Dennis RA Santin AD York L The CA 125 gene: an extracellular superstructure dominated by repeat sequencesTumour Biol2001 22348366

    Not in our library10.1159/000050638

  22. 22.

    Yin BW Lloyd KO Molecular cloning of the ca125 ovarian cancer antigen. identification as a new mucin, muc16J Biol Chem2001 2762737127375

    Not in our library10.1074/jbc.m103554200

  23. 23.

    Rump A Morikawa Y Tanaka M Minami S Umesaki N Takeuchi M Miyajima A Binding of ovarian cancer antigen CA125/MUC16 to mesothelin mediates cell adhesionJ Biol Chem2004 27991909198

    Not in our library10.1074/jbc.m312372200

  24. 24.

    Hattrup CL Gendler SJ Structure and function of the cell surface (Tethered) MucinsAnnu Rev Physiol2007 70431457

    Not in our library10.1146/annurev.physiol.70.113006.100659

  25. 25.

    Comamala M Pinard M Theriault C Matte I Albert A Boivin M Beaudin J Piche A Rancourt C Downregulation of cell surface CA125/MUC16 induces epithelial-to-mesenchymal transition and restores EGFR signalling in NIH:OVCAR3 ovarian carcinoma cellsBr J Cancer2011 104989999

    Not in our library10.1038/bjc.2011.34

  26. 26.

    Bast RC Jr Spriggs DR More than a biomarker: CA125 may contribute to ovarian cancer pathogenesisGynecol Oncol2011 121429430

    Not in our library10.1016/j.ygyno.2011.04.032

  27. 27.

    Skates SJ Xu FJ Yu YH Sjovall K Einhorn N Chang Y Bast RC Jr Knapp RC Toward an optimal algorithm for ovarian cancer screening with longitudinal tumor markersCancer1995 7620042010

    Not in our library10.1002/1097-0142(19951115)76:10+<2004::aid-cncr2820761317>3.0.co;2-g

  28. 28.

    Skates SJ Pauler D Jacobs I Screening based on the risk of cancer calculation from Bayesian heirarchical changepoint and mixture models of longitudinal markersJ2001 96429439

    Not in our library10.1198/016214501753168145

  29. 29.

    Einhorn N Bast R Knapp R Nilsson B Zurawski V Jr Sjovall K Long-term follow-up of the Stockholm screening study on ovarian cancerGynecol Oncol2000 79466470

    Not in our library10.1006/gyno.2000.5983

  30. 30.

    Einhorn N Sjovall K Knapp RC Hall P Scully RE Bast RC Jr Zurawski VR Jr Prospective evaluation of serum CA 125 levels for early detection of ovarian cancerObstet Gynecol1992 801418

    Not in our library

  31. 31.

    Jacobs I Davies AP Bridges J Stabile I Fay T Lower A Grudzinskas JG Oram D Prevalence screening for ovarian cancer in postmenopausal women by CA 125 measurement and ultrasonographyBMJ1993 30610301034

    Not in our library10.1136/bmj.306.6884.1030

  32. 32.

    Buys SS Partridge E Black A Johnson CC Lamerato L Isaacs C Reding DJ Greenlee RT Yokochi LA Kessel B Crawford ED Church TR Andriole GL Weissfeld JL Fouad MN Chia D O'Brien B Ragard LR Clapp JD Rathmell JM Riley TL Hartge P Pinsky PF Zhu CS Izmirlian G Kramer BS Miller AB Xu JL Prorok PC Gohagan JK Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled TrialJAMA2011 30522952303

    Not in our library10.1001/jama.2011.766

  33. 33.

    Partridge E Kreimer AR Greenlee RT Williams C Xu JL Church TR Kessel B Johnson CC Weissfeld JL Isaacs C Andriole GL Ogden S Ragard LR Buys SS Team PP Results from four rounds of ovarian cancer screening in a randomized trialObstet Gynecol2009 113775782

    Not in our library10.1097/aog.0b013e31819cda77

  34. 34.

    Buys SS Partridge E Greene MH Prorok PC Reding D Riley TL Hartge P Fagerstrom RM Ragard LR Chia D Izmirlian G Fouad M Johnson CC Gohagan JK Team PP Ovarian cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial: findings from the initial screen of a randomized trialAm J Obstet Gynecol2005 19316301639

    Not in our library10.1016/j.ajog.2005.05.005

  35. 35.

    Pinsky PF Zhu C Skates SJ Black A Partridge E Buys SS Berg CD Potential effect of the risk of ovarian cancer algorithm (ROCA) on the mortality outcome of the Prostate, Lung, Colorectal and Ovarian (PLCO) trialInt J Cancer2013 13221272133

    Not in our library10.1002/ijc.27909

  36. 36.

    Urban N Screening for ovarian cancer: We now need a definitive randomised trialBMJ1999 31913171318

    Not in our library10.1136/bmj.319.7221.1317

  37. 37.
    Recruitment to multicentre trials--lessons from UKCTOCS: descriptive study · 2008
    No notice
  38. 38.

    Menon U Gentry-Maharaj A Hallett R Ryan A Burnell M Sharma A Lewis S Davies S Philpott S Lopes A Godfrey K Oram D Herod J Williamson K Seif MW Scott I Mould T Woolas R Murdoch J Dobbs S Amso NN Leeson S Cruickshank D McGuire A Campbell S Fallowfield L Singh N Dawnay A Skates SJ Parmar M Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)Lancet Oncol2009 10327340

    Not in our library10.1016/s1470-2045(09)70026-9

  39. 39.

