An update on extracellular vesicles in multiple myeloma: a focus on their role in cell-to-cell cross-talk and as potential liquid biopsy biomarkers

ABSTRACT

Introduction: Multiple myeloma (MM) is characterized by a clonal proliferation of neoplastic plasma cells (PCs) in bone marrow (BM) and the interplay between MM PCs and the BM microenvironment, which plays a relevant role in its pathogenesis. In this important cross-talk, extracellular vesicles (EVs) are active. EVs, including small and medium/large EVs, are lipid bi-layer particles released in circulation by normal and neoplastic cells. A selected cargo of lipids, proteins, and nucleic acids is loaded into EVs, and delivered locally and to distant sites, thus influencing the physiology of recipient cells. In the ‘liquid biopsy’ context, EVs can be isolated from human biofluids proving to be powerful markers in cancer.

Areas covered: Here, we summarize the recent advances on EVs in MM field.

Expert commentary: EVs from MM PCs: i) enhance malignant cell proliferation and aggressiveness through an autocrine loop; ii) are able to transfer drug resistance in sensitive-drug cells; iii) stimulate angiogenesis; iv) increase the activity of osteoclasts; v) have immunosuppressive effects. In addition, EVs from MM stromal cells also promote MM cell proliferation and drug resistance. Finally, we underline the importance of EVs as MM potential biomarkers in ‘cancer liquid biopsy’ and as a potential new therapeutic target.

KEYWORDS:

• exosomes
• extracellular vesicles
• microvesicles
• multiple myeloma
• prognostic biomarkers

Article highlights

• MM pathogenesis is attributed to the cross-talk between plasma cells and BM microenvironment, where the EVs are active actors increasing growth and survival of neoplastic cells.

• MM plasma cell derived-EVs: stimulate endothelial cells to increase angiogenesis, increase proliferation of fibroblasts, enhance activity of osteoclasts, interfere with anti-neoplastic immunity, work through an autocrine loop for both tumor auto-sustaining and aggressiveness.

• Circulating EVs in MM could be useful to monitor minimal residual disease (MRD) after treatment and to identify precociously monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SM) patients who are transforming into symptomatic myeloma.

• The number, the phenotype and the molecular content of EVs could be correlated with tumor stage, risk of recurrence, drug resistance, and overall clinical outcome of patients.

• The blocking of EV secretion and the elimination of circulating MM-EVs could represent two novel possible therapeutic targets.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewers Disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper received funding from Italian Ministry of Health - Ricerca corrente 2018.