Field-Free Isolation of Exosomes from Extracellular Vesicles by Microfluidic Viscoelastic Flows

ACS Nano

DOI: 10.1021/acsnano.7b02277

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Cancer-Associated Fibroblasts Share Characteristics and Pro-tumorigenic Activity with Mesenchymal Stromal Cells

Cancer-associated fibroblasts (CAF) have been suggested to originate from mesenchymal stromal cells (MSC), but their relationship to MSC is not clear. Here we have isolated from primary human neuroblastoma (NB) tumors a population of αFAP- and FSP-1-expressing CAF that share phenotypic and functional characteristics with bone marrow-derived MSC (BM-MSC). Analysis of human NB tumors also confirmed the presence of αFAP- and FSP-1-positive cells in the tumor stroma, and their presence correlated with that of M2 tumor-associated macrophages. These cells (designated CAF-MSC) enhanced in vitro NB cell proliferation, survival, and resistance to chemotherapy and stimulated NB tumor engraftment and growth in immunodeficient mice, indicating an effect independent of the immune system. The pro-tumorigenic activity of MSC in vitro and in xenografted mice was dependent on the co-activation of JAK2/STAT3 and MEK/ERK1/2 in NB cells. In a mouse model of orthotopically implanted NB cells, inhibition of JAK2/STAT3 and MEK/ERK/1/2 by ruxolitinib and trametinib potentiated tumor response to etoposide and increased overall survival. These data point to a new type pro-tumorigenic CAF in the tumor microenvironment (TME) of NB and to STAT3 and ERK1/2 as mediators of their activity.

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Kindlin-2 regulates the growth of breast cancer tumors by activating CSF-1-mediated macrophage infiltration

Interplay between tumor cells and host cells in the tumor microenvironment dictates the development of all cancers. In breast cancer, malignant cells educate host macrophages to adopt a pro-tumorigenic phenotype. In this study, we show how the integrin regulatory protein kindlin-2 (FERMT2) promotes metastatic progression of breast cancer through the recruitment and subversion of host macrophages. Kindlin-2 expression was elevated in BC biopsy tissues where its levels correlated with reduced patient survival. Based on these observations, we used CRISPR/Cas9 technology to ablate Kindlin-2 expression in human MDA-MB-231 and murine 4T1 breast cancer cells. Kindlin-2 deficiency inhibited invasive and migratory properties in vitro without affecting proliferation rates. However, in vivo tumor outgrowth was inhibited by >80% in a manner associated with reduced macrophage infiltration and secretion of the macrophage attractant and growth factor CSF-1. The observed loss of CSF-1 appeared to be caused by a more proximal deficiency in TGF-β-dependent signaling in Kindlin-2 deficient cells. Collectively, our results illuminate a Kindlin-2/TGF-β/CSF-1 signaling axis employed by breast cancer cells to capture host macrophage functions that drive tumor progression.

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Resistance to the antibody-drug conjugate T-DM1 is based in a reduction in lysosomal proteolytic activity

Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) that was approved recently to treat HER2+ breast cancers. Despite its impressive clinical efficacy in many patients, intrinsic and acquired resistance to T-DM1 has emerged as a challenge. To identify mechanisms of T-DM1 resistance, we isolated several resistant HER2+ clones exhibiting stable drug refractoriness in vitro and in vivo. Genomic comparisons showed substantial differences among three of the isolated clones, indicating several potential mechanisms of resistance to T-DM1. However, we observed no differences in HER2 levels and signaling among the resistant models and parental HER2+ cells. Bioinformatics studies suggested that intracellular trafficking of T-DM1 could underlie resistance to T-DM1, and systematic analysis of the path followed by T-DM1 showed that the early steps in the internalization of the drug were unaltered. However, in some of the resistant clones T-DM1 accumulated in lysosomes. In these clones, lysosomal pH was increased and the proteolytic activity of these organelles was deranged. These results were confirmed in T-DM1-resistant cells from patient-derived HER2+ samples. We postulate that resistance to T-DM1 occurs through multiple mechanisms, one of which is impaired lysosomal proteolytic activity. Since other ADC may use the same internalization-degradation pathway to deliver active payloads, strategies aimed at restoring lysosomal functionality might overcome resistance to ADC-based therapies and improve their effectiveness.