    Menon U Kalsi J Jacobs I The UKCTOCS experience–reasons for hope?Int J Gynecol Cancer2012 22Suppl 1S18S20

    Not in our library10.1097/igc.0b013e318251cb47

  40. 40.

    van der Burg ME Lammes FB Verweij J The role of CA 125 and conventional examinations in diagnosing progressive carcinoma of the ovarySurg Gynecol Obstet1993 176310314

    Not in our library

  41. 41.

    van der Burg ME Lammes FB Verweij J CA 125 in ovarian cancerNeth J Med1992 403651

    Not in our library

  42. 42.

    van der Burg ME Lammes FB Verweij J The role of CA 125 in the early diagnosis of progressive disease in ovarian cancerAnn Oncol1990 1301302

    Not in our library10.1093/oxfordjournals.annonc.a057754

  43. 43.

    Tholander B Taube A Lindgren A Sjoberg O Stendahl U Tamsen L Pretreatment serum levels of CA-125, carcinoembryonic antigen, tissue polypeptide antigen, and placental alkaline phosphatase in patients with ovarian carcinoma: influence of histological type, grade of differentiation, and clinical stage of diseaseGynecol Oncol1990 392633

    Not in our library10.1016/0090-8258(90)90394-z

  44. 44.

    Jacobs I Oram D Fairbanks J Turner J Frost C Grudzinskas JG A risk of malignancy index incorporating CA 125, ultrasound and menopausal status for the accurate preoperative diagnosis of ovarian cancerBr J Obstet Gynaecol1990 97922929

    Not in our library10.1111/j.1471-0528.1990.tb02448.x

  45. 45.

    Moore RG Miller MC Disilvestro P Landrum LM Gajewski W Ball JJ Skates SJ Evaluation of the diagnostic accuracy of the risk of ovarian malignancy algorithm in women with a pelvic massObstet Gynecol2011 118280288

    Not in our library10.1097/aog.0b013e318224fce2

  46. 46.

    Moore RG McMeekin DS Brown AK DiSilvestro P Miller MC Allard WJ Gajewski W Kurman R Bast RC Jr Skates SJ A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic massGynecol Oncol2009 1124046

    Not in our library10.1016/j.ygyno.2008.08.031

  47. 47.

    Moore RG Brown AK Miller MC Skates S Allard WJ Verch T Steinhoff M Messerlian G DiSilvestro P Granai CO Bast RC Jr The use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic massGynecol Oncol2008 108402408

    Not in our library10.1016/j.ygyno.2007.10.017

  48. 48.

    Hellstrom I Raycraft J Hayden-Ledbetter M Ledbetter JA Schummer M McIntosh M Drescher C Urban N Hellstrom KE The HE4 (WFDC2) protein is a biomarker for ovarian carcinomaCancer Res2003 6336953700

    Not in our library

  49. 49.

    Simmons AR Baggerly K Bast RC Jr The emerging role of HE4 in the evaluation of epithelial ovarian and endometrial carcinomasOncology (Williston Park)2013 27548556

    Not in our library

  50. 50.

    Bast RC Jr Skates S Lokshin A Moore RG Differential diagnosis of a pelvic mass: improved algorithms and novel biomarkersInt J Gynecol Cancer2012 22Suppl 1S5S8

    Not in our library10.1097/igc.0b013e318251c97d

  51. 51.

    Zhu CS Pinsky PF Cramer DW Ransohoff DF Hartge P Pfeiffer RM Urban N Mor G Bast RC Jr Moore LE Lokshin AE McIntosh MW Skates SJ Vitonis A Zhang Z Ward DC Symanowski JT Lomakin A Fung ET Sluss PM Scholler N Lu KH Marrangoni AM Patriotis C Srivastava S Buys SS Berg CD A framework for evaluating biomarkers for early detection: validation of biomarker panels for ovarian cancerCancer Prev Res (Phila)2011 4375383

    Not in our library10.1158/1940-6207.capr-10-0193

  52. 52.

    Cramer DW Bast RC Jr Berg CD Diamandis EP Godwin AK Hartge P Lokshin AE Lu KH McIntosh MW Mor G Patriotis C Pinsky PF Thornquist MD Scholler N Skates SJ Sluss PM Srivastava S Ward DC Zhang Z Zhu CS Urban N Ovarian cancer biomarker performance in prostate, lung, colorectal, and ovarian cancer screening trial specimensCancer Prev Res (Phila)2011 4365374

    Not in our library10.1158/1940-6207.capr-10-0195

  53. 53.

    Jacobs I Menon U The sine qua non of discovering novel biomarkers for early detection of ovarian cancer: carefully selected preclinical samplesCancer Prev Res (Phila)2011 4299302

    Not in our library10.1158/1940-6207.capr-11-0048

  54. 54.

    Diamandis EP Bast RC Jr Gold P Chu TM Magnani JL Reflection on the discovery of carcinoembryonic antigen, prostate-specific antigen, and cancer antigens CA125 and CA19-9Clin Chem2013 592231

    Not in our library10.1373/clinchem.2012.187047

  55. 55.

    Niloff JM Klug TL Schaetzl E Zurawski VR Jr Knapp RC Bast RC Jr Elevation of serum CA125 in carcinomas of the fallopian tube, endometrium, and endocervixAm J Obstet Gynecol1984 14810571058

    Not in our library10.1016/s0002-9378(84)90444-7

  56. 56.

    O'Brien TJ Raymond LM Bannon GA Ford DH Hardardottir H Miller FC Quirk JG Jr New monoclonal antibodies identify the glycoprotein carrying the CA 125 epitopeAm J Obstet Gynecol1991 16518571864

    Not in our library10.1016/0002-9378(91)90046-t

  57. 57.

    Lloyd KO Yin BW Kudryashov V Isolation and characterization of ovarian cancer antigen CA 125 using a new monoclonal antibody (VK-8): identification as a mucin-type moleculeInt J Cancer1997 71842850

    Not in our library10.1002/(sici)1097-0215(19970529)71:5<842::aid-ijc24>3.0.co;2-8

  58. 58.

