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Review
. 2016 Sep 13;7(37):60698-60711.
doi: 10.18632/oncotarget.10849.

Microenvironment drug resistance in multiple myeloma: emerging new players

Lucia Di Marzo  1 , Vanessa Desantis  1 , Antonio Giovanni Solimando  1 , Simona Ruggieri  2 , Tiziana Annese  2 , Beatrice Nico  2 , Ruggiero Fumarulo  3 , Angelo Vacca  1 , Maria Antonia Frassanito  3
Affiliations
Review

Microenvironment drug resistance in multiple myeloma: emerging new players

Lucia Di Marzo et al. Oncotarget. .

Abstract

Multiple myeloma (MM) drug resistance (DR) is a multistep transformation process based on a powerful interplay between bone marrow stromal cells and MM cells that allows the latter to escape anti-myeloma therapies. Here we present an overview of the role of the bone marrow microenvironment in both soluble factors-mediated drug resistance (SFM-DR) and cell adhesion-mediated drug resistance (CAM-DR), focusing on the role of new players, namely miRNAs, exosomes and cancer-associated fibroblasts.

Keywords: cancer-associated fibroblasts; drug resistance; exosomes; microRNAs; multiple myeloma.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no conflict of interest

Figures

Figure 1
Figure 1. Interplay between MM cells and the surrounding microenvironment
MM cells are surrounded by a complex BMME composed of ECM proteins and several cell types, including BM stromal cells (ECs, mesenchymal stromal cells, CAFs). The cross-talk between MM cells and BM stromal cells is regulated by different mechanisms: (i) cell-to-cell adhesion between MM cells and ECM components/BM stromal cells; and (ii) soluble factors, i.e. cytokines, chemokines, growth factors, exosomes and miRNAs released by the BM stromal cells and MM cells, with autocrine and paracrine effects. Both mechanisms activate several signaling pathways in BM stromal cells and tumor cells, leading to MM drug resistance.
Figure 2
Figure 2. CAFs-derived exosomes and their uptake from MM cells
A. Transmission electron microscopy of exosomes isolated from BM CAFs of MM patients showing heterogeneous features of vesicles with an electrondense core (blue arrow) and multivesicular body (white arrow). Scale bar, 0.2 μm. B. Flow cytometry analysis of exosomes uptake by RPMI8226 cells. The RPMI8226 cells were co-cultured with unlabeled and BODIPY TR ceramide-labeled CAFs-derived exosomes. C. Confocal dual immunofluorescence images of RPMI8226 cells swallowed CAFs-derived exosomes labeled with SYTO RNASelect (green) and BODIPY TR ceramide (red), specific for RNAs and cell membranes, respectively. Scale bar, 7.5 μm.
See this image and copyright information in PMC

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