Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET

El pdf del artículo es el manuscrito de autor.-- et al.Tumor-derived exosomes are emerging mediators of tumorigenesis. We explored the function of melanoma-derived exosomes in the formation of primary tumors and metastases in mice and human subjects. Exosomes from highly metastatic melanomas increased the metastatic behavior of primary tumors by permanently 'educating' bone marrow progenitors through the receptor tyrosine kinase MET. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites and reprogrammed bone marrow progenitors toward a pro-vasculogenic phenotype that was positive for c-Kit, the receptor tyrosine kinase Tie2 and Met. Reducing Met expression in exosomes diminished the pro-metastatic behavior of bone marrow cells. Notably, MET expression was elevated in circulating CD45(-)C-KIT(low/+)TIE2(+) bone marrow progenitors from individuals with metastatic melanoma. RAB1A, RAB5B, RAB7 and RAB27A, regulators of membrane trafficking and exosome formation, were highly expressed in melanoma cells. Rab27A RNA interference decreased exosome production, preventing bone marrow education and reducing, tumor growth and metastasis. In addition, we identified an exosome-specific melanoma signature with prognostic and therapeutic potential comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein. Our data show that exosome production, transfer and education of bone marrow cells supports tumor growth and metastasis, has prognostic value and offers promise for new therapeutic directions in the metastatic process.Peer Reviewe

Association between pain, radiographic severity, and centrally‐mediated symptoms in women with knee osteoarthritis

Objective To examine the relationship between pain, radiographic severity, and a common set of co‐occurring centrally‐mediated symptoms (fatigue, sleep quality, and depression) in women with knee osteoarthritis. Methods Participants underwent knee radiographs, and had repeated assessments of pain severity and other centrally‐mediated symptoms during a 5‐day home monitoring period. To examine associations between pain severity (the average of pain over the home monitoring period), measures of osteoarthritis radiographic severity (Kellgren/Lawrence grade, minimum joint space width), centrally‐mediated symptoms, and demographics (age) were used. Symptoms of fatigue, sleep efficiency, and depression were used in a composite measure representing centrally‐mediated symptoms. Results Using a series of linear regression models in which each variable was entered hierarchically (n = 54), the final model showed that 27% of the variance in pain severity was explained by age, radiographic severity, and centrally‐mediated symptoms. Centrally‐mediated symptoms explained an additional 10% of the variance in pain severity after the other 2 variables were entered. Conclusion Both radiographic severity and centrally‐mediated symptoms were independently and significantly associated with pain severity in women with knee osteoarthritis. In addition to more severe radiographic features, women with higher centrally‐mediated symptoms had greater pain severity. Treatments for women with symptomatic knee osteoarthritis may be optimized by addressing both peripheral and central sources of pain.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/88108/1/20583_ftp.pd

Subgroups of older adults with osteoarthritis based upon differing comorbid symptom presentations and potential underlying pain mechanisms

Abstract Introduction Although people with knee and hip osteoarthritis (OA) seek treatment because of pain, many of these individuals have commonly co-occurring symptoms (for example, fatigue, sleep problems, mood disorders). The purpose of this study was to characterize adults with OA by identifying subgroups with the above comorbid symptoms along with illness burden (a composite measure of somatic symptoms) to begin to examine whether subsets may have differing underlying pain mechanisms. Methods Community-living older adults with symptomatic knee and hip OA (n = 129) participated (68% with knee OA, 38% with hip OA). Hierarchical agglomerative cluster analysis was used. To determine the relative contribution of each variable in a cluster, multivariate analysis of variance was used. Results We found three clusters. Cluster 1 (n = 45) had high levels of pain, fatigue, sleep problems, and mood disturbances. Cluster 2 (n = 38) had intermediate degrees of depression and fatigue, but low pain and good sleep. Cluster 3 (n = 42) had the lowest levels of pain, fatigue, and depression, but worse sleep quality than Cluster 2. Conclusions In adults with symptomatic OA, three distinct subgroups were identified. Although replication is needed, many individuals with OA had symptoms other than joint pain and some (such as those in Cluster 1) may have relatively stronger central nervous system (CNS) contributions to their symptoms. For such individuals, therapies may need to include centrally-acting components in addition to traditional peripheral approaches.http://deepblue.lib.umich.edu/bitstream/2027.42/112389/1/13075_2011_Article_3201.pd

Sentinel Case of Candida auris in the Western United States Following Prolonged Occult Colonization in a Returned Traveler from India.

Candida auris is an emerging multidrug-resistant yeast with high mortality. We report the sentinel C. auris case on the United States West Coast in a patient who relocated from India. We identified close phylogenetic relatedness to the South Asia clade and ERG11 Y132F and FKS1 S639Y mutations potentially explaining antifungal resistance

The capture of extracellular vesicles endogenously released by xenotransplanted tumours induces an inflammatory reaction in the premetastatic niche

