Piperigkou Zoi, Mohr Benedikt, Karamanos Nikos, Götte Martin
Department of Gynecology and Obstetrics, Münster University Hospital, Münster, Germany.
Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26500, Patras, Greece.
Cell Tissue Res. 2016 Sep;365(3):643-55. doi: 10.1007/s00441-016-2452-4. Epub 2016 Jul 1.
Cancer cell behavior is not only governed by tumor cell-autonomous properties but also by the surrounding tumor stroma. Cancer-associated fibroblasts, blood vessels, immune cells and the extracellular matrix of the tumor microenvironment have a profound influence on tumor progression. Proteoglycans control various normal and pathological processes, modulating cell proliferation and motility, cell-matrix interactions, immune cell recruitment and angiogenesis. They are major mediators of cancer cell behavior though a dynamic interplay with extracellular matrix components. During cancer progression, their altered expression can promote the activation of several signaling cascades regulating crucial functional properties of cancer cells. Notably, the function of cell surface proteoglycans can be altered by ectodomain shedding, which converts membrane-bound coreceptors into soluble paracrine effector molecules. In this review, we highlight the importance of proteoglycans and their soluble counterparts in cancer progression and the consequences of their interactions with the adjacent stroma. The dynamic interplay among shed proteoglycans and proteolytic enzymes has a significant impact both on tumor cells and their surrounding stroma, with important implications for the diagnosis of this disease and for novel therapeutic approaches. Graphical Abstract Syndecan shedding. The mechanism of shedding involves the proteolytic cleavage of their ectodomain near the plasma membrane by metzincin enzymes, such as metalloproteinases. N-acetylglucosamine-alpha-L-iduronic acid/beta-D-glucuronic acid (HS) chains can be additionally cleaved by heparanase. Syndecan core protein can be further processed by intramembrane enzymatic cleavage. Syndecans are in a dynamic interplay with the extracellular matrix and several receptor-tyrosine-kinases (RTKs) and various growth factors, for which they act as co-receptors, thus mediating numerous signaling pathways.
癌细胞的行为不仅受肿瘤细胞自主特性的支配，还受周围肿瘤基质的影响。癌症相关的成纤维细胞、血管、免疫细胞以及肿瘤微环境的细胞外基质对肿瘤进展有着深远的影响。蛋白聚糖控制着各种正常和病理过程，调节细胞增殖和运动、细胞-基质相互作用、免疫细胞募集和血管生成。它们通过与细胞外基质成分的动态相互作用，成为癌细胞行为的主要调节因子。在癌症进展过程中，它们表达的改变可促进调节癌细胞关键功能特性的多个信号级联的激活。值得注意的是，细胞表面蛋白聚糖的功能可通过胞外域脱落而改变，这将膜结合的共受体转化为可溶性旁分泌效应分子。在本综述中，我们强调了蛋白聚糖及其可溶性对应物在癌症进展中的重要性，以及它们与相邻基质相互作用的后果。脱落的蛋白聚糖与蛋白水解酶之间的动态相互作用对肿瘤细胞及其周围基质都有重大影响，对该疾病的诊断和新的治疗方法具有重要意义。
Syndecan脱落。脱落机制涉及由金属锌蛋白酶（如金属蛋白酶）在质膜附近对其胞外域进行蛋白水解切割。N-乙酰葡糖胺-α-L-艾杜糖醛酸/β-D-葡糖醛酸（HS）链可被乙酰肝素酶进一步切割。Syndecan核心蛋白可通过膜内酶切进一步加工。Syndecans与细胞外基质、几种受体酪氨酸激酶（RTK）和各种生长因子处于动态相互作用中，它们作为这些因子的共受体，从而介导众多信号通路。