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Huwe1 sustains normal ovarian epithelial cell transformation and tumor growth through the histone H1.3-H19 cascade

Ubiquitination-directed protein degradation is important in many cancers for tumor initiation and maintenance, and E3 ligases containing HECT domains are emerging as new therapeutic targets. In contrast to many other E3 ligases, the role of HUWE1 in ovarian cancer where HUWE1 is dysregulated has been unclear. Here we report that genetic deletion of Huwe1 in the mouse inhibits transformation of ovary surface epithelium cells without significantly affecting cell survival and apoptosis, and that Huwe1 deletion after tumors have been initiated inhibits tumor growth. In Huwe1-deficient cells, expression of histone H1.3 increased, inhibiting the expression of noncoding RNA H19. H19 silencing phenocopied the effects of Huwe1 deficiency, whereas H1.3 silencing partially rescued the expression of H19 and the Huwe1 null phenotype. Inducible silencing of HUWE1 in human ovarian cancer cells produced a similar phenotype. Mechanistically, HUWE1 bound and ubiquitinated H1.3, which was consequently marked for destruction by proteasomes. Our results establish that HUWE1 plays an essential role in promoting ovarian cancer.

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Post-transcriptional regulation of PARG mRNA by HuR facilitates DNA repair and resistance to PARP inhibitors

The majority of pancreatic ductal adenocarcinomas (PDA) rely on the mRNA stability factor HuR (ELAV-L1) to drive cancer growth and progression. Here we show that CRISPR-Cas9-mediated silencing of the HuR locus increases the relative sensitivity of PDA cells to PARP inhibitors (PARPi). PDA cells treated with PARPi stimulated translocation of HuR from the nucleus to the cytoplasm, specifically promoting stabilization of a new target, polyADP-ribose glycohydrolase (PARG) mRNA, by binding a unique sequence embedded in its 3′ untranslated region (UTR). HuR-dependent upregulation of PARG expression facilitated DNA repair via hydrolysis of polyADP-ribose on related repair proteins. Accordingly, strategies to inhibit HuR directly promoted DNA damage accumulation, inefficient PAR removal, and persistent PARP-1 residency on chromatin (PARP-1 trapping). Immunoprecipitation assays demonstrated that the PARP1 protein binds and post-translationally modifies HuR in PARPi-treated PDA cells. In a mouse xenograft model of human PDA, PARPi monotherapy combined with targeted silencing of HuR significantly reduced tumor growth compared to PARPi therapy alone. Our results highlight the HuR-PARG axis as an opportunity to enhance PARPi-based therapies.

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SOX5/6/21 prevent oncogene-driven transformation of brain stem cells

Molecular mechanisms preventing self-renewing brain stem cells from oncogenic transformation are poorly defined. We show that the expression levels of SOX5, SOX6 and SOX21 (SOX5/6/21) transcription factors increase in stem cells of the subventricular zone (SVZ) upon oncogenic stress, whereas their expression in human glioma decreases during malignant progression. Elevated levels of SOX5/6/21 promoted SVZ cells to exit the cell cycle, while genetic ablation of SOX5/6/21 dramatically increased the capacity of these cells to form glioma-like tumors in an oncogene-driven mouse brain tumor model. Loss-of-function experiments revealed that SOX5/6/21 prevent detrimental hyper proliferation of oncogene expressing SVZ cells by facilitating an anti-proliferative expression profile. Consistently, restoring high levels of SOX5/6/21 in human primary glioblastoma cells enabled expression of CDK inhibitors and decreased p53 protein turnover, which blocked their tumorgenic capacity through cellular senescence and apoptosis. Altogether, these results provide evidence that SOX5/6/21 play a central role in driving a tumor suppressor response in brain stem cells upon oncogenic insult.

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Consultant: Hayden Island DEQ permits don't talk safety - KOIN.com

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Consultant: Hayden Island DEQ permits don't talk safety KOIN.com PORTLAND, Ore. (KOIN) — An oil recycling plant in North Portland that neighbors say is making them sick is now being required by the Oregon DEQ to install new emission controls later this month. But an environmental consultant told KOIN 6 News the DEQ ...

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Erratum to: Do epinephrine auto-injectors have an unsuitable needle length in children and adolescents at risk for anaphylaxis from food allergy?

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The effects of the location of cancer stem cell marker CD133 on the prognosis of hepatocellular carcinoma patients

CD133 (prominin-1) is widely believed to be a cancer stem cell marker in various solid tumor types, and CD133 has been correlated with tumor-initiating capacity. Recently, the nuclear location of CD133 express...

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Regulation of early growth response 2 expression by secreted frizzled related protein 1

Secreted frizzled-related protein 1 (SFRP1) expression is down-regulated in a multitude of cancers, including breast cancer. Loss of Sfrp1 also exacerbates weight gain as well as inflammation. Additionally, loss ...

