CXCR4-SDF-1 interaction potentially mediates trafficking of circulating tumor cells in primary breast cancer.

M Mego,D Manasova,J Mardiak,P Gronesova,G Minarik,M Cristofanilli,D Pindak,M Karaba,Z Cierna,S Cingelova,D Cholujova,J Sufliarsky,J M Reuben,J Benca,T Sedlackova

doi:10.1186/s12885-016-2143-2

Abstract

BackgroundCytokines are involved in cancer invasion and metastasis. Circulating tumor cells (CTCs) play key role in tumor dissemination and are an independent survival predictor in breast cancer patients. The aim of this study was to assess correlation between CTCs and plasma cytokines in primary breast cancer (PBC) patients.MethodsThis study included 147 chemotherapy naïve PBC patients. Peripheral blood mononuclear cells (PBMC) were depleted of hematopoetic cells using RossetteSep™ negative selection kit. RNA extracted from CD45-depleted PBMC was interrogated for expression of EMT (Twist1, Snail1, Slug, Zeb1) and epithelial (Ck19) gene transcripts by qRT-PCR. The concentrations of 51 plasma cytokines were measured using multiplex bead arrays.ResultsCTCs were detected in 25.2 % patients. CTCs exhibiting only epithelial markers (CTC_EP) and only EMT markers (CTC_EMT) were present evenly in 11.6 % patients, while CTCs co-expressing both markers were detected in 2.0 % patients. Patients with presence of CTC_EP in peripheral blood had significantly elevated levels of plasma IFN-α2, IL-3, MCP-3, β-NGF, SCF, SCGF-β, TNF-β and SDF-1 compared to patients without CTC_EP. CTC_EP exhibited overexpression of SDF-1 receptor and CXCR4, but not other corresponding cytokine receptor, and in multivariate analysis SDF-1 was independently associated with CTC_EP. There was an inverse correlation between CTC_EMT and plasma cytokines CTACK, β-NGF and TRAIL, while presence of either subtype of CTCs was associated with increased level of TGF-β2.ConclusionUsing cytokine profiling, we identified cytokines associated with CTCs subpopulations in peripheral blood of PBC. Our data suggest that CXCR4-SDF-1 axis is involved in mobilization and trafficking of epithelial CTCs.

Highlights

IntroductionCirculating tumor cells (CTCs) play key role in tumor dissemination and are an independent survival predictor in breast cancer patients
Cytokines are involved in cancer invasion and metastasis
We investigated the association between Circulating tumor cells (CTCs) and peripheral blood cytokines with the intent of demonstrating which cytokines are involved in CTCs trafficking

Summary

Introduction

Circulating tumor cells (CTCs) play key role in tumor dissemination and are an independent survival predictor in breast cancer patients. The aim of this study was to assess correlation between CTCs and plasma cytokines in primary breast cancer (PBC) patients. Metastatic cascade is a multistep process that enables the migration of tumor cells from the primary site to a distant location, where they can potentially establish a new cancer growth [1]. Circulating tumor cells (CTCs) are cancer cells that mediate tumor dissemination and play the key role in the metastatic cascade [1]. Increasing evidence suggest that CTCs are involved in Metastatic cascade is a highly inefficient process and only a very limited number of tumor cells that enter the blood circulation are capable of forming metastases [7,8,9]. Other components of peripheral blood including platelets, coagulation factors, various signaling molecules, growth factors and chemokines might protect

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