Evel. Also, Tarbell et al. [132] proved that glycocalyx can sense interstitial flow by utilizing a mathematical model, which was consistent together with the experimental research obtained by Shi et al [133]. They embedded smooth muscle cells in 3D collagen and revealed that heparan sulfate proteoglycans act as a mechanosensor in interstitial flow induced cell migration to activate the FAK-ERK pathway and Kainate Receptor Antagonist drug upregulate matrix metalloproteinase (MMP) expression. By using exactly the same cell/collagen suspension model to mimic the 3D interstitial flow microenvironment, Qazi H et al. [134] observed that cancer cell glycocalyx mediates CBP/p300 Inhibitor Storage & Stability mechanotransduction in interstitial flow induced cell motility and metastasis by regulating MMP-1, MMP-2, CD44, and three integrin expression. That is the very first study attempting to clarify the involvement of glycocalyx in cancer invasion from a mechanotransduction point. Later, Qazi et al. [135] extended their study by knockdown HS synthetic enzyme NDST1 from the extremely metastatic renal carcinoma cells (SN12L1) and comparing the invasion capacity of parental and knockdown cells. The results show that flow enhanced invasion was suppressed in HS depletion cells. In addition, they injected parental or knockdown cells into kidney capsules in mice and observed a 95 reduction in metastasis from the NDST1 knockdown cells injected internet site to distant organs, when compared with controls cells. These findings support the essential part with the cancer cell glycocalyx in interstitial flow-induced metastasis. Integrin-FAK signaling directs proliferation of metastatic cancer cells [136]. In another study, Chakraborty et al. [60] showed that Agrin may serve as a mechanotransduction signal, because it can activate the integrin-FAK pathway. In a later study, Chakraborty et al. [137] suggested that Agrin is actually a mechanotransducing signal activating Yes-associated protein (YAP) via the integrin-focal adhesion-Lrp4/MuSK receptor pathway and that it promotes oncogenesis by means of YAP-dependent transcription. These findings have already been discussed elsewhere at the same time, highlighting that Agrin serves as a mechanotransduction signal to activate YAP by suppressing the Hippo pathway and stimulating integrin-focal adhesion (FA), therefore promoting liver cancer improvement [138]. 5. Glycocalyx-targeting Therapeutic Approaches Expertise from the roles of glycocalyx in cancer is beneficial in discovering promising biomarkers for early diagnosis, prediction, and treatment of clinical cancer.Int. J. Mol. Sci. 2018, 19,11 ofIt has been verified by Terkelsen T et al. [139] that N-glycans secreted by breast cancer might be connected with their patterns in serum. They recommended that profiling of N-glycans may possibly serve as novel biomarkers to improve the diagnosis and prognosis of breast cancer. Very recently, by integrating glycoproteomics with a novel reverse phase glycoprotein array, Chen et al. [140] verified 20 new potential biomarkers in extracellular vesicles from breast cancer sufferers. The association involving ABO blood groups and threat of occurrence of ovarian and vulvar cancer has been extensively studied [141]. Detailed serological cancer markers with clinical applications can be located in another review by Pinho et al [12]. Herein, we mainly focus around the strategies of cancer therapy targeting HS, HA, and syndecan, as described within this paper. 5.1. HS Targeting Therapy The primary HS targeting strategies in clinic are according to its important role in angiogenesis, a complex method that involves endothelial cell p.