    Nap M Vitali A Nustad K Bast RC Jr O'Brien TJ Nilsson O Seguin P Suresh MR Bormer OP Saga T de Bruijn HW Nozawa S Kreutz FT Jette D Sakahara H Gadnell M Endo K Barlow EH Warren D Paus E Hammarstrom S Kenemans P Hilgers J Immunohistochemical characterization of 22 monoclonal antibodies against the CA125 antigen: 2nd report from the ISOBM TD-1 WorkshopTumour Biol1996 17325331

    Not in our library

  59. 59.

    Nustad K Bast RC Jr Brien TJ Nilsson O Seguin P Suresh MR Saga T Nozawa S Bormer OP de Bruijn HW Nap M Vitali A Gadnell M Clark J Shigemasa K Karlsson B Kreutz FT Jette D Sakahara H Endo K Paus E Warren D Hammarstrom S Kenemans P Hilgers J Specificity and affinity of 26 monoclonal antibodies against the CA 125 antigen: first report from the ISOBM TD-1 workshop: International Society for Oncodevelopmental Biology and MedicineTumour Biol1996 17196219

    Not in our library10.1159/000217982

  60. 60.

    Nustad K Lebedin Y Lloyd KO Shigemasa K de Bruijn HW Jansson B Nilsson O Olsen KH O'Brien TJ Epitopes on CA 125 from cervical mucus and ascites fluid and characterization of six new antibodies. Third report from the ISOBM TD-1 workshopTumour Biol2002 23303314

    Not in our library10.1159/000068570

  61. 61.

    Warren DJ Nustad K Beard JB O'Brien TJ Expression and epitope characterization of a recombinant CA 125 repeat: fourth report from the ISOBM TD-1 workshopTumour Biol2009 305160

    Not in our library10.1159/000209988

  62. 62.

    O'Brien TJ Hardin JW Bannon GA Norris JS Quirk JG Jr CA 125 antigen in human amniotic fluid and fetal membranesAm J Obstet Gynecol1986 1555055

    Not in our library10.1016/0002-9378(86)90076-1

  63. 63.

    Hanisch FG Uhlenbruck G Peter-Katalinic J Egge H Structural studies on oncofetal carbohydrate antigens (Ca 19–9, Ca 50, and Ca 125) carried by O-linked sialyloligosaccharides on human amniotic mucinsCarbohydr Res1988 1782947

    Not in our library10.1016/0008-6215(88)80100-9

  64. 64.

    Davis HM Zurawski VR Jr Bast RC Jr Klug TL Characterization of the CA 125 antigen associated with human epithelial ovarian carcinomasCancer Res1986 4661436148

    Not in our library

  65. 65.

    Van Lenten L Ashwell G Studies on the chemical and enzymatic modification of glycoproteins. A general method for the tritiation of sialic acid-containing glycoproteinsJ Biol Chem1971 24618891894

    Not in our library

  66. 66.

    Ozgur K Patankar MS Oehninger S Clark GF Direct evidence for the involvement of carbohydrate sequences in human sperm-zona pellucida bindingMol Hum Reprod1998 4318324

    Not in our library10.1093/molehr/4.4.318

  67. 67.

    Lloyd KO Yin BW Synthesis and secretion of the ovarian cancer antigen CA 125 by the human cancer cell line NIH:OVCAR-3Tumour Biol2001 227782

    Not in our library10.1159/000050600

  68. 68.

    Quirk JG Jr Brunson GL Long CA Bannon GA Sanders MM O'Brien TJ CA 125 in tissues and amniotic fluid during pregnancyAm J Obstet Gynecol1988 159644649

    Not in our library10.1016/s0002-9378(88)80026-7

  69. 69.

    Hardardottir H Parmley TH 2nd Quirk JG Jr Sanders MM Miller FC O'Brien TJ Distribution of CA 125 in embryonic tissues and adult derivatives of the fetal peridermAm J Obstet Gynecol1990 16319251931

    Not in our library10.1016/0002-9378(90)90775-3

  70. 70.

    Fendrick JL Staley KA Gee MK McDougald SR Quirk JG Jr O'Brien TJ Characterization of CA 125 synthesized by the human epithelial amnion WISH cell lineTumour Biol1993 14310318

    Not in our library10.1159/000217844

  71. 71.

    O'Brien TJ Beard JB Underwood LJ Shigemasa K The CA 125 gene: a newly discovered extension of the glycosylated N- terminal domain doubles the size of this extracellular superstructureTumour Biol2002 23154169

    Not in our library10.1159/000064032

  72. 72.

    Yin BW Dnistrian A Lloyd KO Ovarian cancer antigen CA125 is encoded by the MUC16 mucin geneInt J Cancer2002 98737740

    Not in our library10.1002/ijc.10250

  73. 73.

    Konishi I Fendrick JL Parmley TH Quirk JG Jr O'Brien TJ Epidermal growth factor enhances secretion of the ovarian tumor- associated cancer antigen CA125 from the human amnion WISH cell lineJ Soc Gynecol Investig1994 18996

    Not in our library10.1177/107155769400100118

  74. 74.

    Fendrick JL Konishi I Geary SM Parmley TH Quirk JG Jr O'Brien TJ CA125 phosphorylation is associated with its secretion from the WISH human amnion cell lineTumour Biol1997 18278289

    Not in our library10.1159/000218041

  75. 75.

    Bressan A Bozzo F Maggi CA Binaschi M OC125, M11 and OV197 epitopes are not uniformly distributed in the tandem-repeat region of CA125 and require the entire SEA domainDis Markers2013 34257267

    Not in our library10.1155/2013/917898

  76. 76.

