This article focuses on the emerging views and concepts concerning the role of cell surface and extracellular heparan sulfate-like glycosaminoglycans (HSGAGs) in tumor biology. HSGAGs, found ubiquitously both at the cell surface and in the extracellular matrix (ECM), play a critical role in regulating tumor initiation, progression, and metastasis. The diverse biological functions of HSGAGs include the regulation of coagulation, growth factor signaling, cell adhesion, proliferation, and mobility. HSGAGs, depending on their location (anchored at the cell surface or soluble as free GAGs), the signaling molecules they associate with, and their fine structures, can either promote or inhibit the tumorigenic process.
Heparin and low-molecular weight heparins (LMWHs), complex, sulfated polysaccharides isolated from endogenous sources, are potent modulators of hemostasis. Heparin and LMWHs interact with multiple components of the coagulation cascade to inhibit the clotting process. Pharmaceutical preparations of these complex polysaccharides, typically isolated from porcine intestinal mucosa, are heterogeneous in length and composition and, hence, highly polydisperse. Because of the structural heterogeneity of heparin and LMWHs, correlating their activity with a particular structure or structural motif has been a challenging task. Herein, we demonstrate a practical analytical method that enables the measurement of a structural correlate to in vivo anticoagulant function. With this understanding we have developed LMWHs with increased anticoagulant activity and decreased polydispersity. In addition to the pronounced anti-Xa and anti-IIa activity of these LMWHs, we also demonstrate that they possess desirable in vivo pharmacokinetic properties, the ability to cause the release of tissue factor pathway inhibitor (TFPI) from the endothelium, complete bioavailability through s.c. delivery, and the ability to inhibit both venous and arterial thromboses. Importantly, from a clinical safety point of view, unlike LMWHs presently used in the clinic, we show that these LMWHs are rapidly and completely neutralized by protamine. Together, the findings presented herein demonstrate a facile approach for the creation of designer LMWHs with optimal activity profiles.
For a number of growth factors and cytokines, ligand dimerization is believed to be central to the formation of an active signaling complex. In the case of fibroblast growth factor-2 (FGF2) signaling, heparin/heparan sulfate-like glycosaminoglycans (HLGAGs) are involved through interaction with both FGF2 and its receptors (FGFRs) in assembling a tertiary complex and modulating FGF2 activity. Biochemical data have suggested different modes of HLGAG-induced FGF2 dimerization involving specific protein-protein contacts. In addition, several recent x-ray crystallography studies of FGF⅐FGFR and FGF⅐FGFR⅐HLGAG complexes have revealed other modes of molecular assemblage, with no FGF-FGF contacts. All these different biochemical and structural findings have clarified less and in fact raised more questions as to which mode of FGF2 dimerization, if any, is essential for signaling. In this study, we address the issue of FGF2 dimerization in signaling using a combination of biochemical, biophysical, and site-directed mutagenesis approaches. Our findings presented here provide direct evidence of FGF2 dimerization in mediating FGF2 signaling.Fibroblast growth factors (FGFs) 1 are involved in a wide range of physiological processes, including morphogenesis, as well as disease processes such as tumor angiogenesis (1-3). The FGF family consists of at least 20 members, including the well characterized acidic FGF (FGF1) and basic FGF (FGF2), both of which are potent mitogens of many cell types (4, 5). FGF signaling is mediated primarily through high affinity interactions with cell-surface FGF receptors (FGFRs), transmembrane polypeptides composed of immunoglobulin-like and tyrosine kinase domains (6, 7). FGF binding to different isoforms of FGFR is believed to trigger receptor dimerization, followed by transphosphorylation of specific tyrosine residues (8). In turn, phosphorylated tyrosine residues activate other signaling proteins, leading to cell proliferation, migration, and survival.For proper presentation to FGFR, FGF2 and other members of the FGF family interact with heparin/heparan sulfate-like glycosaminoglycans (HLGAGs). Consisting of a disaccharide repeat of glucosamine and uronic acid, HLGAGs are heterogeneous in length (10 -100 disaccharide units) and chemical composition (including differential sulfation, acetylation, and epimerization of each disaccharide unit) (9 -12). Found in the extracellular matrix and on the cell surface as part of proteoglycans, HLGAGs modulate FGF2 activity by low affinity interactions with specific FGF2-and FGFR-binding sites (13-15), facilitating FGF2 binding to FGFR. HLGAGs promote FGF2-induced activation of FGFR through a number of mechanisms, including regulating the diffusion rate of FGF2 (16, 17) and possibly dictating the specificity of FGF2-FGFR binding through interactions with both .Another hypothesis is that FGF2 binding to HLGAGs induces ligand oligomerization, which in turn induces dimerization and transphosphorylation of FGFR. Biochemical studies have demonstrated that HLGAGs...
Although heparin and low-molecular-weight heparins (LMWH) have been widely used clinically as anticoagulants, their broader use has been limited by the lack of noninvasive delivery methods for this class of molecules. In this study, we demonstrate an efficient, rapid, and reproducible delivery system for heparin through the lungs that is not confined to particles of a certain geometric or aerodynamic diameter. Importantly, blood levels after intrapulmonary administration of either heparin or LMWH were comparable to that of s.c. administration but are characterized by a more rapid onset of action (t 1/2 ؍ 40 min vs. 2.5 h, respectively). Furthermore, we show in animal models, that inhaled heparin species efficiently inhibit diseases such as thrombosis and emphysema, and that the repetitive inhalation of formulated LMWH results in no observable toxicity from the delivery of reproducible systemic levels of heparin or LMWH.
