Platelet-Derived Microparticles From Obese Individuals: Characterization of Number, Size, Proteomics, and Crosstalk With Cancer and Endothelial Cells

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Abstract

Rationale: Obesity is a risk factor for atherothrombosis and various cancers. However, the mechanisms are not yet completely clarified.

Objectives: We aimed to verify whether the microparticles (MPs) released from thrombin-activated platelets differed in obese and non-obese women for number, size, and proteomics cargo and the capacity to modulate in vitro the expression of (i) genes related to the epithelial to mesenchymal transition (EMT) and the endothelial to mesenchymal transition (EndMT), and (ii) cyclooxygenase (COX)-2 involved in the production of angiogenic and inflammatory mediators.

Methods and Results: MPs were obtained from thrombin activated platelets of four obese and their matched non-obese women. MPs were analyzed by cytofluorimeter and protein content by liquid chromatography-mass spectrometry. MPs from obese women were not different in number but showed increased heterogeneity in size. In obese individuals, MPs containing mitochondria (mitoMPs) expressed lower CD41 levels and increased phosphatidylserine associated with enhanced Factor V representing a signature of a prothrombotic state. Proteomics analysis identified 44 proteins downregulated and three upregulated in MPs obtained from obese vs. non-obese women. A reduction in the proteins of the α-granular membrane and those involved in mitophagy and antioxidant defenses-granular membrane was detected in the MPs of obese individuals. MPs released from platelets of obese individuals were more prone to induce the expression of marker genes of EMT and EndMT when incubated with human colorectal cancer cells (HT29) and human cardiac microvascular endothelial cells (HCMEC), respectively. A protein, highly enhanced in obese MPs, was the pro-platelet basic protein with pro-inflammatory and tumorigenic actions. Exclusively MPs from obese women induced COX-2 in HCMEC.

Conclusion: Platelet-derived MPs of obese women showed higher heterogeneity in size and contained different levels of proteins relevant to thrombosis and tumorigenesis. MPs from obese individuals presented enhanced capacity to cause changes in the expression of EMT and EndMT marker genes and to induce COX-2. These effects might contribute to the increased risk for the development of thrombosis and multiple malignancies in obesity.

Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01581801.

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RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics

Myron Best, Nik Sol, Irsan Kooi … (2015)

Summary Tumor-educated blood platelets (TEPs) are implicated as central players in the systemic and local responses to tumor growth, thereby altering their RNA profile. We determined the diagnostic potential of TEPs by mRNA sequencing of 283 platelet samples. We distinguished 228 patients with localized and metastasized tumors from 55 healthy individuals with 96% accuracy. Across six different tumor types, the location of the primary tumor was correctly identified with 71% accuracy. Also, MET or HER2-positive, and mutant KRAS, EGFR, or PIK3CA tumors were accurately distinguished using surrogate TEP mRNA profiles. Our results indicate that blood platelets provide a valuable platform for pan-cancer, multiclass cancer, and companion diagnostics, possibly enabling clinical advances in blood-based “liquid biopsies”.

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Obesity and cancer risk: recent review and evidence.

Karen Basen-Engquist, Maria Chang (2011)

The prevalence of overweight and obesity is increasing worldwide, and the evidence base for a link between obesity and cancer is growing. In the United States, approximately 85,000 new cancer cases per year are related to obesity. Recent research has found that as the body mass index increases by 5 kg/m2, cancer mortality increases by 10%. Additionally, studies of patients who have had bariatric surgery for weight loss report reductions in cancer incidence and mortality, particularly for women. The goal of this review is to provide an update of recent research, with a focus on epidemiologic studies on the link between obesity and cancer. In addition, we will briefly review hypothesized mechanisms underlying the relationship between obesity and cancer. High priorities for future research involve additional work on the underlying mechanisms, and trials to examine the effect of lifestyle behavior change and weight loss interventions on cancer and intermediate biomarkers.

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Aspirin and Cancer.

