Extracellular Neuroglobin as a Stress-Induced Factor Activating Pre-Adaptation Mechanisms against Oxidative Stress and Chemotherapy-Induced Cell Death in Breast Cancer.

Marco Fiocchetti,Virginia Solar Fernandez,Maria Marino,Paolo Cercola,Annalisa Massari,Stefano Leone,Francesco Cavaliere,Marco Segatto

doi:10.3390/cancers12092451

Marco Fiocchetti, Virginia Solar Fernandez + Show 6 more

Open Access

https://doi.org/10.3390/cancers12092451

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Abstract

Components of tumor microenvironment, including tumor and/or stromal cells-derived factors, exert a critical role in breast cancer (BC) progression. Here we evaluated the possible role of neuroglobin (NGB), a monomeric globin that acts as a compensatory protein against oxidative and apoptotic processes, as part of BC microenvironment. The extracellular NGB levels were evaluated by immunofluorescence of BC tissue sections and by Western blot of the culture media of BC cell lines. Moreover, reactive oxygen species (ROS) generation, cell apoptosis, and cell migration were evaluated in different BC cells and non-tumorigenic epithelial mammary cells treated with BC cells (i.e., Michigan Cancer Foundation-7, MCF-7) conditioned culture media and extracellular NGB. Results demonstrate that NGB is a component of BC microenvironment. NGB is released in tumor microenvironment by BC cells only under oxidative stress conditions where it can act as autocrine/paracrine factor able to communicate cell resilience against oxidative stress and chemotherapeutic treatment.

Highlights

Tumor microenvironment encompasses a complex mixture of cancer and non-cancerous cells and the extracellular matrix (ECM) [1,2,3].A binary intertwined connection exists between all the components of tumor microenvironment as demonstrated in breast cancer (BC) [2,3]
We demonstrated that sub-nanomolar and nanomolar concentrations of recombinant NGB deeply impact on breast cancer cells phenotype by increasing antioxidant response and promoting cell resistance against apoptotic cell death induced by docetaxel, a chemotherapeutic drug commonly used in clinical practice against breast cancer [24]
A growing body of evidence indicates that the cross talk between epithelial cancer cells, non-cancerous stromal cells, and tumor microenvironment is a key determinant of cancer phenotype [59,60,61] and strategies targeting such interactions may be promising for new therapies [2,62,63,64]

Summary

Introduction

Tumor microenvironment encompasses a complex mixture of cancer and non-cancerous cells (i.e., immune and endothelial cells, fibroblasts, adipocytes) and the extracellular matrix (ECM) [1,2,3].A binary intertwined connection exists between all the components of tumor microenvironment as demonstrated in breast cancer (BC) [2,3]. Tumor cells directly interact each other and sculpt the ECM by releasing a variety of proteins that act as autocrine or paracrine factors influencing cancer and non-cancer cell proliferation, differentiation, and survival [1]. On the other hand, released factors from cancer-associated fibroblasts (CAF) and adipocytes (CAA) contribute to the tumorigenic phenotype of pre-malignant and malignant epithelial cells [4] promoting tumor cell proliferation, invasiveness, and growth. Among different factors, including growth factors, cytokines, chemokines, and microRNAs, released by breast cancer cells to cope with stressful conditions altering the tumor microenvironment [1], the 17β-Estradiol (E2)-inducible compensatory protein named neuroglobin (NGB) [7] deserves particular consideration for its pro-survival and anti-apoptotic role in BC [8].

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Discussion

Conclusion