Understanding the Unique Attributes of MUC16 (CA125): Potential Implications in Targeted Therapy

Cancer Research - Tập 75 Số 22 - Trang 4669-4674 - 2015
Srustidhar Das1, Surinder K. Batra1,2,3
11Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
22Department of Pathology, University of Nebraska Medical Center, Omaha, Nebraska.
33Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.

Tóm tắt

Abstract CA125, the most widely used ovarian cancer biomarker, was first identified approximately 35 years ago in an antibody screen against ovarian cancer antigen. Two decades later, it was cloned and characterized to be a transmembrane mucin, MUC16. Since then, several studies have investigated its expression, functional, and mechanistic involvement in multiple cancer types. Antibody-based therapeutic approaches primarily using antibodies against the tandem repeat domains of MUC16 (e.g., oregovomab and abagovomab) have been the modus operandi for MUC16-targeted therapy, but have met with very limited success. In addition, efforts have been also made to disrupt the functional cooperation of MUC16 and its interacting partners; for example, use of a novel immunoadhesin HN125 to interfere MUC16 binding to mesothelin. Since the identification of CA125 to be MUC16, it is hypothesized to undergo proteolytic cleavage, a process that is considered to be critical in determining the kinetics of MUC16 shedding as well as generation of a cell-associated carboxyl-terminal fragment with potential oncogenic functions. In addition to our experimental demonstration of MUC16 cleavage, recent studies have demonstrated the functional importance of carboxyl terminal fragments of MUC16 in multiple tumor types. Here, we provide how our understanding of the basic biologic processes involving MUC16 influences our approach toward MUC16-targeted therapy. Cancer Res; 75(22); 4669–74. ©2015 AACR.

Từ khóa


Tài liệu tham khảo

O'Brien, 2001, The CA 125 gene: an extracellular superstructure dominated by repeat sequences, Tumour Biol, 22, 348, 10.1159/000050638

O'Brien, 2002, The CA 125 gene: a newly discovered extension of the glycosylated N-terminal domain doubles the size of this extracellular superstructure, Tumour Biol, 23, 154, 10.1159/000064032

Yin, 2002, Ovarian cancer antigen CA125 is encoded by the MUC16 mucin gene, Int J Cancer, 98, 737, 10.1002/ijc.10250

Govindarajan, 2010, Membrane-tethered mucins have multiple functions on the ocular surface, Exp Eye Res, 90, 655, 10.1016/j.exer.2010.02.014

Marcos-Silva, 2014, Characterization of binding epitopes of CA125 monoclonal antibodies, J Proteome Res, 13, 3349, 10.1021/pr500215g

Macao, 2006, Autoproteolysis coupled to protein folding in the SEA domain of the membrane-bound MUC1 mucin, Nat Struct Mol Biol, 13, 71, 10.1038/nsmb1035

Fendrick, 1997, CA125 phosphorylation is associated with its secretion from the WISH human amnion cell line, Tumour Biol, 18, 278, 10.1159/000218041

Konishi, 1994, Epidermal growth factor enhances secretion of the ovarian tumor-associated cancer antigen CA125 from the human amnion WISH cell line, J Soc Gynecol Investig, 1, 89, 10.1177/107155769400100118

Goodell, 2009, Characterization of the tumor marker muc16 (ca125) expressed by murine ovarian tumor cell lines and identification of a panel of cross-reactive monoclonal antibodies, J Ovarian Res, 2, 8, 10.1186/1757-2215-2-8

Bast, 1981, Reactivity of a monoclonal antibody with human ovarian carcinoma, J Clin Invest, 68, 1331, 10.1172/JCI110380

Das, 2015, Membrane proximal ectodomain cleavage of MUC16 occurs in the acidifying golgi/post-golgi compartments, Sci Rep, 5, 9759, 10.1038/srep09759

Seelenmeyer, 2003, The cancer antigen CA125 represents a novel counter receptor for galectin-1, J Cell Sci, 116, 1305, 10.1242/jcs.00312

Xiong, 2011, Notch signaling modulates MUC16 biosynthesis in an in vitro model of human corneal and conjunctival epithelial cell differentiation, Invest Ophthalmol Vis Sci, 52, 5641, 10.1167/iovs.11-7196

Seo, 2007, Regulation of membrane-associated mucins in the human corneal epithelial cells by dexamethasone, Cornea, 26, 709, 10.1097/ICO.0b013e31804f5a09

Das, 2015, Carboxyl-terminal domain of MUC16 imparts tumorigenic and metastatic functions through nuclear translocation of JAK2 to pancreatic cancer cells, Oncotarget, 6, 5772, 10.18632/oncotarget.3308

Haridas, 2011, Pathobiological implications of MUC16 expression in pancreatic cancer, PLoS ONE, 6, e26839, 10.1371/journal.pone.0026839

Haridas, 2014, MUC16: Molecular analysis and its functional implications in benign and malignant conditions, FASEB J, 28, 4183, 10.1096/fj.14-257352

Boivin, 2009, CA125 (MUC16) tumor antigen selectively modulates the sensitivity of ovarian cancer cells to genotoxic drug-induced apoptosis, Gynecol Oncol, 115, 407, 10.1016/j.ygyno.2009.08.007