The capture of tumour-derived extracellular vesicles (TEVs) by cells in the tumour microenvironment (TME) contributes to metastasis and notably to the formation of the pre-metastatic niche (PMN). However, due to the challenges associated with modelling release of small EVs in vivo, the kinetics of PMN formation in response to endogenously released TEVs have not been examined. Here, we have studied the endogenous release of TEVs in mice orthotopically implanted with metastatic human melanoma (MEL) and neuroblastoma (NB) cells releasing GFP-tagged EVs (GFTEVs) and their capture by host cells to demonstrate the active contribution of TEVs to metastasis. Human GFTEVs captured by mouse macrophages in vitro resulted in transfer of GFP vesicles and the human exosomal miR-1246. Mice orthotopically implanted with MEL or NB cells showed the presence of TEVs in the blood between 5 and 28 days after implantation. Moreover, kinetic analysis of TEV capture by resident cells relative to the arrival and outgrowth of TEV-producing tumour cells in metastatic organs demonstrated that the capture of TEVs by lung and liver cells precedes the homing of metastatic tumour cells, consistent with the critical roles of TEVs in PMN formation. Importantly, TEV capture at future sites of metastasis was associated with the transfer of miR-1246 to lung macrophages, liver macrophages, and stellate cells. This is the first demonstration that the capture of endogenously released TEVs is organotropic as demonstrated by the presence of TEV-capturing cells only in metastatic organs and their absence in non-metastatic organs. The capture of TEVs in the PMN induced dynamic changes in inflammatory gene expression which evolved to a pro-tumorigenic reaction as the niche progressed to the metastatic state. Thus, our work describes a novel approach to TEV tracking in vivo that provides additional insights into their role in the earliest stages of metastatic progression.The authors would like to thank Mrs. J. Rosenberg for her help in the formatting of the manuscript, and the personnel of the Core Facilities of the Saban Research Institute at Children's Hospital Los Angeles (Flow Cytometry, Extracellular Vesicle, Cell Imaging, and Animal Imaging Cores) for their expertise and assistance. This work was supported by National Institutes of Health/National Cancer Institute grant R01 CA207983 to Y.A. DeClerck

The Grizzly, February 4, 1983

Trouble at Cutillo\u27s: Frats Earn Reputation as Animals • Drinking Concerns Richter • Economics Council Sponsors Entrepreneur-Related Forum • President\u27s Corner • Wismer Tries Again • Pfacelift at Pfahler • Bear Blades Burnished Beat Wilmington Twice • Serendipity Celebration Features Films • Writing Center Welcomes Students • Who\u27s Who in Who\u27s Who? • Commentary: Speak Up for Coed Housing • Didja Ever Wonder • Wrestlers Earn Split • Lewis on Wall Street • Disruptive Fans Cause Flare-up at Widener • Top Individual Efforts Mark Gymnastics Team • Interview: Chupein Named to All-League Team • Lady Hoops Still Struggling • Men\u27s Basketball Find Road a Bit Bumpy • Swimmers Maul Terrors of Western Marylandhttps://digitalcommons.ursinus.edu/grizzlynews/1092/thumbnail.jp

A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma

Tumors are capable of coopting hematopoietic cells to create a suitable microenvironment to support malignant growth. Here, we have demonstrated that upregulation of kinase insert domain receptor (KDR), also known as VEGFR2, in a myeloid cell sublineage is necessary for malignant progression of gliomas in transgenic murine models and is associated with high-grade tumors in patients. KDR expression increased in myeloid cells as myeloid-derived suppressor cells (MDSCs) accumulated, which was associated with the transformation and progression of low-grade fibrillary astrocytoma to high-grade anaplastic gliomas. KDR deficiency in murine BM-derived cells (BMDCs) suppressed the differentiation of myeloid lineages and reduced granulocytic/monocytic populations. The depletion of myeloid-derived KDR compromised its proangiogenic function, which inhibited the angiogenic switch necessary for malignant progression of low-grade to high-grade tumors. We also identified inhibitor of DNA binding protein 2 (ID2) as a key upstream regulator of KDR activation during myeloid differentiation. Deficiency of ID2 in BMDCs led to downregulation of KDR, suppression of proangiogenic myeloid cells, and prevention of low-grade to high-grade transition. Tumor-secreted TGF-β and granulocyte-macrophage CSF (GM-CSF) enhanced the KDR/ID2 signaling axis in BMDCs. Our results suggest that modulation of KDR/ID2 signaling may restrict tumor-associated myeloid cells and could potentially be a therapeutic strategy for preventing transformation of premalignant gliomas.This study was supported by the Department of Defense Con- gressionally Directed Medical Research Programs (DOD CDMRP, CA120318 to Y. Huang), Elizabeth’s Hope (J. Greenfield), the Starr Foundation, the Paduano Foundation, the Champalimaud Foun- dation, the Malcolm Hewitt Wiener Foundation, the POETIC Foundation, the Sohn Foundation, the Hartwell Foundation, and the Children’s Cancer and Blood Foundation (all to D. Lyden). Address correspondence to: David Lyden, Department of Pediatrics, Weill Medical Medicine, 413 E. 69th Street, Box 284, New York, New York 10021, USA. Phone: 646.962.6238; E-mail: [email protected]. Or to: Jeffrey P. Greenfield, Department of Neurological Surgery, Weill Cornell Medicine, 525 E 68th Street, Box 99, New York, New York 10065, USA. Phone: 212.746.2363; E-mail: [email protected]. HP’s present address is: Microenvironment and Metastasis Group, Department of Molecular Oncology, Spanish National Cancer Research Center (CNIO), Madrid, Spain.S