RANTES and IL-6 cooperate in inducing a more aggressive phenotype in breast cancer cells.

Marianna Gallo,Daniela Frezzetti,Antonio Barbieri,Cristin Roma,Claudio Arra,Antonella De Luca,Nicoletta Chicchinelli,Gerardo Botti,Nicola Normanno,Giosuè Scognamiglio

doi:10.18632/oncotarget.24784

Marianna Gallo, Daniela Frezzetti + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.24784

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Abstract

Both the CC chemokine ligand 5 (CCL5/RANTES) and interleukin-6 (IL-6), released by mesenchymal stem cells (MSCs) as well as by neoplastic cells, promote breast cancer cell progression through autocrine and paracrine mechanisms. In order to assess the effects of the simultaneous overexpression of RANTES and IL-6 on the tumor cell phenotype, we overexpressed both proteins in MCF-7 and MDA-MB-231 human breast cancer cell lines. MCF-7 cells co-expressing RANTES and IL-6 had a greater ability to form colonies in soft agar, compared to cells overexpressing RANTES or IL-6. In addition, both MCF-7 and MDA-MB-231 clones co-expressing RANTES and IL-6 showed a significantly higher ability to migrate and to invade. The analysis of phosphorylated ERK1/2, AKT and STAT3 signal transduction proteins revealed that several signaling pathways are simultaneously activated in cells overexpressing both factors. Finally, the overexpression of RANTES and IL-6 in MCF-7 cells significantly increased the in vivo tumor growth. Collectively, our data suggest that the simultaneous expression of IL-6 and RANTES produces a more aggressive phenotype in breast cancer cells and provide evidence that IL-6 and RANTES might represent potential targets for novel therapeutic strategies aimed to block the tumor-stroma interaction.

Highlights

Cancer progression towards metastasis is a multistep process in which tumor cells escape from the primary tumor site and colonize distant organs [1]
We addressed the role of the simultaneous expression of IL-6 and RANTES in breast cancer progression using two cell lines belonging to different subtypes of breast cancer, the luminal cell line MCF-7, which has a low metastatic potential and invasive ability, and MDA-MB-231 cells, a basal breast cancer cell line with a high metastatic potential
The analysis revealed that MCF-7RANTES+IL6 and MDA-MB-231RANTES+IL6 cells secreted higher amounts of IL-6 and RANTES than cells transfected with empty vectors (Table 1)

Summary

Introduction

Cancer progression towards metastasis is a multistep process in which tumor cells escape from the primary tumor site and colonize distant organs [1]. A variety of soluble cytokines and chemokines, released by cells of the tumor microenvironment including mesenchymal stem cells (MSCs) as well as by neoplastic cells, acts through autocrine and paracrine mechanisms and promotes the ability of cancer cells to metastasize [1, 3]. Among these factors, we previously demonstrated that MSCs produced significant amounts of the CC chemokine ligand 5 (RANTES/CCL5, hereafter referred to as RANTES) and interleukin (IL)-6 [4]. We confirmed that RANTES is able to induce the migration of human breast cancer cell lines representative of different breast carcinoma subtypes [4]

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