Exosomes are small membranous vesicles secreted into body fluids by multiple cell types, including tumor cells, and in various disease conditions. Tumor exosomes contain intact and functional mRNAs, ...small RNAs (including miRNAs), and proteins that can alter the cellular environment to favor tumor growth. Molecular profiling may increase our understanding of the role of exosomes in melanoma progression and may lead to discovery of useful biomarkers.
In the present study, we used mRNA array profiling to identify thousands of exosomal mRNAs associated with melanoma progression and metastasis. Similarly, miRNA array profiling identified specific miRNAs, such as hsa-miR-31, -185, and -34b, involved in melanoma invasion. We also used proteomic analysis and discovered differentially expressed melanoma exosomal proteins, including HAPLN1, GRP78, syntenin-1, annexin A1, and annexin A2. Importantly, normal melanocytes acquired invasion ability through molecules transported in melanoma cell-derived exosomes.
Our results indicate that melanoma-derived exosomes have unique gene expression signatures, miRNA and proteomics profiles compared to exosomes from normal melanocytes. To the best of our knowledge, this is the first in-depth screening of the whole transcriptome/miRNome/proteome expression in melanoma exosomes. These results provide a starting point for future more in-depth studies of tumor-derived melanoma exosomes, which will aid our understanding of melanoma biogenesis and new drug-targets that may be translated into clinical applications, or as non-invasive biomarkers for melanoma.
One of the defining characteristics of a pre-metastatic niche, a fundamental requirement for primary tumor metastasis, is infiltration of immunosuppressive macrophages. How these macrophages acquire ...their phenotype remains largely unexplored. Here, we demonstrate that tumor-derived exosomes (TDEs) polarize macrophages toward an immunosuppressive phenotype characterized by increased PD-L1 expression through NF-kB-dependent, glycolytic-dominant metabolic reprogramming. TDE signaling through TLR2 and NF-κB leads to increased glucose uptake. TDEs also stimulate elevated NOS2, which inhibits mitochondrial oxidative phosphorylation resulting in increased conversion of pyruvate to lactate. Lactate feeds back on NF-κB, further increasing PD-L1. Analysis of metastasis-negative lymph nodes of non-small-cell lung cancer patients revealed that macrophage PD-L1 positively correlates with levels of GLUT-1 and vesicle release gene YKT6 from primary tumors. Collectively, our study provides a novel mechanism by which macrophages within a pre-metastatic niche acquire their immunosuppressive phenotype and identifies an important link among exosomes, metabolism, and metastasis.
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•TDEs stimulate de novo synthesis of PD-L1 in macrophages•TDEs activate NF-κB, which augments glycolysis, leading to increased lactate production•Lactate drives PD-L1 expression through the NF-κB pathway•Macrophage PD-L1 in the dLNs correlates with YKT6 expression levels in primary NSCLC
Morrissey et al. report that tumor-derived exosomes stimulate pre-metastatic niche macrophages toward an immunosuppressive phenotype through NF-kB-dependent, glycolytic-dominant metabolic reprogramming, thus promoting tumor metastasis. These pro-metastatic macrophages are characterized by increased de novo synthesis of PD-L1 and increased lactate production.
Random Truths and Universal Nonsense McMasters, Kelly M.
Journal of the American College of Surgeons,
April 2020, 2020-04-00, 20200401, Letnik:
230, Številka:
4
Journal Article
Highlights • Melanoma cell–derived exosomes promote phenotype switching in primary melanocytes. • MAPK pathway and let-7i were involved in exosome-mediated EMT. • EMT-related miRNAs (miR-191and ...let-7a) in exosomes may be used for melanoma diagnosis. • Targeting exosome-mediated EMT may be an approach to prevent tumor progression.
Ablative therapies have been increasingly utilized in the treatment of locally advanced pancreatic cancer (LAPC). Irreversible electroporation (IRE) is an energy delivery system, effective in ...ablating tumors by inducing irreversible membrane destruction of cells. We aimed to demonstrate efficacy of treatment with IRE as part of multimodal treatment of LAPC.
From July 2010 to October 2014, patients with radiographic stage III LAPC were treated with IRE and monitored under a multicenter, prospective institutional review board-approved registry. Perioperative 90-day outcomes, local failure, and overall survival were recorded.
A total of 200 patients with LAPC underwent IRE alone (n = 150) or pancreatic resection plus IRE for margin enhancement (n = 50). All patients underwent induction chemotherapy, and 52% received chemoradiation therapy as well for a median of 6 months (range, 5-13 months) before IRE. IRE was successfully performed in all patients. Thirty-seven percent of patients sustained complications, with a median grade of 2 (range, 1-5). Median length of stay was 6 days (range, 4-36 days). With a median follow-up of 29 months, 6 patients (3%) have experienced local recurrence. Median overall survival was 24.9 months (range: 4.9-85 months).
For patients with LAPC (stage III), the addition of IRE to conventional chemotherapy and radiation therapy results in substantially prolonged survival compared with historical controls. These results suggest that ablative control of the primary tumor may prolong survival.
Background
This study was designed to evaluate the safety, efficiency, effectiveness, and overall long-term outcome in patients treated with microwave thermal ablation of hepatic tumors. Microwave ...ablation technology represents the next generation in ablative techniques for the treatment of hepatic malignancies. Currently there have been no large reports of its use in the United States with appropriate long-term follow-up.
Methods
An institutional review board-approved prospective phase II study of microwave ablation of hepatic malignancies from January 2004 to January 2009 was performed. All complications were recorded up to 90 days from operation and reported using an established five-point grading scale.
Results
One hundred patients underwent 270 ablations for hepatic malignancies. The most tumor types were as follows: metastatic colorectal cancer (50%), hepatocellular carcinoma (17%), metastatic carcinoid (11%), and other metastatic disease (22%). A majority of patents (53%) underwent combination hepatic resection and microwave ablation; 38% underwent ablation alone, 9% underwent ablation and additional organ resection, with 68% open procedures. Median tumor size was 3.0 (range, 0.6–6.0) cm, median number of tumors was 2 (range, 1–18), and median total ablation time was 13 (range, 5–45) min. Overall 90-day mortality was 0% and morbidity was 29%. One patient developed a hepatic abscess and no patients experienced bleeding complications. After a median follow-up of 36 months, 5 patients (5%) had incomplete ablation, 2 (2%) had local recurrence at the ablated site, and 37 (37%) developed intrahepatic recurrence at nonablated sites.
Conclusions
Microwave ablation of hepatic tumors is a safe and effective method for treating unresectable hepatic tumors, with a low rate of local recurrence.
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