Deconstruction of a Metastatic Tumor Microenvironment Reveals a Common Matrix Response in Human Cancers.

We have profiled, for the first time, an evolving human metastatic microenvironment by measuring gene expression, matrisome proteomics, cytokine and chemokine levels, cellularity, extracellular matrix organization, and biomechanical properties, all on the same sample. Using biopsies of high-grade serous ovarian cancer metastases that ranged from minimal to extensive disease, we show how nonmalignant cell densities and cytokine networks evolve with disease progression. Multivariate integration of the different components allowed us to define, for the first time, gene and protein profiles that predict extent of disease and tissue stiffness, while also revealing the complexity and dynamic nature of matrisome remodeling during development of metastases. Although we studied a single metastatic site from one human malignancy, a pattern of expression of 22 matrisome genes distinguished patients with a shorter overall survival in ovarian and 12 other primary solid cancers, suggesting that there may be a common matrix response to human cancer.Significance: Conducting multilevel analysis with data integration on biopsies with a range of disease involvement identifies important features of the evolving tumor microenvironment. The data suggest that despite the large spectrum of genomic alterations, some human malignancies may have a common and potentially targetable matrix response that influences the course of disease. Cancer Discov; 8(3); 304-19. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 253

A Strong B-cell Response Is Part of the Immune Landscape in Human High-Grade Serous Ovarian Metastases

This work was funded by Cancer Research UK (A16354), Swiss Cancer League (BIL KLS2883-02-2012); the European Research Council (ERC322566); Barts and The London Charity (467/1307 to ML and BLT 297/2249 to 2 PRC); Bloodwise (Bennett Fellowship to MC; ref 12002); UNC University Cancer Research Fund and UNC Oncology Clinical Translational Research Training Program (5K12CA120780; to BV); National Cancer Institute (P50 CA058223; to JSS)

Th17 Cells Are Involved in the Local Control of Tumor Progression in Primary Intraocular Lymphoma

BACKGROUND: Th17 cells play an important role in the pathogenesis of many autoimmune diseases, but despite some reports of their antitumor properties, too little is known about their presence and role in cancers. Specifically, knowledge is sparse about the relation of Th17 to lymphoma microenvironments and, more particularly, to the microenvironment of primary intraocular B-cell lymphoma (PIOL), an aggressive lymphoma with a poor prognosis. METHODS AND PRINCIPAL FINDINGS: In this work, we investigated the presence of Th17 cells and their related cytokines in a syngeneic model of PIOL, a subtype of non-Hodgkin lymphoma. The very small number of lymphocytes trafficking in normal eyes, which represent a low background as compared to tumor-bearing eyes, allows us to develop the present model to characterize the different lymphocyte subsets present when a tumor is developing. IL-21 mRNA was expressed concomitantly with IL-17 mRNA in tumor-bearing eyes and intracellular expression of IL-17A and IL-21 in infiltrating CD4(+) T lymphocytes. Interestingly, IL-17A production by T cells was negatively correlated with tumor burden. We also showed that IL-21 but not IL-17 inhibits tumor cell proliferation in vitro. CONCLUSIONS: These data demonstrate that IL-17A and IL-21-producing CD4(+) T cells, referred as Th17 cells, infiltrate this tumor locally and suggest that Th17-related cytokines may counteract tumor progression via IL-21 production. Thus, Th17 cells or their related cytokines could be considered to be a new therapeutic approach for non-Hodgkin B-cell lymphomas, particularly those with an ocular localization

Brain energy rescue:an emerging therapeutic concept for neurodegenerative disorders of ageing

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes

Hospital outbreak of multiple clones of Pseudomonas aeruginosa carrying the unrelated metallo-β-lactamase gene variants blaVIM-2 and blAVIM-4