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Salvage Surgery Prolonged Survival for Select Patients after TME for Rectal Cancer

Salvage surgery is associated with prolonged survival in patients with rectal cancer who have lung and liver recurrence after TME. (Source: CancerNetwork)

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Maintenance Therapy in Mantle Cell Lymphoma

This video reviews different strategies for maintenance therapy in mantle cell lymphoma, as well as highlighting upcoming research in this setting. (Source: CancerNetwork)

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Today in Music History - July 19 - National Post

Today in Music History - July 19 National Post In 1981, tenor Roger Doucet died of cancer in Montreal at age 62. His stirring rendition of ... cancer. He was 59. In 2011, R&B star R. Kelly was hospitalized after emergency throat surgery in Chicago, where surgeons drained an abscess on one of his ...

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This woman's photo showing a thyroid cancer symptom that she completely missed is going viral - INSIDER

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This woman's photo showing a thyroid cancer symptom that she completely missed is going viral INSIDER Lorna Nickson Brown was shocked when she was told she had thyroid cancer in 2015 — the otherwise healthy and energetic 26-year-old didn't see the gaunt face and shriveled body of a cancer patient in the mirror. "This isn't what I thought cancer looked ...

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Influence of bisphosphonates on the adherence and metabolism of epithelial cells and gingival fibroblasts to titanium surfaces

Abstract

Objectives

To evaluate the effects of sodium alendronate (SA) and zoledronic acid (ZA), on the adhesion and metabolism of epithelial cells and gingival fibroblasts to titanium surfaces considering cell functions related to an effective mucosal barrier around the implant.

Materials and methods

Cells were seeded onto titanium discs and incubated for 24 h. Then, serum-free DMEM containing selected bisphosphonates (0, 0.5, 1, or 5 μM) was added for 24 and 48 h. Factors related to the achievement of an effective mechanical and immunological barrier—cell adhesion, viability, collagen epidermal growth factor, and immunoglobulin synthesis—were evaluated. Data were analyzed by Kruskal-Wallis and Mann-Whitney tests as well as by ANOVA and Tukey's tests, (α = 0.05).

Results

The presence of bisphosphonates culminated in lower cell adhesion to the titanium discs, particularly for SA at 5 μM (40%) and ZA at all concentrations (from 30 to 50%, according to increased concentrations). Reduced cell viability occurred after exposing these cells to ZA (40%); however, only 5 μM SA-treated cells had decreased viability (30%). Reduced synthesis of growth factors and collagen was observed when cells were reated with ZA (20 and 40%, respectively), while about 70% of IgG synthesis was enhanced.

Conclusion

Bisphosphonates negatively affected the adhesion and metabolism of oral mucosal cells, and this effect was related to the type of bisphosphonate as well as to concentration and period of treatment.

Clinical relevance

The negative effects of bisphosphonates on oral mucosal cells can hamper the formation of an effective biological seal in osseointegrated implants.

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E-cigarette Use and Indicators of Cardiovascular Disease Risk

Abstract

Purpose of Review

The aim is to provide a detailed review of literature from studies examining the relation of electronic cigarette (e-cigarette) use to indicators of risk for cardiovascular disease. In addition to discussing clinical and cell culture studies, we discuss possible mechanisms for the observed effects.

Recent Findings

Studies have compared the effect of e-cigarette use (or vapor) and combustible cigarette smoking on a range of measures. These include heart rate, blood pressure, and vagal tone; aortic stiffness and endothelial function; platelet aggregation and adhesion; expression of genes for antioxidant defense and immune system function; and indices of oxidative stress. The majority of studies found some evidence of a significant risk effect for e-cigarettes, although the evidence was not totally consistent within and between studies. Suggestive evidence also implicates a possible effect of e-cigarettes on inflammation processes. The magnitude of the effect for e-cigarettes was sometimes lower than those found for cigarettes, but several studies showed comparable effects.

Summary

The findings overall provide evidence of some risk to the cardiovascular system from e-cigarettes, but conclusions are qualified because each study was heterogeneous in its design and evidence on cardiac morbidity from prospective human studies is not yet available. The studies have helped to identify possible agents and mechanisms for producing risk, including reactive oxygen species and oxidative stress, fine and ultrafine particles, and nicotine. Longitudinal data from clinical and epidemiological studies are needed to clarify these relationships in healthy populations and investigate the impact of e-cigarette use among persons with pre-existing cardiovascular disease.

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