    Berman ZT Moore LJ Knudson KE Whelan RJ Synthesis and structural characterization of the peptide epitope of the ovarian cancer biomarker CA125 (MUC16)Tumour Biol2010 31495502

    Not in our library10.1007/s13277-010-0062-4

  77. 77.

    Bork P Patthy L The SEA module: a new extracellular domain associated with O-glycosylationProtein Sci1995 414211425

    Not in our library10.1002/pro.5560040716

  78. 78.

    Maeda T Inoue M Koshiba S Yabuki T Aoki M Nunokawa E Seki E Matsuda T Motoda Y Kobayashi A Hiroyasu F Shirouzu M Terada T Hayami N Ishizuka Y Shinya N Tatsuguchi A Yoshida M Hirota H Matsuo Y Tani K Arakawa T Carninci P Kawai J Hayashizaki Y Kigawa T Yokoyama S Solution structure of the SEA domain from the murine homologue of ovarian cancer antigen CA125 (MUC16)J Biol Chem2004 2791317413182

    Not in our library10.1074/jbc.m309417200

  79. 79.

    Laver WG Air GM Webster RG Smith-Gill SJ Epitopes on protein antigens: misconceptions and realitiesCell1990 61553556

    Not in our library10.1016/0092-8674(90)90464-p

  80. 80.

    Kui Wong N Easton RL Panico M Sutton-Smith M Morrison JC Lattanzio FA Morris HR Clark GF Dell A Patankar MS Characterization of the oligosaccharides associated with the human ovarian tumor marker CA125J Biol Chem2003 2782861928634

    Not in our library10.1074/jbc.m302741200

  81. 81.

    Chen K Gentry-Maharaj A Burnell M Steentoft C Marcos-Silva L Mandel U Jacobs I Dawnay A Menon U Blixt O Microarray Glycoprofiling of CA125 improves differential diagnosis of ovarian cancerJ Proteome Res2013 1214081418

    Not in our library10.1021/pr3010474

  82. 82.

    Akita K Yoshida S Ikehara Y Shirakawa S Toda M Inoue M Kitawaki J Nakanishi H Narimatsu H Nakada H Different levels of sialyl-Tn antigen expressed on MUC16 in patients with endometriosis and ovarian cancerInt J Gynecol Cancer2012 22531538

    Not in our library10.1097/igc.0b013e3182473292

  83. 83.

    Saldova R Struwe WB Wynne K Elia G Duffy MJ Rudd PM Exploring the glycosylation of serum CA125Int J Mol Sci2013 141563615654

    Not in our library10.3390/ijms140815636

  84. 84.

    Jankovic MM Milutinovic BS Glycoforms of CA125 antigen as a possible cancer markerCancer Biomark2008 43542

    Not in our library10.3233/cbm-2008-4104

  85. 85.

    Mitic N Milutinovic B Jankovic M Assessment of sialic acid diversity in cancer- and non-cancer related CA125 antigen using sialic acid-binding Ig-like lectins (Siglecs)Dis Markers2012 32187194

    Not in our library10.1155/2012/309203

  86. 86.

    Milutinovic B Mitic N Jankovic M Identification of pregnancy-associated CA125-reactive protein as a carbohydrate-binding immunoglobulin GArch Biochem Biophys2010 4996976

    Not in our library10.1016/j.abb.2010.05.011

  87. 87.

    Jankovic MM Milutinovic BS Pregnancy-associated CA125 antigen as mucin: evaluation of ferning morphologyMol Hum Reprod2007 13405408

    Not in our library10.1093/molehr/gam022

  88. 88.

    Jankovic MM Tapuskovic BS Molecular forms and microheterogeneity of the oligosaccharide chains of pregnancy-associated CA125 antigenHum Reprod2005 2026322638

    Not in our library10.1093/humrep/dei095

  89. 89.

    Wahrenbrock MG Varki A Multiple hepatic receptors cooperate to eliminate secretory mucins aberrantly entering the bloodstream: are circulating cancer mucins the “tip of the iceberg”?Cancer Res2006 6624332441

    Not in our library10.1158/0008-5472.can-05-3851

  90. 90.

    Chen Y Clark S Wong T Chen Y Chen Y Dennis MS Luis E Zhong F Bheddah S Koeppen H Gogineni A Ross S Polakis P Mallet W Armed antibodies targeting the mucin repeats of the ovarian cancer antigen, MUC16, are highly efficacious in animal tumor modelsCancer Res2007 6749244932

    Not in our library10.1158/0008-5472.can-06-4512

  91. 91.

    Dharma Rao T Park KJ Smith-Jones P Iasonos A Linkov I Soslow RA Spriggs DR Novel monoclonal antibodies against the proximal (carboxy-terminal) portions of MUC16Appl Immunohistochem Mol Morphol2010 18462472

    Not in our library10.1097/pai.0b013e3181dbfcd2

  92. 92.

    Kerschner JE Mucin gene expression in human middle ear epitheliumLaryngoscope2007 11716661676

    Not in our library10.1097/mlg.0b013e31806db531

  93. 93.

    Davies JR Kirkham S Svitacheva N Thornton DJ Carlstedt I MUC16 is produced in tracheal surface epithelium and submucosal glands and is present in secretions from normal human airway and cultured bronchial epithelial cellsInt J Biochem Cell Biol2007 3919431954

    Not in our library10.1016/j.biocel.2007.05.013

  94. 94.

    Blalock TD Spurr-Michaud SJ Tisdale AS Heimer SR Gilmore MS Ramesh V Gipson IK Functions of MUC16 in corneal epithelial cellsInvest Ophthalmol Vis Sci2007 4845094518

    Not in our library10.1167/iovs.07-0430

  95. 95.

    Hori Y Spurr-Michaud SJ Russo CL Argueso P Gipson IK Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16Invest Ophthalmol Vis Sci2005 4640504061

    Not in our library10.1167/iovs.05-0627

  96. 96.

