Abbreviations: LLC -Lewis lung carcinoma; MVD -microvascular density; CAIX -carbonyl anhydrase IX 2 AbstractAntiangiogenic therapies in cancer exert their effects in the context of age-related comorbidities, which affect the entirety of the vascular system. Among those conditions, the impact of atherosclerosis is especially prevalent, but poorly understood, and not reflected in mouse models routinely used for testing antiangiogenic therapeutics. Our earlier work suggested that these obstacles can be overcome with the use of atherosclerosis-prone ApoE-/-mice harbouring syngeneic transplantable Lewis Lung Carcinoma (LLC). Here we report that, sunitinib, the clinically approved, antiangiogenic inhibitor impedes global tumor growth to a greater extent in aged then in young mice. This activity was coupled with changes in the tumor microenvironment, which in aged mice was characterized by pronounced hypoxia, reduction in microvascular density (MVD) and lower pericyte coverage, relative to young controls. We also detected soluble VEGR2 in plasma of sunitinib treated mice. Interestingly, sunitinib modulated tumor infiltration with bone marrow-derived cells (CD45+), recruitment of M2-like macrophages (CD163+) and activation of inflammatory pathways (phospho-STAT3) in a manner that was agedependent. We suggest that age and atherosclerosis may alter the effects of sunitinib on the tumor microenvironment, and that these considerations may also apply more broadly to other forms of antiangiogenic treatment in cancer.
Alzheimer's Disease (AD) is a progressive neurodegenerative disease that is characterised by the presence of neurofibrillary tangles and senile plaques. The apolipoprotein E (apoE) protein exists as three different isofom (apoE2, apoE3 and apoE4). Studies have implicated the type 4 allele as a susceptibility factor in the pathogenesis of late-onset familial and sporadic AD.in this study we have sought to investigate the intracellular fate of apoE derived ftom several sources. The d h b u t i o n of apoE was studied in fixed cells by conventional fluorescence microscopy, confocal and electron microscopy. To monitor the fate of apoE in living cells, apoE-GFP fusion proteins were observed at 37°C using an inverted microscope.We found that recombinant human apoE in combination with lipid preparations, such as BVLDL fium cholesterol fed rabbits, failed to enter COS-7 cells in vitro. However, uptake and transport of apoE was observed when conditioned media from stable cell lines expressing human apoE, human CSF and conditioned media from cells secreting human apoE-GFP fusion protein was used. Our results demonstrate rapid intracellular redistribution of apoE and suggest that the internalised apoE may localise to other organelles in addition to the endosomal-lysosomal pathway.Alzheimer disease (AD) braiis contain numerous plaques which are predominantly composed of AD, a 40 to 42 amino acid fiagxnent of the Pamyloid precursor protein. Several studies have shown that AP is neurotoxic to cultured cells and have described various mechanisms through which its neurotoxicity is mediated. There is however a lack of consensus as to how AP kills neurones. In this study we used 2-diimensional (2D) gel electrophoresis to analyse the change in total protein expression profiles of primary rat and human cortical cultures after administration of micromolar concmtrations of fibrillar AP. The 2D protein profile of tau was also investigated by immunoblotting in response to AP treatment. It was established that AP reduced cell viability within 4 days of AP treatment and this correlated with a marked reduction in the total number of proteins separated. The 2D protein profiles were examined over a four day time course and candidate proteins were detected which may be selectively involved in AP toxicity.
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