Oncogenic KIT-containing exosomes increase gastrointestinal stromal tumor cell invasion

During tumor development, constant interplay occurs between tumor cells and surrounding stromal cells. We report evidence that gastrointestinal stromal tumor (GIST) cells invade the interstitial stroma through the release of the oncogenic protein tyrosine kinase (KIT)-containing exosomes, which triggers the phenotypic conversion of progenitor smooth muscle cells to tumor-promoting cells. These recipient cells display morphologic changes and acquire tumor-associated phenotypes, including enhanced adhesion to extracellular matrix proteins, activation of intracellular pathways downstream of KIT, expression of Interstitial Cell of Cajal–like markers, and release of various matrix metalloproteinases (MMPs), particularly MMP1. This report shows stimulation of MMP1 production by stromal cells via uptake of tumor-derived exosomes, which leads to tumor cell invasion. Exosomes derived from GIST patients but not healthy donors show enhanced MMP1 secretion by smooth muscle cells and tumor cell invasion, whereas selective blocking of exosome-mediated MMP1 secretion decreases tumor invasiveness. Our study indicates that exosome release and subsequent MMP1 induction creates a positive feedback mechanism established between tumor and stromal cells that drives GIST development and offers unique insights for potential therapeutic strategies to block GIST progression and metastatic spread.With the ultimate goal of fulfilling their needs for exogenous supply of growth factors, chemokines, cytokines, and matrix-degrading enzymes, tumor cells communicate with their surrounding stroma using several intercellular communication mechanisms (1, 2). In the last decade, various tumors have been shown to rely on the release of bioactive membrane vesicles known as exosomes (3). Tumor cells of various origins constitutively release these vesicles, which are believed to be important in the processes of malignant transformation and tumor progression. Exosomes share certain common characteristics, including their shape, size, density, and general protein composition (3). Their effects are mediated via transfer of cargo that comprises an array of proteins (4), RNA (5), and mitochondrial DNA (6). Accordingly, their role as mediators in tumor progression has been the focus of several recent studies (7, 8). However, the majority of these studies focused on human malignancies of epithelial origin (i.e., carcinomas), whereas little attention has been given to the tumor microenvironment associated with malignancies of mesenchymal origin (i.e., sarcomas).Sarcomas represent an interesting and unique tumor type in which cancer cells of mesenchymal origin are surrounded by stromal cells of the same origin. The focus of this study is on the most common mesenchymal tumor of the digestive tract, gastrointestinal stromal tumor (GIST) (9). Approximately 75% of GISTs contain oncogenic mutations in the receptor tyrosine kinase c-KIT [normal cellular homolog of the viral oncoprotein v-Kit (v-Kit, Hardy Zuckerman 4 feline sarcoma viral oncogene homolog)] (10, 11), which plays a central role in the pathogenesis of this disease (10, 12). GISTs are believed to arise from the Interstitial Cells of Cajal (ICCs) (13), the pacemaker cells of the gastrointestinal tract, or interstitial mesenchymal precursor stem cells (14). This similarity between GISTs and ICCs is further borne out by the expression of the KIT protein (also called CD117) in nonneoplastic ICC and most GISTs (11). The identification of a fundamental hallmark of the biology of GISTs (i.e., gain-of-function KIT mutations) resulted in the rapid transformation of the treatment paradigm for this tumor type (15, 16). Small molecule tyrosine kinase inhibitors, most notably imatinib mesylate (also known as Gleevec), have been developed and were found to be effective in the treatment of GISTs (16–18). However, the median time to recurrence for patients with metastatic GIST receiving imatinib is only 2 y. Although much is known about the molecular genetic features of GIST, the importance of their interactions with the stromal microenvironment during metastasis has received little attention. Therefore, we investigated the role of exosomes in mediating the complex interplay between tumor and stroma during progression. We report evidence that (i) GIST cells secrete a high number of oncogenic KIT-containing exosomes, (ii) stromal cell uptake of GIST-derived exosomes promotes the generation of ICC-like cells and induce tumor invasiveness, and (iii) circulating exosomes from GIST patients induce matrix metalloproteinase 1 (MMP1) secretion by host stromal cells.     

End-expiratory lung volume decreases during REM sleep despite continuous positive airway pressure

Sleep and Breathing - Patients with obstructive sleep apnea (OSA) may experience apneas and hypopneas primarily during stage R (REM) sleep when end-expiratory lung volume (EELV) reaches its nadir....     

