Mucins in cancer: function, prognosis and therapy

Abstract

Epithelia are protected from adverse conditions by a mucous barrier. The secreted and transmembrane mucins that constitute the mucous barrier are largely unrecognized as effectors of carcinogenesis. However, both types of mucins are intimately involved in inflammation and cancer. Moreover, diverse human malignancies overexpress transmembrane mucins to exploit their role in signalling cell growth and survival. Mucins have thus been identified as markers of adverse prognosis and as attractive therapeutic targets. Notably, the findings that certain transmembrane mucins induce transformation and promote tumour progression have provided the experimental basis for demonstrating that inhibitors of their function are effective as anti-tumour agents in preclinical models.The epithelium is a laterally connected layer of cells with apical-basal polarity that separates multicellular animals from the external environment. Most epithelia are single cell layers and as such require robust defence mechanisms to maintain the integrity of the epithelial barrier. Secreted mucins appeared early in metazoan evolution as part of that defence and further emerged as more complex transmembrane structures that participate in the protection, repair and survival of epithelia in vertebrates. The mucins function in limiting the activation of inflammatory responses at the interface with the environment. Deregulation of mucin production has therefore provided an important link between inflammation and cancer. Moreover, carcinoma cells derived from epithelia, including those of the breast, prostate, lung and pancreas, commonly overexpress transmembrane mucins to exploit their role in promoting growth and survival. In this context, certain transmembrane mucins are sufficient to induce transformation and tumours in animal models, and thereby represent highly attractive targets for anticancer treatment. Somewhat paradoxically for what evolved as a protective mechanism for epithelial cells, transmembrane mucins are also aberrantly expressed in malignant haematopoietic cells. The exploitation of mucin function therefore seems to be a strikingly common theme for promoting the survival of diverse human carcinomas and haematological malignancies. Importantly for this Review, recent work has demonstrated that certain mucins are indeed direct drug targets and that inhibitors of mucin function block survival and tumorigenicity of human tumours in experimental models. Competing interests statementThe author declares competing financial interests: see web version for details. DATABASES Mucin family membersThe mucin family includes proteins that contain tandem repeat structures with a high proportion of prolines, threonines and serines (which constitute the PTS domain). Mucins are further defined by extensive glycosylation of the PTS domain through GalNAc O-linkages at the threonine and serine residues. The human mucin (MUC) family consists of membersdesignated MUC1 to MUC21 -that have been sub-classified into secreted and transmembrane forms. The se...

Construction of a set of novel and robust gene expression signatures predicting prostate cancer recurrence

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“…The former may play a role in the alteration of protein glycosylation, which is well known for being an important aspect of tumorigenesis (Munkley et al ., 2016). Abnormalities in MUC1 glycosylation have been well demonstrated in tumorigenesis (Kufe, 2009; de Paula Peres et al ., 2015). Thus, the inclusion of MGAT4B in the 15‐gene panel is in accordance with the panel being derived from a 9‐gene MUC1 genomic signature (Lin et al ., 2017).…”

Label‐free Raman spectroscopic imaging to extract morphological and chemical information from a formalin‐fixed, paraffin‐embedded rat colon tissue section

“…Detection of mucins during Raman analysis therefore provides an additional scope for assessing tissue homoeostasis and early metastatic potential (Bresalier et al . 1996; Kufe 2009; Mekenkamp et al . 2012).…”

Case-control Study of Single Nucleotide Polymorphisms of PSCA and MUC1 Genes with Gastric Cancer in a Chinese

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