    Argueso P Spurr-Michaud S Russo CL Tisdale A Gipson IK MUC16 mucin is expressed by the human ocular surface epithelia and carries the H185 carbohydrate epitopeInvest Ophthalmol Vis Sci2003 4424872495

    Not in our library10.1167/iovs.02-0862

  97. 97.

    Govindarajan B Gipson IK Membrane-tethered mucins have multiple functions on the ocular surfaceExp Eye Res2010 90655663

    Not in our library10.1016/j.exer.2010.02.014

  98. 98.

    Duraisamy S Ramasamy S Kharbanda S Kufe D Distinct evolution of the human carcinoma-associated transmembrane mucins, MUC1, MUC4 AND MUC16Gene2006 3732834

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  99. 99.

    Govindarajan B Menon BB Spurr-Michaud S Rastogi K Gilmore MS Argueso P Gipson IK A metalloproteinase secreted by Streptococcus pneumoniae removes membrane mucin MUC16 from the epithelial glycocalyx barrierPLoS One2012 7e32418

    Not in our library10.1371/journal.pone.0032418

  100. 100.

    Blalock TD Spurr-Michaud SJ Tisdale AS Gipson IK Release of membrane-associated mucins from ocular surface epitheliaInvest Ophthalmol Vis Sci2008 4918641871

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  101. 101.

    Govindarajan B Gipson IK Membrane-tethered mucins have multiple functions on the ocular surfaceExp Eye Res2010 90655663

    Not in our library10.1016/j.exer.2010.02.014

  102. 102.

    Argueso P Tisdale A Spurr-Michaud S Sumiyoshi M Gipson IK Mucin characteristics of human corneal-limbal epithelial cells that exclude the rose bengal anionic dyeInvest Ophthalmol Vis Sci2006 47113119

    Not in our library10.1167/iovs.05-0735

  103. 103.

    Argueso P Guzman-Aranguez A Mantelli F Cao Z Ricciuto J Panjwani N Association of cell surface mucins with galectin-3 contributes to the ocular surface epithelial barrierJ Biol Chem2009 2842303723045

    Not in our library10.1074/jbc.m109.033332

  104. 104.
    CA125/MUC16 is dispensable for mouse development and reproduction. · 2009
    Not checked
  105. 105.

    Wang Y Cheon DJ Lu Z Cunningham SL Chen CM Luo RZ Xing D Orsulic S Bast RC Jr Behringer RR MUC16 expression during embryogenesis, in adult tissues, and ovarian cancer in the mouseDifferentiation2008 7610811092

    Not in our library10.1111/j.1432-0436.2008.00295.x

  106. 106.
    MUC16 provides immune protection by inhibiting synapse formation between NK and ovarian tumor cells · 2010
    No notice
  107. 107.

    Davis DM Chiu I Fassett M Cohen GB Mandelboim O Strominger JL The human natural killer cell immune synapseProc Natl Acad Sci U S A1999 961506215067

    Not in our library10.1073/pnas.96.26.15062

  108. 108.

    Orange JS The lytic NK cell immunological synapse and sequential steps in its formationAdv Exp Med Biol2007 601225233

    Not in our library10.1007/978-0-387-72005-0_23

  109. 109.

    Mace EM Orange JS New views of the human NK cell immunological synapse: recent advances enabled by super- and high-resolution imaging techniquesFront Immunol2012 3421

    Not in our library10.3389/fimmu.2012.00421

  110. 110.

    Jentoft N Why are proteins O-glycosylated?Trends Biochem Sci1990 15291294

    Not in our library10.1016/0968-0004(90)90014-3

  111. 111.

    Komatsu M Yee L Carraway KL Overexpression of sialomucin complex, a rat homologue of MUC4, inhibits tumor killing by lymphokine-activated killer cellsCancer Res1999 5922292236

    Not in our library

  112. 112.
    Identification of Siglec-9 as the receptor for MUC16 on human NK cells, B cells, and monocytes · 2010
    No notice
  113. 113.

    Lanier LL Up on the tightrope: natural killer cell activation and inhibitionNat Immunol2008 9495502

    Not in our library10.1038/ni1581

  114. 114.

    Crocker PR Clark EA Filbin M Gordon S Jones Y Kehrl JH Kelm S Le Douarin N Powell L Roder J Schnaar RL Sgroi DC Stamenkovic K Schauer R Schachner M van den Berg TK van der Merwe PA Watt SM Varki A Siglecs: a family of sialic-acid binding lectins [letter]Glycobiology1998 8v

    Not in our library10.1093/oxfordjournals.glycob.a018832

  115. 115.

    Angata T Varki A Siglec-7: a sialic acid-binding lectin of the immunoglobulin superfamilyGlycobiology2000 10431438

    Not in our library10.1093/glycob/10.4.431

  116. 116.

    Zhang JQ Nicoll G Jones C Crocker PR Siglec-9, a novel sialic acid binding member of the immunoglobulin superfamily expressed broadly on human blood leukocytesJ Biol Chem2000 2752212122126

    Not in our library10.1074/jbc.m002788200

  117. 117.

    Crocker PR Varki A Siglecs in the immune systemImmunology2001 103137145

    Not in our library10.1046/j.0019-2805.2001.01241.x

  118. 118.

    Varki A Angata T Siglecs–the major subfamily of I-type lectinsGlycobiology2006 161R27R

    Not in our library10.1093/glycob/cwj126

  119. 119.

    Crocker PR Paulson JC Varki A Siglecs and their roles in the immune systemNat Rev Immunol2007 7255266

    Not in our library10.1038/nri2056

  120. 120.