Matte, 2014, MUC16 mucin (CA125) attenuates TRAIL-induced apoptosis by decreasing TRAIL receptor R2 expression and increasing c-FLIP expression, BMC Cancer, 14, 234, 10.1186/1471-2407-14-234

Akita, 2013, CA125/MUC16 interacts with src family kinases, and over-expression of its C-terminal fragment in human epithelial cancer cells reduces cell-cell adhesion, Eur J Cell Biol, 92, 257, 10.1016/j.ejcb.2013.10.005

Giannakouros, 2015, Transformation of NIH3T3 mouse fibroblast cells by MUC16 mucin (CA125) is driven by its cytoplasmic tail, Int J Oncol, 46, 91, 10.3892/ijo.2014.2707

Cheon, 2009, CA125/MUC16 is dispensable for mouse development and reproduction, PLoS ONE, 4, e4675, 10.1371/journal.pone.0004675

Mai, 2011, Challenges related to developing serum-based biomarkers for early ovarian cancer detection, Cancer Prev Res, 4, 303, 10.1158/1940-6207.CAPR-11-0053

Kim, 2013, Somatic mutaome profile in human cancer tissues, Genomics Inform, 11, 239, 10.5808/GI.2013.11.4.239

Streppel, 2012, Mucin 16 (cancer antigen 125) expression in human tissues and cell lines and correlation with clinical outcome in adenocarcinomas of the pancreas, esophagus, stomach, and colon, Hum Pathol, 43, 1755, 10.1016/j.humpath.2012.01.005

Shimizu, 2012, Coexpression of MUC16 and mesothelin is related to the invasion process in pancreatic ductal adenocarcinoma, Cancer Sci, 103, 739, 10.1111/j.1349-7006.2012.02214.x

Theriault, 2011, MUC16 (CA125) regulates epithelial ovarian cancer cell growth, tumorigenesis and metastasis, Gynecol Oncol, 121, 434, 10.1016/j.ygyno.2011.02.020

Berek, 2004, Randomized, placebo-controlled study of oregovomab for consolidation of clinical remission in patients with advanced ovarian cancer, J Clin Oncol, 22, 3507, 10.1200/JCO.2004.09.016

Sabbatini, 2013, Abagovomab as maintenance therapy in patients with epithelial ovarian cancer: a phase III trial of the AGO OVAR, COGI, GINECO, and GEICO–the MIMOSA study, J Clin Oncol, 31, 1554, 10.1200/JCO.2012.46.4057

Felder, 2014, MUC16 (CA125): Tumor biomarker to cancer therapy, a work in progress, Mol Cancer, 13, 129, 10.1186/1476-4598-13-129

Dharma Rao, 2010, Novel monoclonal antibodies against the proximal (carboxy-terminal) portions of MUC16, Appl Immunohistochem Mol Morphol, 18, 462, 10.1097/PAI.0b013e3181dbfcd2

Chekmasova, 2010, Successful eradication of established peritoneal ovarian tumors in SCID-beige mice following adoptive transfer of T cells genetically targeted to the MUC16 antigen, Clin Cancer Res, 16, 3594, 10.1158/1078-0432.CCR-10-0192

Carew, 2006, Targeting endoplasmic reticulum protein transport: a novel strategy to kill malignant B cells and overcome fludarabine resistance in CLL, Blood, 107, 222, 10.1182/blood-2005-05-1923

Argueso, 2009, Association of cell surface mucins with galectin-3 contributes to the ocular surface epithelial barrier, J Biol Chem, 284, 23037, 10.1074/jbc.M109.033332

Belisle, 2010, Identification of siglec-9 as the receptor for MUC16 on human NK cells, B cells, and monocytes, Mol Cancer, 9, 118, 10.1186/1476-4598-9-118

Gubbels, 2006, Mesothelin-MUC16 binding is a high affinity, N-glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors, Mol Cancer, 5, 50, 10.1186/1476-4598-5-50

Chen, 2012, Mucin 16 is a functional selectin ligand on pancreatic cancer cells, FASEB J, 26, 1349, 10.1096/fj.11-195669

Blalock, 2007, Functions of MUC16 in corneal epithelial cells, Invest Ophthalmol Vis Sci, 48, 4509, 10.1167/iovs.07-0430

Lakshmanan, 2012, MUC16 induced rapid G2/M transition via interactions with JAK2 for increased proliferation and anti-apoptosis in breast cancer cells, Oncogene, 31, 805, 10.1038/onc.2011.297

Garg, 2014, Novel treatment option for MUC16-positive malignancies with the targeted TRAIL-based fusion protein meso-TR3, BMC Cancer, 14, 35, 10.1186/1471-2407-14-35

Xiang, 2011, HN125: A novel immunoadhesin targeting MUC16 with potential for cancer therapy, J Cancer, 2, 280, 10.7150/jca.2.280

Thông tin
Thông tin xuất bản

Cancer Research

Tập 75 Số 22

4669-4674

Thông tin tác giả