An exploratory analysis of extracellular vesicle-associated and soluble cytokines in cancer-related fatigue in men with prostate cancer

Dilorom Sass; Wendy Fitzgerald; Jennifer J Barb; Kevin Kupzyk; Leonid Margolis; Leorey Saligan

doi:10.1016/j.bbih.2020.100140

An exploratory analysis of extracellular vesicle-associated and soluble cytokines in cancer-related fatigue in men with prostate cancer

Brain Behav Immun Health. 2020 Sep 25:9:100140. doi: 10.1016/j.bbih.2020.100140. eCollection 2020 Dec.

Authors

Dilorom Sass^{1

2}, Wendy Fitzgerald³, Jennifer J Barb⁴, Kevin Kupzyk², Leonid Margolis³, Leorey Saligan¹

Affiliations

¹ National Institute of Nursing Research, National Institute of Nursing Research, National Institutes of Health, Bethesda, MD, USA.
² University of Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE, 68105, USA.
³ National Institute of Child Health and Human Development, Section on Intercellular Interactions, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
⁴ Clinical Center, National Institutes of Health, Bethesda, MD, USA.

Abstract

Background: Cancer Related Fatigue (CRF) is one of the most prevalent and distressing symptoms associated with cancer treatments. The exact etiology of CRF and its mechanisms are poorly understood. Cytokine dysregulation was hypothesized to be one of these mechanisms. Here, we explored the associations of soluble and extracellular vesicle (EV)-associated markers that include cytokines, heat shock proteins (hsp27, hsp70, hsp90), and neurotrophic factors (BDNF) with CRF.

Methods: Plasma was collected from men (n = 40) with non-metastatic prostate cancer receiving external beam radiation therapy (EBRT) at the start of the treatment, and three months after EBRT. CRF was assessed using the Functional Assessment of Cancer Therapy - Fatigue (FACT-F) from all participants. EVs were characterized via Nanoparticle Tracking Analysis, electron microscopy, and Western blot. Concentrations of EV-associated and soluble markers were measured with a multiplexed immunoassay system. Bivariate correlation analyses and independent T tests analyzed the relationships of CRF with the markers.

Findings: As CRF worsened, concentrations of EV-associated markers were upregulated. EV-associated fold changes of Eotaxin, hsp27, IP-10, MIP-3α, were significantly higher in fatigued participants compared to non-fatigued EBRT participants three months after treatment. This was not observed in soluble markers. Concentrations of EV-associated CRP and MCP-1, soluble survivin, IFNα2, IL-8, IL-12p70, and MCP-1 significantly correlated with lower (worsening) CRF scores at the start of and three months after treatment.

Interpretation: Concentrations of EV-associated markers increased in fatigued men with prostate cancer three months after EBRT. Both EV-associated and soluble markers correlated with worsening CRF. EV-associated markers, which have not been previously studied in depth, may provide additional insights and serve as potential biomarkers for CRF.

Keywords: Cancer-related fatigue; Cytokines; Exosomes; Extracellular vesicles.