    Yamaji T Teranishi T Alphey MS Crocker PR Hashimoto Y A small region of the natural killer cell receptor, Siglec-7, is responsible for its preferred binding to alpha2,8-disialyl and branched alpha2,6-sialyl residues: a comparison with Siglec-9J Biol Chem2001 1063246332

    Not in our library10.1074/jbc.m110146200

  121. 121.

    Avril T Floyd H Lopez F Vivier E Crocker PR The membrane-proximal immunoreceptor tyrosine-based inhibitory motif is critical for the inhibitory signaling mediated by Siglecs-7 and -9, CD33-related Siglecs expressed on human monocytes and NK cellsJ Immunol2004 17368416849

    Not in our library10.4049/jimmunol.173.11.6841

  122. 122.
    Glycan elongation beyond the mucin associated Tn antigen protects tumor cells from immune-mediated killing. · 2013
    Not checked
  123. 123.

    Dunn GP Bruce AT Ikeda H Old LJ Schreiber RD Cancer immunoediting: from immunosurveillance to tumor escapeNat Immunol2002 3991998

    Not in our library10.1038/ni1102-991

  124. 124.

    Dunn GP Old LJ Schreiber RD The immunobiology of cancer immunosurveillance and immunoeditingImmunity2004 21137148

    Not in our library10.1016/j.immuni.2004.07.017

  125. 125.

    Dunn GP Old LJ Schreiber RD The three Es of cancer immunoeditingAnnu Rev Immunol2004 22329360

    Not in our library10.1146/annurev.immunol.22.012703.104803

  126. 126.

    Tang Z Qian M Ho M The role of mesothelin in tumor progression and targeted therapyAnticancer Agents Med Chem2013 13276280

    Not in our library10.2174/1871520611313020014

  127. 127.

    Chen SH Hung WC Wang P Paul C Konstantopoulos K Mesothelin binding to CA125/MUC16 promotes pancreatic cancer cell motility and invasion via MMP-7 activationSci Rep2013 31870

    Not in our library10.1038/srep01870

  128. 128.

    Shimizu A Hirono S Tani M Kawai M Okada K Miyazawa M Kitahata Y Nakamura Y Noda T Yokoyama S Yamaue H Coexpression of MUC16 and mesothelin is related to the invasion process in pancreatic ductal adenocarcinomaCancer Sci2012 103739746

    Not in our library10.1111/j.1349-7006.2012.02214.x

  129. 129.

    Higashi M Yamada N Yokoyama S Kitamoto S Tabata K Koriyama C Batra SK Yonezawa S Pathobiological implications of MUC16/CA125 expression in intrahepatic cholangiocarcinoma-mass forming typePathobiology2012 79101106

    Not in our library10.1159/000335164

  130. 130.
    Mesothelin-MUC16 binding is a high affinity, N-glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors · 2006
    No notice
  131. 131.

    Scholler N Garvik B Hayden-Ledbetter M Kline T Urban N Development of a CA125-mesothelin cell adhesion assay as a screening tool for biologics discoveryCancer Lett2006 247130136

    Not in our library10.1016/j.canlet.2006.03.029

  132. 132.

    Sathyanarayana BK Hahn Y Patankar MS Pastan I Lee B Mesothelin, Stereocilin, and Otoancorin are predicted to have superhelical structures with ARM-type repeatsBMC Struct Biol2009 91

    Not in our library10.1186/1472-6807-9-1

  133. 133.

    Hassan R Schweizer C Lu KF Schuler B Remaley AT Weil SC Pastan I Inhibition of mesothelin-CA-125 interaction in patients with mesothelioma by the anti-mesothelin monoclonal antibody MORAb-009: Implications for cancer therapyLung Cancer2010 68455459

    Not in our library10.1016/j.lungcan.2009.07.016

  134. 134.

    Chopra A 111In-Labeled CHX-A''-DTPA-conjugated MORAb-009, a chimeric monoclonal antibody directed against mesothelinMolecular Imaging and Contrast Agent Database (MICAD)2004 MD: Bethesda

    Not in our library

  135. 135.

    Hassan R Cohen SJ Phillips M Pastan I Sharon E Kelly RJ Schweizer C Weil S Laheru D Phase I clinical trial of the chimeric anti-mesothelin monoclonal antibody MORAb-009 in patients with mesothelin-expressing cancersClin Cancer Res2010 1661326138

    Not in our library10.1158/1078-0432.ccr-10-2275

  136. 136.

    Hassan R Ho M Mesothelin targeted cancer immunotherapyEur J Cancer2008 444653

    Not in our library10.1016/j.ejca.2007.08.028

  137. 137.

    Kaneko O Gong L Zhang J Hansen JK Hassan R Lee B Ho M A binding domain on mesothelin for CA125/MUC16J Biol Chem2009 28437393749

    Not in our library10.1074/jbc.m806776200

  138. 138.

    Xiang X Feng M Felder M Connor JP Man YG Patankar MS Ho M HN125: A Novel Immunoadhesin Targeting MUC16 with Potential for Cancer TherapyJ Cancer Educ2011 2280291

    Not in our library10.7150/jca.2.280

  139. 139.

    Chen SH Dallas MR Balzer EM Konstantopoulos K Mucin 16 is a functional selectin ligand on pancreatic cancer cellsFASEB J2012 2613491359

    Not in our library10.1096/fj.11-195669

  140. 140.

    Ligtenberg MJ Kruijshaar L Buijs F van Meijer M Litvinov SV Hilkens J Cell-associated episialin is a complex containing two proteins derived from a common precursorJ Biol Chem1992 26761716177

    Not in our library

  141. 141.

    Hilkens J Buijs F Biosynthesis of MAM-6, an epithelial sialomucin. Evidence for involvement of a rare proteolytic cleavage step in the endoplasmic reticulumJ Biol Chem1988 26342154222

    Not in our library

  142. 142.