Gliomas are the most aggressive primary intracranial malignancies with poor overall survival. ITGA5 is one member of the integrin adhesion molecule family and is implicated in cancer metastasis and oncogenesis. However, few studies have explored the association between tumor immune microenvironment and ITGA5 expression level in gliomas. Firstly, we analyzed 3,047 glioma patient samples collected from the TCGA, the CGGA, and the GEO databases, proving that high ITGA5 expression positively related to aggressive clinicopathological features and poor survival in glioma patients. Then, based on the ITGA5 level, immunological characteristics and genomic alteration were explored through multiple algorithms. We observed that ITGA5 was involved in pivotal oncological pathways, immune-related processes, and distinct typical genomic alterations in gliomas. Notably, ITGA5 was found to engage in remolding glioma immune infiltration and immune microenvironment, manifested by higher immune cell infiltration when ITGA5 is highly expressed. We also demonstrated a strong correlation between ITGA5 and immune checkpoint molecules that may be beneficial from immune checkpoint blockade strategies. In addition, ITGA5 was found to be a robust and sensitive indicator for plenty of chemotherapy drugs through drug sensitivity prediction. Altogether, our comprehensive analyses deciphered the prognostic, immunological, and therapeutic value of ITGA5 in glioma, thus improving individual and precise therapy for combating gliomas.
Glioma is the most common and fatal tumor of the central nervous system in humans. Despite advances in surgery, radiotherapy, and chemotherapeutic agents, glioma still has a poor prognosis. The tumor microenvironment (TME) of glioma is of highly complex heterogeneity, which relies on a network-based communication between glioma cells and other stromal cell types. Exosomes are the most common type of naturally occurring extracellular vesicles, ranging in size from 40 to 160 nm, and can serve as carriers for proteins, RNAs, and other biologically active molecules. Recent evidence has shown that glioma-derived exosomes (GDEs) can be integrally detected in the local tissue and circulatory blood samples, and also can be transferred to recipient cells to mediate transmission of genetic information. Non-coding RNAs (ncRNAs) mainly including microRNA, long non-coding RNA, and circular RNA, account for a large portion of the human transcriptome. A broad range of ncRNAs encapsulated in GDEs is reported to exert regulatory functions in various pathophysiological processes of glioma. Herein, this review summarizes the latest findings on the fundamental roles of GDE ncRNAs that have been implicated in glioma behaviors, immunological regulation, diagnosis potential, and treatment resistance, as well as the current limitations and perspectives. Undoubtedly, a thorough understanding of this area will provide comprehensive insights into GDE-based clinical applications for combating gliomas.
It is commonly recognized, that glioblastoma is a large complex composed of neoplastic and non-neoplastic cells. Tumor-associated macrophages account for the majority of tumor bulk and play pivotal roles in tumor proliferation, migration, invasion, and survival. There are sophisticated interactions between malignant cells and tumor associated-macrophages. Tumor cells release a variety of chemokines, cytokines, and growth factors that subsequently lead to the recruitment of TAMs, which in return released a plethora of factors to construct an immunosuppressive and tumor-supportive microenvironment. In this article, we have reviewed the biological characteristics of glioblastoma-associated macrophages and microglia, highlighting the emerging molecular targets and related signal pathways involved in the interaction between TAMs and glioblastoma cells, as well as the potential TAMs-associated therapeutic targets for glioblastoma.
Background and Purpose Dopamine agonists targeting D2 receptor have been used for decades in treating pituitary adenomas. There has been little clear evidence implicating the canonical G protein signalling as the mechanism by which D2 receptor suppresses the growth of pituitary tumours. We hypothesize that β‐arrestin2‐dependent signalling is the molecular mechanism dictating D2 receptor inhibitory effects on pituitary tumour growth. Experimental Approach The involvement of G protein and β‐arrestin2 in bromocriptine‐mediated growth suppression in rat MMQ and GH3 tumour cells was assessed. The anti‐growth effect of a β‐arrestin2‐biased agonist, UNC9994, was tested in cultured cells, tumour‐bearing nude mice and primary cultured human pituitary adenomas. The effect of G protein signalling on tumour growth was also analysed by using a G protein‐biased agonist, MLS1547, and a Gβγ inhibitor, gallein, in vitro. Key Results β‐arrestin2 signalling but not G protein pathways mediated the suppressive effect of bromocriptine on pituitary tumour growth. UNC9994 inhibited pituitary tumour cell growth in vitro and in vivo. The suppressive function of UNC9994 was obtained by inducing intracellular reactive oxygen species generation through downregulating mitochondrial complex I subunit NDUFA1. The effects of Gαi/o signalling and Gβγ signalling via D2 receptor on pituitary tumour growth were cell‐type‐dependent. Conclusion and Implications Given the very low expression of Gαi/o proteins in pituitary tumours and the complexity of the responses of pituitary tumours to G protein signalling pathways, our study reveals D2 receptor β‐arrestin2‐biased ligand may be a more promising choice to treat pituitary tumours with improved therapeutic selectivity.
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