Association of pulse pressure,pulse pressure index,and ambulatory arterial stiffness index with kidney function in a cross‐sectional pediatric chronic kidney disease cohort from the CKiD study

The morbidity and mortality of adult and pediatric chronic kidney disease (CKD) and end‐stage renal disease (ESRD) populations are mainly driven by cardiovascular disease (CVD). Improving CVD outcomes focuses on risk assessment of factors including diastolic blood pressure (DBP), systolic blood pressure (SBP), left ventricular mass index (LVMI), pulse pressure (PP), and pulse pressure index (PPi), which is calculated as PP/SBP. These markers are also proven predictors of CKD progression; however, their role in children has not been established. This study aims to evaluate the relationship between PP, PPi, ambulatory arterial stiffness index (AASI), and proteinuria with kidney function in pediatric CKD patients; it is a retrospective analysis of 620 patients (1‐16 years) from the NIDDK Chronic Kidney Disease in Children (CKiD) registry. The authors analyzed data for three separate cohorts: an overall CKD as well as immunological versus non‐immunological cause for CKD groups. An inverse relationship was found between SBP, DBP, and PP with iGFR and LVMI in the overall CKD group. Our immunological CKD subgroup showed significantly higher serum creatinine, SBP, DBP, and PP values with significantly lower serum albumin levels compared to the non‐immunological group. There were no significant differences with iohexol‐based glomerular filtration rate (iGFR), LVMI, PPi, or high‐sensitivity C‐reactive protein (hs‐CRP) between the two groups. A subgroup analysis demonstrated that SBP, DBP, and PP all correlated significantly with LVMI in the immunological CKD patients but not the non‐immunological subgroup. Additionally, AASI data in the overall CKD population were significantly correlated with PP, PPi, and DBP. This study is one of the first to correlate noninvasive measurements of vascular compliance including PP, PPi, and AASI with iGFR and LVMI in a pediatric CKD cohort. Improving our understanding of surrogate markers for early CVD is integral to improving the care of pediatric CKD population as these patients have yet to develop the hard end points of ESRD, heart failure, myocardial infarction, or stroke.     

Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery

One of the promises of nanoparticle (NP) carriers is the reformulation of promising therapeutics that have failed clinical development due to pharmacologic challenges. However, current nanomedicine research has been focused on the delivery of established and novel therapeutics. Here we demonstrate proof of the principle of using NPs to revive the clinical potential of abandoned compounds using wortmannin (Wtmn) as a model drug. Wtmn is a potent inhibitor of phosphatidylinositol 3' kinase-related kinases but failed clinical translation due to drug-delivery challenges. We engineered a NP formulation of Wtmn and demonstrated that NP Wtmn has higher solubility and lower toxicity compared with Wtmn. To establish the clinical translation potential of NP Wtmn, we evaluated the therapeutic as a radiosensitizer in vitro and in vivo. NP Wtmn was found to be a potent radiosensitizer and was significantly more effective than the commonly used radiosensitizer cisplatin in vitro in three cancer cell lines. The mechanism of action of NP Wtmn radiosensitization was found to be through the inhibition of DNA-dependent protein kinase phosphorylation. Finally, NP Wtmn was shown to be an effective radiosensitizer in vivo using two murine xenograft models of cancer. Our results demonstrate that NP drug-delivery systems can promote the readoption of abandoned drugs such as Wtmn by overcoming drug-delivery challenges.     

Endothelial progenitor cell capture stent: safety and effectiveness

The endothelial progenitor cell (EPC) capture stent is an innovative device that makes use of the ability of bone marrow-derived EPCs to migrate to injured arterial segments to facilitate healing. The EPC antibody surface, consisting of a covalently coupled polysaccharide intermediate coating with anti-human CD34 antibodies, is attached to a stainless steel stent. Upon stent placement, the anti-human CD34 antibodies will attract circulating EPCs, which are expected to develop into mature functional endothelium. This accelerated healing strategy aims to lower the risk of restenosis and stent thrombosis, as well as obviate prolonged dual antiplatelet therapy. Since the first-in-man study in 2003, a number of small-to-medium size registry and postmarketing studies that confirmed the good safety profile of the EPC capture stent have been published. However, due to lack of large-scale randomized trials, its effectiveness, compared with bare metal stents and drug-eluting stents, cannot be ascertained. Based on restudy angiographic data, instent late loss was approximately 0.7-0.9 mm, which compares unfavorably with that of drug-eluting stents. In order to improve the effectiveness of the EPC capture stent in reducing restenosis-while maintaining its pro-healing property-a bioengineered sirolimus-eluting stent known as the Combo stent was recently designed to combine the EPC capture technology with the abluminal elution of sirolimus. Data from animal studies have been encouraging. The first-in-man study of the Combo stent has been completed and results were presented. (J Interven Cardiol 2012;25:493-500).