    Komatsu M Arango ME Carraway KL Synthesis and secretion of Muc4/sialomucin complex: implication of intracellular proteolysisBiochem J2002 3684148

    Not in our library10.1042/bj20020862

  143. 143.

    Albrecht H Carraway KL 3rd MUC1 and MUC4: switching the emphasis from large to smallCancer Biother Radiopharm2011 26261271

    Not in our library10.1089/cbr.2011.1017

  144. 144.

    Senapati S Das S Batra SK Mucin-interacting proteins: from function to therapeuticsTrends Biochem Sci2010 35236245

    Not in our library10.1016/j.tibs.2009.10.003

  145. 145.

    Li Y Ren J Yu W Li Q Kuwahara H Yin L Carraway KL 3rd Kufe D The epidermal growth factor receptor regulates interaction of the human DF3/MUC1 carcinoma antigen with c-Src and beta-cateninJ Biol Chem2001 2763523935242

    Not in our library10.1074/jbc.c100359200

  146. 146.

    Raina D Ahmad R Chen D Kumar S Kharbanda S Kufe D MUC1 oncoprotein suppresses activation of the ARF-MDM2-p53 pathwayCancer Biol Ther2008 719591967

    Not in our library10.4161/cbt.7.12.6956

  147. 147.

    Boivin M Lane D Piche A Rancourt C CA125 (MUC16) tumor antigen selectively modulates the sensitivity of ovarian cancer cells to genotoxic drug-induced apoptosisGynecol Oncol2009 115407413

    Not in our library10.1016/j.ygyno.2009.08.007

  148. 148.

    Theriault C Pinard M Comamala M Migneault M Beaudin J Matte I Boivin M Piche A Rancourt C MUC16 (CA125) regulates epithelial ovarian cancer cell growth, tumorigenesis and metastasisGynecol Oncol2011 121434443

    Not in our library10.1016/j.ygyno.2011.02.020

  149. 149.

    Lakshmanan I Ponnusamy MP Das S Chakraborty S Haridas D Mukhopadhyay P Lele SM Batra SK MUC16 induced rapid G2/M transition via interactions with JAK2 for increased proliferation and anti-apoptosis in breast cancer cellsOncogene2012 31805817

    Not in our library10.1038/onc.2011.297

  150. 150.

    Reinartz S Failer S Schuell T Wagner U CA125 (MUC16) gene silencing suppresses growth properties of ovarian and breast cancer cellsEur J Cancer2011 4815581569

    Not in our library10.1016/j.ejca.2011.07.004

  151. 151.

    Schmalfeldt B Prechtel D Harting K Spathe K Rutke S Konik E Fridman R Berger U Schmitt M Kuhn W Lengyel E Increased expression of matrix metalloproteinases (MMP)-2, MMP-9, and the urokinase-type plasminogen activator is associated with progression from benign to advanced ovarian cancerClin Cancer Res2001 723962404

    Not in our library

  152. 152.

    Kenny HA Kaur S Coussens LM Lengyel E The initial steps of ovarian cancer cell metastasis are mediated by MMP-2 cleavage of vitronectin and fibronectinJ Clin Invest2008 11813671379

    Not in our library10.1172/jci33775

  153. 153.

    Akita K Tanaka M Tanida S Mori Y Toda M Nakada H CA125/MUC16 interacts with Src family kinases, and over-expression of its C-terminal fragment in human epithelial cancer cells reduces cell-cell adhesionEur J Cell Biol2013 92257263

    Not in our library10.1016/j.ejcb.2013.10.005

  154. 154.

    Cancer Genome Atlas Research NIntegrated genomic analyses of ovarian carcinomaNature2011 474609615

    Not in our library10.1038/nature10166

  155. 155.
    MicroRNA-200c modulates the expression of MUC4 and MUC16 by directly targeting their coding sequences in human pancreatic cancer. · 2013
    Not checked
  156. 156.

    Baum RP Hertel A Baew-Christow T Noujaim AA Hor G Schmidt HAE, Stuttgart RHA novel Tc-99m labeled monoclonal antibody against CA125 (B43.13) for radioimmunodetection pf ovarian cancer-initial resultsNuclear Medicine1992 New York: Schattuer670672

    Not in our library

  157. 157.

    Mobus VJ Baum RP Bolle M Kreienberg R Noujaim AA Schultes BC Nicodemus CF Immune responses to murine monoclonal antibody-B43.13 correlate with prolonged survival of women with recurrent ovarian cancerAm J Obstet Gynecol2003 1892836

    Not in our library10.1067/mob.2003.347

  158. 158.

    Noujaim AA Schultes BC Baum RP Madiyalakan R Induction of CA125-specific B and T cell responses in patients injected with MAb-B43.13–evidence for antibody-mediated antigen-processing and presentation of CA125 in vivoCancer Biother Radiopharm2001 16187203

    Not in our library10.1089/10849780152389384

  159. 159.

    Schultes BC Zhang C Xue LY Noujaim AA Madiyalakan R Immunotherapy of human ovarian carcinoma with OvaRex MAb-B43.13 in a human-PBL-SCID/BG mouse modelHybridoma1999 184755

    Not in our library10.1089/hyb.1999.18.47

  160. 160.

    Schultes BC Baum RP Niesen A Noujaim AA Madiyalakan R Anti-idiotype induction therapy: anti-CA125 antibodies (Ab3) mediated tumor killing in patients treated with Ovarex mAb B43.13 (Ab1)Cancer Immunol Immunother1998 46201212

    Not in our library10.1007/s002620050479

  161. 161.

    Ma J Samuel J Kwon GS Noujaim AA Madiyalakan R Induction of anti-idiotypic humoral and cellular immune responses by a murine monoclonal antibody recognizing the ovarian carcinoma antigen CA125 encapsulated in biodegradable microspheresCancer Immunol Immunother1998 471320

    Not in our library10.1007/s002620050499

  162. 162.

