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Exosomes in Cancer Disease, Progression, and Drug Resistance
Published in Vladimir Torchilin, Handbook of Materials for Nanomedicine, 2020
Taraka Sai Pavan Grandhi, Rajeshwar Nitiyanandan, Kaushal Rege
Melo et al. [98] identified exosomes expressing a cell surface proteoglycan Glypican-1 which was enriched on pancreatic cancer cells. It has been previously shown that Glypican-1 is over expressed in both breast and pancreatic cancers [99, 100]. The authors observed that circulating exosomes (crExos) concentrations were significantly higher in cancer patients in comparison to healthy controls. Surprisingly, the authors also observed that the size of the pancreatic cancer patient-derived crExos was significantly smaller than those isolated from healthy patients, but this was not the case with breast cancer-derived crExos. Glypican-1 expression in healthy patient–derived crExos was found to be at a baseline level whereas nearly 75% of the pancreatic cancer-derived crExos expressed Gylpican-1 at higher levels than healthy patients. The authors also showed that crExos expressing Glypican-1 performed consistently better than the current gold standard biomarker for pancreatic cancer, Carbohydrate antigen 19-9 (CA19-9) [101, 102].
Centralized Endothelial Mechanobiology, Endothelial Dysfunction, and Atherosclerosis
Published in Jiro Nagatomi, Eno Essien Ebong, Mechanobiology Handbook, 2018
Ian Chandler Harding, Eno Essien Ebong
It remains to be defined whether mechanosensors at different parts of the cell, for example, apical (i.e., glycocalyx) versus junctional (i.e., PECAM) versus basal (i.e., integrins and focal adhesions, which have not been discussed here), work together to maintain vascular homeostasis or whether activation of one complex must precede the activation of others. It is likely that the answer lies somewhere between the two. On the one hand, multiple mechanosensors have been shown to independently elicit the same shear stress responses in ECs (Table 7.1). For example, surface glycocalyx is responsible for shear stress-induced nitric oxide production in an eNOS-dependent manner [158,159], while eNOS activation also depends on PECAM-1, a cell-to-cell junction protein [85]. There is also evidence to support the idea that mechanosensors depend on each other to control shear-regulated cell function. Glycocalyx has been observed to reorganize cytoskeletal proteins upstream of cell-to-cell junction formation [41,42,160], which may be important for the localization and function of PECAM-1. For example, the G protein subunit Gαq/11 complexes with PECAM-1 at cell-to-cell junctions in response to uniform but not disturbed flow [161], and this flow-regulated association is abolished upon degradation of the heparan sulfate component of the glycocalyx [162]. Recently, it was shown that heparan sulfate-bound glypican plays an important role in converting flow-derived mechanical signals into phosphorylation of PECAM and downstream PECAM-mediated events [163]. Future studies are required in order to clarify the mechanisms of mechanotransducer activation and to uncover how they work either independently or together to promote endothelial homeostasis.
Lysosomal Storage Disorders and Enzyme Replacement Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
One distinguishes between HSPGs of the ECM, which are perlecan, agrin, and collagen XVIII (see Marneros and Olsen, 2005, for their physiological role), and HSPGs present on the cell surface as are syndecans and glypicans (unlike the syndecans, glypicans are not transmembrane heparan sulfate proteoglycans, but attached to the cell surface through a glycosylphosphoinositol (GPI) anchor). Distinct glypicans are overexpressed in different types of cancers (Matzuda et al., 2001); the importance to understand cancer-specific signaling for the identification of potential therapeutic targets has been highlighted by Knelson et al. (2014). This also holds in a similar way for syndecans, e.g., syndecan-1; its overexpression stimulates the development of Inflammatory breast cancer (Ibrahim et al., 2017) and prostate cancer (Fujii et al., 2016); however, proteolytically cleaved syndecan-1, leading to a soluble form of this protein through the action of matrix metalloproteinases, was found to decrease proliferation of these cells. This process, termed shedding, is supported by heparanases. It is assumed that cleavage of HS chains improves the activity of proteases due to sterical effects (see Lambaerts et al., 2009, and literature cited therein). Hull et al. (2017) summarized important roles which HSPGs play in a wide-spectrum of cancer-related cellular and physiological functions together with the multiple levels of epigenetic regulation of the enzymes in the heparan sulfate synthesis pathway and discussed how alterations observed in cancer cells serve as potential biomarkers. For a review on heparin/protein interactions see, e.g., Capila et al., 2002, and Peysselon and Ricard-Blum (2014); a report provided by Zulueta et al. (2013) focusses on interactions between proteins and synthetic heparin/HA oligosaccharides. Biological activity of syndecans is not restricted to the HS chain; the transmembrane and cytoplasmic domain of syndecans possess structural features that enable phosphorylation-mediated interactions with various signaling molecules, thus supporting signal transduction across the membrane (for examples, see Lambaerts et al., 2009; Kwon et al., 2016; Cheng et al., 2016). The role of syndecans as key molecules during cancer initiation and progression has been reviewed by Afratis et al. (2017).
Polyclonal antibody production against rGPC3 and their application in diagnosis of hepatocellular carcinoma
Published in Preparative Biochemistry and Biotechnology, 2018
Shenghao Wang, Muhammad Kalim, Keying Liang, Jinbiao Zhan
Glypican-3 (GPC3), a member of the glypican family, is composed of a membrane-associated protein core substituted with various heparan sulfate chains. The core protein of GPC3 is encoded by the GPC3 gene located at q26.2 of human X chromosome. It possesses 40 kDa N-terminal and 30 kDa C-terminal proteins. This protein has a conserved sequence of 14 cysteine residues, so it is easy to form disulfide within the molecule.[1] It also has two heparin sulfate chains at C-terminal near cell membrane.[2] GPC3 is overexpressed in 70% of HCC tissues but does not express in benign liver lesions, cirrhosis, hepatitis, or healthy adult tissues. So, GPC3 has been used as immunohistochemical markers for distinguishing HCC with benign liver lesions[3] because GPC3 can be cleaved from GPI anchoring site from the outer surface of the cell membrane and enter the bloodstream.[4] Clinical and laboratory studies revealed that GPC3-positive HCC patients have a lower survival rate than GPC3-negative HCC patients and showed the high potency of GPC3 in the prognosis of primary liver cancer.