Clinical potential of mucins in diagnosis, prognosis, and therapy of ovarian cancer

Abstract

Knowledge of mucins and their multiple roles in various normal and pathological processes has improved greatly in the past two decades. Mucins belong to a family of glycoproteins characterised by densely O-glycosylated repetitive domains and expressed by various surface epithelial cells. Altered expression of mucins is present in various diseases, including cancer. Ovarian cancer is the sixth most common cancer worldwide and the seventh leading cause of cancer-related deaths in women. The most common ovarian cancer is epithelial ovarian carcinoma, which is characterised by few early symptoms, widespread peritoneal dissemination, and ascites at advanced stages that result in poor prognosis. After diagnosis, 5 year survival is only 35-45%. Therefore, improved strategies for early diagnosis and treatment are needed. Because of the surface epithelial origin of epithelial ovarian cancer, mucins are obvious biomolecules for investigation as markers for early diagnosis and as therapeutic targets. We discuss the potential role and clinical usefulness of mucins in early diagnosis, prognosis, and treatment of ovarian cancer.

Figure 1. Mucins in progression of ovarian cancer

During early events of transformation and later stages of cancer progression, there is a change in mucin expression profiles and their post-translational modifications (mucin switching) that might have a role in aberrant growth and invasion (reprogramming of cell signalling) of ovarian cancer cells (A), exfoliation of tumour cells (alteration of cell-cell/cell-extracellular matrix adhesion; B), or tumour-cell spheroid formation by homotypic interaction (C), immune suppression by phenotypic change of natural killer (NK) cells (D), or inhibiting the components of complement system (E), adhesion to mesothelial cells by formation of novel heterotypic adhesion (F), and invasion into parenchyma of secondary tumour site and establishment of the secondary tumour (G).

Figure 2. Mucin-based targeted therapy

Overexpression, multiplicity of epitopes, and cancer-associated post-translational modifications of mucins make them potential candidates for targeted therapeutics. Antibodies conjugated with radioisotopes or cytotoxic drugs (such as iodine-131-labelled OC125 [monoclonal antigen-binding fragment] or humanised CTM01 conjugated with calicheamicin) enable targeted delivery to ovarian cancer cells.

Figure 3. Mucin-based ovarian cancer vaccines in clinical trials

Antigen-based vaccine (A): MUC1 (G5)–KLH peptides are taken up by antigen presenting cells (APC), processed, and presented with MHCII molecules on the cell surface, the presented antigens are recognised by the antigen-specific T cells, leading to humoral immune response, binding of the antibody to the target tandem-repeat region of MUC1 might inhibit ligand-receptor interaction or generate antibody-dependent cellular cytotoxicity leading to cell death. Cell-based vaccine (B): Autologous dendritic cells (DC) are derived from peripheral blood monocytes pulsed in vitro with the tumour antigen (Mannan-MUC1 fusion protein [MFP]), antigens are endocytosed, processed, and presented by mature dendritic cells displaying MHC-TAA complex on the surface, which are infused back into the patients where they activate cytotoxic T lymphocytes (CTLs). Antibody-based vaccines (C): MUC16 antibody B43.13 is believed to bind to the secreted MUC16 and form a complex that is taken up by APC, processed, and presented on the cell surface, where it can activate TAA-specific CTLs, which recognise and kill tumour cells in an antigen-specific manner. Alternatively, murine monoclonal antibody against TAA (Ab1) is injected into mice to generate an anti-idiotypic vaccine, such as abagovomab (Ab2β), Ab2β is injected into patients, taken in by APCs and TAA+MHC are displayed on the cell surface, anti-idiotypic antibodies are directed against the idiotopes of TAA antibodies and thus serve as the surrogates of TAA, in patients antibodies against idiotypic antibodies elicit humoral and cellular response and a subset of antibodies against these (Ab3) recognise the epitopes on TAAs. The Ab3 antibodies and the CTLs target tumour cells in a TAA-specific manner and provide the antitumour immune response.