    Reinsberg J Krebs D Are human anti-idiotypic anti-OC125 antibodies formed after immunization with the anti-CA125 antibody B43.13?Hybridoma1997 165963

    Not in our library10.1089/hyb.1997.16.59

  163. 163.

    Madiyalakan R Sykes TR Dharampaul S Sykes CJ Baum RP Hor G Noujaim AA Antiidiotype induction therapy: evidence for the induction of immune response through the idiotype network in patients with ovarian cancer after administration of anti-CA125 murine monoclonal antibody B43.13Hybridoma1995 14199203

    Not in our library10.1089/hyb.1995.14.199

  164. 164.

    Baum RP Niesen A Hertel A Nancy A Hess H Donnerstag B Sykes TR Sykes CJ Suresh MR Noujaim AA Hor G Activating anti-idiotypic human anti-mouse antibodies for immunotherapy of ovarian carcinomaCancer1994 7311211125

    Not in our library10.1002/1097-0142(19940201)73:3+<1121::aid-cncr2820731353>3.0.co;2-q

  165. 165.

    Baum RP Noujaim AA Nanci A Moebus V Hertel A Niesen A Donnerstag B Sykes T Boniface G Hor G Clinical course of ovarian cancer patients under repeated stimulation of HAMA using MAb OC125 and B43.13Hybridoma1993 12583589

    Not in our library10.1089/hyb.1993.12.583

  166. 166.

    Berek JS Immunotherapy of ovarian cancer with antibodies: a focus on oregovomabExpert Opin Biol Ther2004 411591165

    Not in our library10.1517/14712598.4.7.1159

  167. 167.

    Berek JS Taylor PT Gordon A Cunningham MJ Finkler N Orr J Jr Rivkin S Schultes BC Whiteside TL Nicodemus CF Randomized, placebo-controlled study of oregovomab for consolidation of clinical remission in patients with advanced ovarian cancerJ Clin Oncol2004 2235073516

    Not in our library10.1200/jco.2004.09.016

  168. 168.

    Reinartz S Kohler S Schlebusch H Krista K Giffels P Renke K Huober J Mobus V Kreienberg R DuBois A Sabbatini P Wagner U Vaccination of patients with advanced ovarian carcinoma with the anti-idiotype ACA125: immunological response and survival (phase Ib/II)Clin Cancer Res2004 1015801587

    Not in our library10.1158/1078-0432.ccr-03-0056

  169. 169.

    Reinartz S Hombach A Kohler S Schlebusch H Wallwiener D Abken H Wagner U Interleukin-6 fused to an anti-idiotype antibody in a vaccine increases the specific humoral immune response against CA125+ (MUC-16) ovarian cancerCancer Res2003 6332343240

    Not in our library

  170. 170.

    Reinartz S Wagner U Giffels P Gruenn U Schlebusch H Wallwiener D Immunological properties of a single-chain fragment of the anti- idiotypic antibody ACA125Cancer Immunol Immunother2000 49186192

    Not in our library10.1007/s002620000126

  171. 171.

    Reinartz S Boerner H Koehler S Von Ruecker A Schlebusch H Wagner U Evaluation of immunological responses in patients with ovarian cancer treated with the anti-idiotype vaccine ACA125 by determination of intracellular cytokines–a preliminary reportHybridoma1999 184145

    Not in our library10.1089/hyb.1999.18.41

  172. 172.

    Wagner U Schlebusch H Kohler S Schmolling J Grunn U Krebs D Immunological responses to the tumor-associated antigen CA125 in patients with advanced ovarian cancer induced by the murine monoclonal anti-idiotype vaccine ACA125Hybridoma1997 163340

    Not in our library10.1089/hyb.1997.16.33

  173. 173.

    Sabbatini P Dupont J Aghajanian C Derosa F Poynor E Anderson S Hensley M Livingston P Iasonos A Spriggs D McGuire W Reinartz S Schneider S Grande C Lele S Rodabaugh K Kepner J Ferrone S Odunsi K Phase I study of abagovomab in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancerClin Cancer Res2006 1255035510

    Not in our library10.1158/1078-0432.ccr-05-2670

  174. 174.

    Sabbatini P Harter P Scambia G Sehouli J Meier W Wimberger P Baumann KH Kurzeder C Schmalfeldt B Cibula D Bidzinski M Casado A Martoni A Colombo N Holloway RW Selvaggi L Li A del Campo J Cwiertka K Pinter T Vermorken JB Pujade-Lauraine E Scartoni S Bertolotti M Simonelli C Capriati A Maggi CA Berek JS Pfisterer J Abagovomab as maintenance therapy in patients with epithelial ovarian cancer: a phase III trial of the AGO OVAR, COGI, GINECO, and GEICO–the MIMOSA studyJ Clin Oncol2013 3115541561

    Not in our library10.1200/jco.2012.46.4057

  175. 175.

    Pfisterer J Harter P Simonelli C Peters M Berek J Sabbatini P du Bois A Abagovomab for ovarian cancerExpert Opin Biol Ther2011 11395403

    Not in our library10.1517/14712598.2011.553598

  176. 176.

    Grisham RN Berek J Pfisterer J Sabbatini P Abagovomab: an anti-idiotypic CA-125 targeted immunotherapeutic agent for ovarian cancerImmunotherapy2011 3153162

    Not in our library10.2217/imt.10.100

  177. 177.

    Belisle JA Gubbels JA Raphael CA Migneault M Rancourt C Connor JP Patankar MS Peritoneal natural killer cells from epithelial ovarian cancer patients show an altered phenotype and bind to the tumour marker MUC16 (CA125)Immunology2007 122418429

    Not in our library10.1111/j.1365-2567.2007.02660.x

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