Objectives: The possible contribution of metallo-β-lactamases in the frequent detection of carbapenem-resistant Pseudomonas aeruginosa isolates in a tertiary Greek hospital in Central Greece was investigated. Materials and methods: All carbapenem-resistant (imipenem- and/or meropenem-resistant) P. aeruginosa isolates recovered from separate patients during a 1 year period in the Clinical Microbiology Laboratory at the University Hospital of Thessaly, Larissa, Greece, were studied for metallo-β-lactamases. They were tested by Etest MBL, PCR analysis and nucleotide sequencing. DNA fingerprints were obtained by pulsed-field gel electrophoresis (PFGE) of Xbaldigested chromosomal DNA. Results: A blaVIM gene was detected in 47 of the 53 (88.7%) carbapenem-resistant P. aeruginosa isolates. PFGE grouped the blaVIM-positive isolates in six unrelated genotypes; one type included two subtypes. Nucleotide sequencing of the PCR amplicons of a randomly selected isolate from each one of the seven subtypes, detected the variant sequences blaVIM-2 in four and blaVIM-4 in three cases, respectively. They were carried as single gene cassettes or along with an aminoglycoside resistance gene (aacA29a) in class 1 integrons. Conclusions: These findings suggest that different strains of P. aeruginosa carrying unrelated metallo-β-lactamase gene variants predominate in our hospital environment

Macrophage scavenger receptor a promotes tumor progression in murine models of ovarian and pancreatic cancer.

Alternatively activated macrophages express the pattern recognition receptor scavenger receptor A (SR-A). We demonstrated previously that coculture of macrophages with tumor cells upregulates macrophage SR-A expression. We show in this study that macrophage SR-A deficiency inhibits tumor cell migration in a coculture assay. We further demonstrate that coculture of tumor-associated macrophages and tumor cells induces secretion of factors that are recognized by SR-A on tumor-associated macrophages. We tentatively identified several potential ligands for the SR-A receptor in tumor cell-macrophage cocultures by mass spectrometry. Competing with the coculture-induced ligand in our invasion assay recapitulates SR-A deficiency and leads to similar inhibition of tumor cell invasion. In line with our in vitro findings, tumor progression and metastasis are inhibited in SR-A(-/-) mice in two in vivo models of ovarian and pancreatic cancer. Finally, treatment of tumor-bearing mice with 4F, a small peptide SR-A ligand able to compete with physiological SR-A ligands in vitro, recapitulates the inhibition of tumor progression and metastasis observed in SR-A(-/-) mice. Our observations suggest that SR-A may be a potential drug target in the prevention of metastatic cancer progression

A highly carbapenem-resistant Pseudomonas aeruginosa isolate with a novel bla(VIM-4)/bla(P1b) integron overexpresses two efflux pumps and lacks OprD

Objectives: A Pseudomonas aeruginosa clinical isolate that exhibited high-level carbapenem resistance and produced metallo-beta-lactamase (MBL) was recovered from a Greek patient. This study was conducted to determine the underlying mechanisms that conferred the carbapenem resistance phenotype. Methods: MICs were determined by Etest and Etest MBL. PCR assays were performed for identification of bla(VIM-type), other antibiotic resistance and efflux pump genes and mapping of class 1 integrons. Expression of efflux pump genes was quantified by real-time PCR. Nucleotide sequencing was used to determine the bla(VIM) allele. The location of the MBL allele was investigated by mating experiments, plasmid analysis and hybridization studies. Results: The isolate was highly carbapenem-resistant (MICs of imipenem and meropenern were 512 and 128 mg/L, respectively) and multidrug-resistant. It harboured the P-lactamase genes bla(VIM-4) and bla(P1b) in a novel class 1 integron named InV4P1, and a second integron with aac(6')-lb and bla(OXA-35) gene cassettes. The isolate was deficient in porin OprD and overexpressed eff lux pumps MexAB-OprM and MexXY-OprM. Conjugation experiments failed to detect transferable MBL determinants, plasmids were not visualized and bla(VIM) was detected by PCR in the chromosomal band. Conclusions: Multiple carbapenem resistance mechanisms are demonstrated to coexist in a single A aeruginosa isolate and might confer the high-level carbapenem resistance