Tumor microenvironment is essential for multiple myeloma (MM) growth, progression, and drug resistance through provision of survival signals and secretion of growth and proangiogenic factors. This paper examines the importance of macrophages within MM bone marrow (BM) microenvironment, referred to as MM-associated macrophages, as a potential niche component that supports tumor plasma cells. These macrophages are derived from peripheral blood monocytes recruited into the tumor. Upon activation by MM plasma cells and mesenchymal stromal cells, macrophages can release growth factors, proteolytic enzymes, cytokines, and inflammatory mediators that promote plasma cell growth and survival. Macrophages promote tumor progression through several mechanisms including angiogenesis, growth, and drug resistance. Indeed, these macrophages are essential for the induction of an angiogenic response through vasculogenic mimicry, and this ability proceeds in step with progression of the plasma cell tumors. Data suggest that macrophages play an important role in the biology and survival of patients with MM, and they may be a target for the MM antivascular management.

Tumor cells actively incorporate molecules (e.g., proteins, lipids, RNA) into particles named extracellular vesicles (EVs). Several groups have demonstrated that EVs can be transferred to target (recipient) cells, making EVs an important means of intercellular communication. Indeed, EVs are able to modulate the functions of target cells by reprogramming signaling pathways. In a cancer context, EVs promote the formation of a supportive tumor microenvironment (TME) and (pre)metastatic niches. Recent studies have revealed that immune cells, tumor cells and their secretome, including EVs, promote changes in the TME and immunosuppressive functions of immune cells (e.g., natural killer, dendritic cells, T and B cells, monocytes, macrophages) that allow tumor cells to establish and propagate. Despite the growing knowledge on EVs and on their roles in cancer and as modulators of the immune response/escape, the translation into clinical practice remains in its early stages, hence requiring improved translational research in the EVs field. Here, we comprehensively review the current knowledge and most recent research on the roles of EVs in tumor immune evasion and immunosuppression in both solid tumors and hematological malignancies. We also highlight the clinical utility of EV-mediated immunosuppression targeting and EV-engineering. Importantly, we discuss the controversial role of EVs in cancer biology, current limitations and future perspectives to further the EV knowledge into clinical practice.

Angiogenesis is a constant hallmark of multiple myeloma progression and has prognostic potential. Multiple myeloma cells interact with surrounding host cells and extracellular matrix, this crosstalk affecting the most important aspects of the malignant phenotype, both at primary and secondary tumor sites. The pathophysiology of multiple myeloma-induced angiogenesis involves both direct production of angiogenic cytokines by plasma cells and their induction within the bone marrow microenvironment cells. A direct involvement of bone marrow macrophages and mast cells in vasculogenic mimicry has been demonstrated, thus contributing together with circulating endothelial cells and endothelial precursor cells to the multiple myeloma neovascularization. The role of host cells or the niche microenvironment and extracellular matrix represents an intense area of research, finalized at a better understanding of the pathophysiological modifications of the complete tumor entity, i.e. malignant cells and microenvironment.

In contrast to the pluripotentembryonic stem cells(ESCs) which are able to give rise to all cell types of the body, mammalianadult stem cells(ASCs) appeared to be more limited in their differentiation potential and to be committed to their tissue of origin. Recently, surprising new findings have contradicted central dogmas of commitment of ASCs by showing their plasticity to differentiate across tissue lineage boundaries, irrespective of classical germ layer designations. The present paper supports the plasticity of thebone marrow stem cells(BMSCs), bringing the most striking and the latest evidences of the transdifferentiation properties of thebone marrow hematopoietic and mesenchymal stem cells(BMHSCs, and BMMSCs), the two BM populations of ASCs better characterized. In addition, we report the possible mechanisms that may explain these events, outlining the clinical importance of these phenomena and the relative problems.

Multiple myeloma (MM) is the second most common hematological malignancy, and despite the introduction of innovative therapies, remains an incurable disease. Identifying early and minimally or non-invasive biomarkers for predicting clinical outcomes and therapeutic responses is an active field of investigation. Malignant plasma cells (PCs) reside in the bone marrow (BM) microenvironment (BMME) which comprises cells (e.g., tumour, immune, stromal cells), components of the extracellular matrix (ECM) and vesicular and non-vesicular (soluble) molecules, all factors that support PCs’ survival and proliferation. The interaction between PCs and BM stromal cells (BMSCs), a hallmark of MM progression, is based not only on intercellular interactions but also on autocrine and paracrine circuits mediated by soluble or vesicular components. In fact, PCs and BMSCs secrete various cytokines, including angiogenic cytokines, essential for the formation of specialized niches called “osteoblastic and vascular niches”, thus supporting neovascularization and bone disease, vital processes that modulate the pathophysiological PCs–BMME interactions, and ultimately promoting disease progression. Here, we aim to discuss the roles of cytokines and growth factors in pathogenetic pathways in MM and as prognostic and predictive biomarkers. We also discuss the potential of targeted drugs that simultaneously block PCs’ proliferation and survival, PCs–BMSCs interactions and BMSCs activity, which may represent the future goal of MM therapy.