Proteoglycans are a group of molecules that contain at least one glycosaminoglycan chain, such as a heparan, dermatan, chondroitin, or keratan sulfate, covalently attached to the protein core. These molecules are categorized based on their structure, localization, and function, and can be found in the extracellular matrix, on the cell surface, and in the cytoplasm. Cell-surface heparan sulfate proteoglycans, such as syndecans, are the primary type present in healthy liver tissue. However, deterioration of the liver results in overproduction of other proteoglycan types. The purpose of this article is to provide a current summary of the most relevant data implicating proteoglycans in the development and progression of human and experimental liver cancer. A review of our work and other studies in the literature indicate that deterioration of liver function is accompanied by an increase in the amount of chondroitin sulfate proteoglycans. The alteration of proteoglycan composition interferes with the physiologic function of the liver on several levels. This article details and discusses the roles of syndecan-1, glypicans, agrin, perlecan, collagen XVIII/endostatin, endocan, serglycin, decorin, biglycan, asporin, fibromodulin, lumican, and versican in liver function. Specifically, glypicans, agrin, and versican play significant roles in the development of liver cancer. Conversely, the presence of decorin could potentially provide protective effects.

Numerical centrosome aberrations underlie certain developmental abnormalities and may promote cancer. A cell maintains normal centrosome numbers by coupling centrosome duplication with segregation, which is achieved through sustained association of each centrosome with a mitotic spindle pole. Although the microcephaly- and primordial dwarfism-linked centrosomal protein CEP215 has been implicated in this process, the molecular mechanism responsible remains unclear. Here, using proteomic profiling, we identify the minus end-directed microtubule motor protein HSET as a direct binding partner of CEP215. Targeted deletion of the HSET-binding domain of CEP215 in vertebrate cells causes centrosome detachment and results in HSET depletion at centrosomes, a phenotype also observed in CEP215-deficient patient-derived cells. Moreover, in cancer cells with centrosome amplification, the CEP215–HSET complex promotes the clustering of extra centrosomes into pseudo-bipolar spindles, thereby ensuring viable cell division. Therefore, stabilization of the centrosome–spindle pole interface by the CEP215–HSET complex could promote survival of cancer cells containing supernumerary centrosomes.

Heparan sulfate (HS), duetoits abilitytointeract with a multitude of HS-binding factors, is involved in a variety of physiological and pathological processes. Remarkably diverse fine structure of HS, shaped by non-exhaustive enzymatic modifications, influences the interaction of HS with its partners. Here we characterized the HS profile of normal human and rat liver, as well as alterations of HS related to liver fibrogenesis and carcinogenesis, by using sulfation-specific antibodies. The HS immunopattern was compared with the immunolocalization of selected HS proteoglycans. HS samples from normal liver and hepatocellular carcinoma (HCC) were subjected to disaccharide analysis. Expression changes of nine HS-modifying enzymes in human fibrogenic diseases and HCC were measured by quantitative RT-PCR. Increased abundance and altered immunolocalization of HS was paralleled by elevated mRNA levels of HS-modifying enzymes in the diseased liver. The strong immunoreactivity of the normal liver for 3- O-sulfated epitope further increased with disease, along with upregulation of 3-OST-1. Modest 6- O-undersulfation of HCC HS is probably explained by Sulf overexpression. Our results may prompt further investigation of the role of highly 3- O-sulfated and partially 6- O-desulfated HS in pathological processes such as hepatitis virus entry and aberrant growth factor signaling in fibrogenic liver diseases and HCC.

Despite the growing number of therapies that target cancer-specific pathways, cytotoxic treatments remain important clinical tools. The rationale for targeting cell proliferation by chemotherapeutic agents stems from the assumption that tumours harbour a greater fraction of actively dividing cells than normal tissues. One such group of cytotoxic drugs impair microtubule polymers, which are cytoskeletal components of cells essential for many processes including mitosis. However, in addition to their antimitotic action, these agents cause debilitating and dose-limiting neurotoxicity because of the essential functions of microtubules in neurons. To overcome this limitation, drugs against mitosis-specific targets have been developed over the past decade, albeit with variable clinical success. Here we review the key lessons learnt from antimitotic therapies with a focus on inhibitors of microtubule motor proteins. Furthermore, based on the cancer genome data, we describe a number of motor proteins with tumour type-specific alterations, which warrant further investigation in the quest for cytotoxic targets with increased cancer specificity.

Biliary tract cancers are relatively common malignant gastrointestinal tumors in the elderly. Claudins are integral components of tight junctions that play important roles in maintaining epithelial cell polarity, controlling paracellular diffusion, and regulating cell growth and differentiation. The expression profile of claudins has been extensively characterized, but few reports exist on their expression in the normal and neoplastic biliary tract. Our aim was therefore to study claudins by IHC reactions in normal and neoplastic biliary tract samples. We detected that claudin expressions differ in the normal sample groups: the normal gallbladder strongly expressed claudin-2, −3, −4, and −10, but only weak reactions were seen in normal intrahepatic bile ducts. Although each cancer type expressed several claudins with various intensities, only claudin-4 presented especially strong immunoreactions in extrahepatic bile duct cancers and gallbladder carcinomas, whereas claudin-1 and −10 presented in intrahepatic bile duct cancers. Comparing the normal and carcinoma groups, the most significant decrease was detected in the expression of claudin-10. In conclusion, the expression pattern of claudins is different in the various parts of the normal and neoplastic biliary tract; moreover, an unequivocal decrease was detected in the carcinomas compared with their corresponding normal samples. This manuscript contains online supplemental material at http://www.jhc.org . Please visit this article online to view these materials.