A5031319377- Proteoglycans and glycosaminoglycans research
- Fibroblast Growth Factor Research
- Glycosylation and Glycoproteins Research
- Cancer, Hypoxia, and Metabolism
- Connective tissue disorders research
- Pancreatic and Hepatic Oncology Research
- Cancer Cells and Metastasis
- Neuropeptides and Animal Physiology
- Diet, Metabolism, and Disease
- Tribology and Lubrication Engineering
- NF-κB Signaling Pathways
- Pancreatitis Pathology and Treatment
- Cancer Research and Treatments
- Skin Protection and Aging
- Blood properties and coagulation
- Platelet Disorders and Treatments
- Mesenchymal stem cell research
Cancer Research UK
2017
University of Cambridge
2017
Halozyme Therapeutics (United States)
2012-2016
University of Eastern Finland
2006-2014
Pancreatic stellate cells (PSCs) differentiate into cancer-associated fibroblasts (CAFs) that produce desmoplastic stroma, thereby modulating disease progression and therapeutic response in pancreatic ductal adenocarcinoma (PDA). However, it is unknown whether CAFs uniformly carry out these tasks or if subtypes of with distinct phenotypes PDA exist. We identified a CAF subpopulation elevated expression α-smooth muscle actin (αSMA) located immediately adjacent to neoplastic mouse human...
<h3>Objective</h3> Pancreatic ductal adenocarcinoma (PDA) is characterised by stromal desmoplasia and vascular dysfunction, which critically impair drug delivery. This study examines the role of an abundant extracellular matrix component, megadalton glycosaminoglycan hyaluronan (HA), as a novel therapeutic target in PDA. <h3>Methods</h3> Using genetically engineered mouse model PDA, authors enzymatically depleted HA clinically formulated PEGylated human recombinant PH20 hyaluronidase...
Extensive accumulation of the glycosaminoglycan hyaluronan is found in pancreatic cancer. The role synthases 2 and 3 (HAS2, 3) was investigated cancer growth tumor microenvironment. Overexpression HAS3 increased synthesis BxPC-3 cells. In vivo, overexpression led to faster growing xenograft tumors with abundant extracellular accumulation. Treatment pegylated human recombinant hyaluronidase (PEGPH20) removed dramatically decreased rate compared parental tumors. PEGPH20 had a weaker effect on...
Hyaluronan synthases (HASs) are plasma membrane enzymes that simultaneously elongate, bind, and extrude the growing hyaluronan chain directly into extracellular space. In cells transfected with green fluorescent protein (GFP)-tagged Has3, dorsal surface was decorated by up to 150 slender, 3-20-microm-long microvillus-type protrusions, which also contained filamentous actin, receptor CD44, lipid raft microdomains. Enzymatic activity of HAS required for growth microvilli, were not present in...
Many cell types wear up to 20-μm-wide hyaluronidase-sensitive surface coats, detected by exclusion of sedimenting particles like fixed erythrocytes. The structure the coat is enigmatic, being apparently too thick be accounted random coils or even extended chains just hyaluronan attached surface. We have shown that synthesis enforced green fluorescent protein-hyaluronan synthase transfection creates microvillous protrusions. idea plasma membrane protrusions rather than alone responsible for...
The tumor stroma, consisting of non-malignant cells and the extracellular matrix, undergoes significant quantitative qualitative changes throughout malignant transformation progression. With increasing recognition role microenvironment in disease progression, stromal components have become attractive targets for therapeutic intervention. Stromal accumulation glycosaminoglycan hyaluronan occurs many types is frequently associated with a negative prognosis. Hyaluronan interacts other molecules...
Hyaluronidase (Hyal) and low m.w. hyaluronan (LMW HA) fragments have been widely reported to stimulate the innate immune response. However, most hyaluronidases used were purified from animal tissues (e.g., bovine testis Hyal [BTH]), contain endotoxin other unrelated proteins. We tested a highly recombinant human (rHuPH20) endotoxin-free HA M(r) 5,000 1,500,000 in rodent air pouch model of inflammation determine their potential for stimulation Exogenous LMW (average 200,000) failed induce...
The turnover of hyaluronan (HA), especially the production low-molecular-weight fragments HA, was examined in a model unilateral renal ischaemia–reperfusion (IR) rats. HA extracted from outer and inner stripe medulla (OSOM ISOM) at different times following IR. Its fragmentation measured using membrane filtration size-exclusion chromatography. Quantitative reverse transcription–polymerase chain reaction, zymography immunohistochemistry were used to assess expression localization various...
Hyaluronan synthases (HAS1-3) are integral plasma membrane proteins that synthesize hyaluronan, a cell surface and extracellular matrix polysaccharide necessary for many biological processes. It has been shown HAS is partly localized in cholesterol-rich lipid rafts of MCF-7 cells, cholesterol depletion with methyl-beta-cyclodextrin (MbetaCD) suppresses hyaluronan secretion smooth muscle cells. However, the mechanism by which inhibits production remained unknown. We found from cells MbetaCD...
Total plasma hyaluronan concentration is increased in septic shock. High-molecular-weight has a high intrinsic viscosity. Excessive release of high-molecular-weight sepsis may induce hyperviscosity.Plasma viscosity and the molecular size were determined 20 patients with shock healthy controls. Ex vivo, effects 0.4% 0.047% 1560 kDa, 0.9% saline, 6% hydroxy-ethyl-starch 130 kDa compared to whole blood red cell aggregation at systemic hematocrit 0.4, microcirculatory 0.2.Plasma total protein...
Abstract Pancreatic cancer is one of most deadly cancers with a 5-year survival rate 6%. Accumulation hyaluronan (HA) found in about 87% human pancreatic adenocarcinomas, and removal HA suppresses tumor growth HA-rich preclinical models. In transgenic mouse model (LSL-KrasG12D/+;LSLTrp53R172H/+;Pdx-1-Cre, KPC), by pegylated recombinant PH20 hyaluronidase (PEGPH20) inhibits increases combination gemcitabine compared to monotherapy. this study, we explored the role synthesizing (HAS) enzymes...
Abstract Hyaluronan (also known as hyaluronic acid or HA) is a megadalton sized glycosaminoglycan present in the extracellular matrix. The abnormal accumulation of HA solid tumor microenvironment (TME) several human cancers, including pancreatic, breast, colon and prostate, has been well studied associated with poor prognosis. In certain breast cancer specimens HA-high status, found to be significantly stromal compartment rather than cells. To understand interaction between cells containing...
Abstract The tumor microenvironment is crucial for cancer cell survival and spreading. glycosaminoglycan hyaluronan (HA) accumulated in 50% of malignant breast tumors its accumulation correlates with poor patients. HA synthesized at the surface by synthase enzymes (HAS1-3) extruded to extracellular space where molecules can be attached via interactions receptors or HAS proteins. also interact binding proteins incorporated into surrounding ECM. However, origin exact functions are still...