Source: https://www.nature.com/articles/nrc2761?error=cookies_not_supported&code=8ff5c435-f63d-4d12-98f1-bf3845f84ba9
Timestamp: 2019-04-19 11:04:01+00:00

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Donald Kufe, M.D., is Professor of Medicine at Harvard Medical School, USA. He has worked at the Dana-Farber Cancer Institute, USA, on the molecular biology of human cancer and the development of anticancer agents for nearly 30 years. His research has focused on the function of the mucin 1 (MUC1) oncoprotein in stress signalling and the induction of transformation. Ongoing work includes the development of agents that target MUC1 in human carcinomas and haematopoietic malignancies. He has served as the Deputy Director of the Dana-Farber Cancer Center, as Leader of the Experimental Therapeutics Program and as editor of the textbook Cancer Medicine.
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.
Epithelial cells form a layer in which an apical surface is exposed to the external environment and to other forms of stress in ducts in specialized organs. As such, epithelial cells require robust defence mechanisms to avoid sustaining damage.
Secreted mucins are highly glycosylated proteins that form a physical barrier, which protects epithelial cells from stress-induced damage. Transmembrane mucins also contribute to the physical barrier and transmit growth and survival signals to the interior of the cell.
Deregulation of secreted mucin 2 (MUC2) production has provided an important link between inflammation and cancer. Expression of the transmembrane mucin MUC1 is upregulated in response to chronic inflammation.
Aberrant overexpression of transmembrane mucins is associated with diverse human carcinomas and, somewhat paradoxically, certain haematological malignancies. Human cancers have exploited the function of these mucins in promoting growth and survival.
Overexpression of transmembrane mucins contributes to oncogenesis by promoting receptor tyrosine kinase signalling, loss of epithelial cell polarity, constitutive activation of growth and survival pathways (for example, the Wnt–β-catenin and nuclear factor-κB pathways), and downregulation of stress-induced death pathways.
Gene expression profiling and analysis of protein levels have demonstrated that overexpression of transmembrane mucins is associated with a poor prognosis in several different types of carcinomas. Circulating levels of the transmembrane mucins MUC1 and MUC16 are used to monitor the clinical course of patients with breast and ovarian cancer, respectively.
Overexpression of the transmembrane mucins in human cancers has made them highly attractive targets for the development of vaccines, antibodies and drug inhibitors. Recent work has demonstrated that the MUC1 cytoplasmic domain is a direct drug target and that inhibition of MUC1 function blocks survival and tumorigenicity of human breast and prostate cancers in preclinical models.
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D.W.K. is supported by National Cancer Institute grants CA97098, CA42802 and CA100707.
D.W.K. is a founder of Genus Oncology and a consultant to the company.
Epithelial cells are polarized, with an apical membrane that faces the external environment or a lumen and is opposite the basolateral membrane, which functions in cell–cell interactions and contacts the basement membrane.
The enzymatic process of attaching oligosaccharides, for example O-N-acetylgalactosamine (O-GalNAc), to the hydroxy oxygen of serine and threonine side chains for the generation of O-linked glycans.
A carbohydrate layer on the surface of cells comprised of oligosaccharide side chains of glycoprotein and glycolipid components in the cell membrane.
VWF. An adhesive glycoprotein that functions in attaching platelets to the vessel wall.
A receptor tyrosine kinase that functions as a heterodimerization partner with other Erbb family members. It is overexpressed in 25–30% of human breast cancers and is the target of the monoclonal antibody trastuzumab (Herceptin).
The ERBB3 receptor, which lacks intrinsic kinase activity, is activated by heregulin (also known as neuregulin-1), and ERBB3 in turn forms heterodimers with other Erbb family members, such as ERBB2. Heregulin also functions as a ligand for the ERBB4 receptor.
The human digestive tract is normally colonized by ∼1013 bacteria, known as commensal bacteria, which exist in an ecosystem without the activation of innate and adaptive immune responses, partly owing to the mucin barrier.
A specialized cell with apical granules in the gastrointestinal and respiratory tracts that is dedicated to the production of secreted mucins, such as MUC2.
A Gram-negative microorganism that can colonize the human stomach despite the low pH. H. pylori penetrates the gastric mucosal barrier and attaches to the gastric epithelium, where it induces an inflammatory response.
EBV. A herpes virus that is closely associated with the development of nasopharyngeal carcinoma, Burkitt's lymphoma and Hodgkin's lymphoma. Latent membrane protein 1 is the major EBV oncoprotein that induces MUC1 expression.
A fusion protein that results from the reciprocal translocation between chromosome 9 and chromosome 22 (t(9;22)(q34;q11)) and is responsible for the induction of chronic myelogenous leukaemia.
A non-steroidal anti-oestrogen that targets the oestrogen receptor and increases disease-free and overall survival in breast cancer.

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