Paola Patrignani, Carlo Patrono (2016)

The place of aspirin in primary prevention remains controversial, with North American and European organizations issuing contradictory treatment guidelines. More recently, the U.S. Preventive Services Task Force recommended "initiating low-dose aspirin use for the primary prevention of cardiovascular disease (CVD) and colorectal cancer in adults aged 50 to 59 years who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years." This recommendation reflects increasing evidence for a chemopreventive effect of low-dose aspirin against colorectal (and other) cancer. The intent of this paper is to review the evidence supporting a chemopreventive effect of aspirin, discuss its potential mechanism(s) of action, and provide a conceptual framework for assessing current guidelines in the light of ongoing studies.

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Author and article information

Contributors

Rosalia Grande: URI : http://loop.frontiersin.org/people/641642/overview

Melania Dovizio: URI : http://loop.frontiersin.org/people/50969/overview

Simone Marcone: URI : http://loop.frontiersin.org/people/365842/overview

Annalisa Bruno: URI : http://loop.frontiersin.org/people/12268/overview

Hilary Cassidy: URI : http://loop.frontiersin.org/people/669268/overview

Paola Lanuti: URI : http://loop.frontiersin.org/people/550240/overview

Patricia B. Maguire: URI : http://loop.frontiersin.org/people/477967/overview

Paola Patrignani: URI : http://loop.frontiersin.org/people/10035/overview

Journal

Journal ID (nlm-ta): Front Pharmacol

Journal ID (iso-abbrev): Front Pharmacol

Journal ID (publisher-id): Front. Pharmacol.

Title: Frontiers in Pharmacology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1663-9812

Publication date (Electronic): 22 January 2019

Publication date Collection: 2019

Volume: 10

Electronic Location Identifier: 7

Affiliations

[1] ¹Department of Neurosciences, Imaging and Clinical Sciences, Università degli Studi “G. d’Annunzio” , Chieti, Italy

[2] ²Center of Research on Aging and Translational Medicine (CeSI-MeT), Università degli Studi “G. d’Annunzio” , Chieti, Italy

[3] ³Systems Biology Ireland, Conway SPHERE Research Group Ireland, University College Dublin , Dublin, Ireland

[4] ⁴Conway SPHERE Research Group Ireland, UCD Conway Institute, University College Dublin , Dublin, Ireland

[5] ⁵Department of Internal Medicine, Catholic University , Rome, Italy

[6] ⁶Department of Medicine and Aging Sciences, Università degli Studi “G. d’Annunzio” , Chieti, Italy

Author notes

Edited by: Ying Yu, Shanghai Institutes for Biological Sciences (CAS), China

Reviewed by: Lihong Chen, Dalian Medical University, China; Mallikarjun Bidarimath, Cornell University College of Veterinary Medicine, United States

*Correspondence: Paola Patrignani, ppatrignani@ 123456unich.it

^†These authors have contributed equally to this work as co-first authors

^‡These authors have contributed equally to this work as co-last authors

This article was submitted to Inflammation Pharmacology, a section of the journal Frontiers in Pharmacology

Article

DOI: 10.3389/fphar.2019.00007

PMC ID: 6349702

SO-VID: 147ad4af-c82d-4838-a520-73137726d651

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 08 November 2018

Date accepted : 07 January 2019

Page count

Figures: 10, Tables: 1, Equations: 0, References: 23, Pages: 11, Words: 0

Funding

Funded by: Associazione Italiana per la Ricerca sul Cancro 10.13039/501100005010

Funded by: Science Foundation Ireland 10.13039/501100001602

Funded by: Irish Research Council 10.13039/501100002081

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Platelet-Derived Microparticles From Obese Individuals: Characterization of Number, Size, Proteomics, and Crosstalk With Cancer and Endothelial Cells

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Journal of Circulating Biomarkers

Most cited references 20

RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics

Obesity and cancer risk: recent review and evidence.

Aspirin and Cancer.

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