The multipotent mesenchymal stem/stromal cells (MSCs), initially discovered from bone marrow in 1976, have been identified in nearly all tissues of human body now. The multipotency of MSCs allows them to give rise to osteocytes, chondrocytes, adipocytes, and other lineages. Moreover, armed with the immunomodulation capacity and tumor-homing property, MSCs are of special relevance for cell-based therapies in the treatment of cancer. However, hampered by lack of knowledge about the controversial roles that MSC plays in the crosstalk with tumors, limited progress has been made with regard to translational medicine. Therefore, in this review, we discuss the prospects of MSC-associated anticancer strategies in light of therapeutic mechanisms and signal transduction pathways. In addition, the clinical trials designed to appraise the efficacy and safety of MSC-based anticancer therapies will be assessed according to published data.

Mesenchymal stem/stromal cells in cancer therapy.

Myeloid malignancies and the microenvironment

The bone marrow microenvironment – Home of the leukemic blasts

Several haematological malignancies, including multiple myeloma (MM) and acute myeloid leukaemia (AML), have well-defined precursor states that precede the development of overt cancer. MM is almost always preceded by monoclonal gammopathy of undetermined significance (MGUS), and at least a quarter of all patients with myelodysplastic syndromes (MDS) have disease that evolves into AML. In turn, MDS are frequently anteceded by clonal haematopoiesis of indeterminate potential (CHIP). The acquisition of additional genetic and epigenetic alterations over time clearly influences the increasingly unstable and aggressive behaviour of neoplastic haematopoietic clones; however, perturbations in the bone-marrow microenvironment are increasingly recognized to have key roles in initiating and supporting oncogenesis. In this Review, we focus on the concept that the haematopoietic neoplasia-microenvironment relationship is an intimate rapport between two partners, provide an overview of the evidence supporting a role for the bone-marrow niche in promoting neoplasia, and discuss the potential for niche-specific therapeutic targets.

The bone-marrow niche in MDS and MGUS: implications for AML and MM

Exosomes are paracrine regulators of the tumor microenvironment and contain complex cargo. We previously reported that exosomes released from acute myeloid leukemia (AML) cells can suppress residual hematopoietic stem and progenitor cell (HSPC) function indirectly through stromal reprogramming of niche retention factors. We found that the systemic loss of hematopoietic function is also in part a consequence of AML exosome-directed microRNA (miRNA) trafficking to HSPCs. Exosomes isolated from cultured AML or the plasma from mice bearing AML xenografts exhibited enrichment of miR-150 and miR-155. HSPCs cocultured with either of these exosomes exhibited impaired clonogenicity, through the miR-150- and miR-155-mediated suppression of the translation of transcripts encoding c-MYB, a transcription factor involved in HSPC differentiation and proliferation. To discover additional miRNA targets, we captured miR-155 and its target transcripts by coimmunoprecipitation with an attenuated RNA-induced silencing complex (RISC)-trap, followed by high-throughput sequencing. This approach identified known and previously unknown miR-155 target transcripts. Integration of the miR-155 targets with information from the protein interaction database STRING revealed proteins indirectly affected by AML exosome-derived miRNA. Our findings indicate a direct effect of AML exosomes on HSPCs that, through a stroma-independent mechanism, compromises hematopoiesis. Furthermore, combining miRNA target data with protein-protein interaction data may be a broadly applicable strategy to define the effects of exosome-mediated trafficking of regulatory molecules within the tumor microenvironment.

AML suppresses hematopoiesis by releasing exosomes that contain microRNAs targeting c-MYB.

c-Myc plays part in drug resistance mediated by bone marrow stromal cells in acute myeloid leukemia

SDF-1/CXCR4 axis in myelodysplastic syndromes: Correlation with angiogenesis and apoptosis

Despite advances in the treatment of Hodgkin lymphoma (HL), there is a need for development of reliable prognostic biomarkers and improved stratification of patients for effective therapeutic intervention. The immune microenvironment is the key to HL pathophysiology. The aim of this study was to identify expression of microenvironment-related biomarkers (PD-1, FOXP3, and CSF-1R) immunohistochemically and determine their association with clinicopathological features and prognosis in HL. We found that a high number of non-HRS cells expressing CSF-1R confers inferior overall survival (OS), which is associated with the presence of Epstein-Barr virus in neoplastic cells (P=0.009). Increased FOXP3 expression confered superior OS and progression-free survival (PFS). PD-1 expression had no significant association with OS and PFS. The combination of FOXP3 and PD-1 or CSF-1R may yield better prognostic stratification.

PD-1, FOXP3, and CSF-1R expression in patients with Hodgkin lymphoma and their prognostic value.

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c-Myc plays part in drug resistance mediated by bone marrow stromal cells in acute myeloid leukemia

SDF-1/CXCR4 axis in myelodysplastic syndromes: Correlation with angiogenesis and apoptosis

PD-1, FOXP3, and CSF-1R expression in patients with Hodgkin lymphoma and their prognostic value.