Summary: Interleukin 17A (IL17A), a cytokine involved in allergy, inflammation and osteoclastogenesis, was investigated in multiple myeloma (MM) to assess its role in the osteoclast (OC)‐like activity of marrow immature dendritic cells (iDCs). Comparing nine MM patients with control subjects affected by monoclonal gammopathy of undetermined significance, we found high IL17A expression in the marrow plasma of MM patients in parallel with its deposits within the stromal matrix. Increased expression of the IL17A receptor (IL17RA) was also found in primary myeloma iDCs, which underwent OC‐like transdifferentiation after IL17A stimulation. To assess the role of IL17A, we measured the activity of the IL17/IL17RA pathway in IL17A‐transdifferentiated iDCs and the expression of functional OC genes by Western blotting and real‐time polymerase chain reaction. These cells showed increased RNA transcription of genes enrolled in the maturation of OCs, while NFATC1 and FOS were induced by IL17A, independently of NFKB1 phosphorylation. Moreover, the concurrent phosphorylation of the Lip isoform of CEBPB and the down‐regulation of MAFB supported the activation of IL17RA pathway in OC‐like transdifferentiated iDCs that was apparently unrelated to TNFRSF11A signalling. These data emphasize the involvement of iDCs in MM hyperactive osteoclastogenesis and suggest that their bone resorption activity is also regulated, at least in vitro, by IL17RA.

Recently, genetically modified mesenchymal stem cells (MSCs) have been exploited to deliver anti-cancer bio-drugs directly within the tumour mass. Here, we explored whether adipose-derived MSCs (AD-MSCs), engineered to express the pro-apoptotic ligand TRAIL (also known as TNFSF10), kill multiple myeloma (MM) cells and migrate towards MM cells in vitro. Different MM cell lines were assessed for their sensitivity to recombinant human (rh) TRAIL alone and in combination with the proteasome inhibitor bortezomib, which was shown to enhance the effect of rhTRAIL. TRAIL⁺-AD-MSCs were co-cultured with bortezomib-pretreated MM cells and their killing activity was evaluated in presence or absence of caspase inhibition. AD-MSC migration towards media conditioned by both myeloma cells and myeloma bone fragments was also investigated. Despite moderate MM cell sensitivity to rhTRAIL, TRAIL⁺-AD-MSCs in combination with bortezomib significantly induced myeloma cell death. This effect was associated with caspase-8 activation and abrogated by capsase inhibition. On the other hand, co-culture experiments were performed to evaluate whether unmodified AD-MSCs affect myeloma cell growth in vitro. AD-MSCs appeared ineffective on myeloma cell growth and showed migratory capacity towards MM cells in vitro. These data emphasize the anti-myeloma activity of TRAIL-engineered AD-MSCs and provide support for a future model of a cell-based approach against MM.

Novel cell-based and gene therapies represent promising approaches for the treatment of incurable diseases, including cancer. Following the success of the hematopoietic stem cell-based transplantation, other populations of adult progenitor cells, including mesenchymal stem cells (MSCs), have been identified as powerful therapeutic tools in humans. The intrinsic capability of MSCs to migrate toward injured tissues emphasizes their suitability to deliver anticancer agents for new clinical applications in addition to the tissue repairing capacity. Here, we revisit the experimental history of MSCs, the most exciting features of their biology in keeping with their promising applications in cell-based therapeutic strategies for cancer treatment.

Umbilical cord (UC) mesenchymal stem cells (MSCs) are being currently investigated as an alternative to bone marrow (BM) MSCs for bone repair and regeneration. Here, we describe the gene regulation of their differentiation to osteogenic, adipogenic, and chondrogenic precursors and demonstrate their tendency to differentiate toward the osteoblast lineage. Fibroblast-like cells from the Warthon's Jelly were cultured with dedicated media to obtain osteogenic-, adipogenic-, and chondrogenic-differentiated cells. After induction, a typical fibroblast-like shape with condensed fibers of F-actin was early noted in osteogenic-induced UC-MSCs, whereas those differentiating to adipocytes were flat with minor cytoskeleton relevance. Real-time PCR measured the transcription of master genes of the three lineages, thus revealing a remarkable up-regulation of Runx2 in osteogenic-induced cells with respect to both PPARg and SOX9 for adipogenic- and chondrogenic-differentiating UC-MSCs. However, TAZ, a coactivator of the nuclear transcription of Runx2 previously detected in BM-MSCs, was expressed in osteogenic- and, at lower magnitude, in adipogenic-induced cells, in keeping with its role in the reciprocal control of the differentiation between osteogenic- and adipogenic-induced cells. Its differential role in these cells was confirmed by its accumulation as protein product in the nuclei to activate Runx2 in osteogenic-differentiating UC-MSCs. These data emphasize the predominant expression by UC-MSCs of genes engaged in the osteogenic differentiation and their tendency to differentiate into osteoblasts, being similar in this respect to BM-MSCs. They may, thus, constitute a promising option for bone remodeling in regenerative medicine.

Classical Hodgkin’s lymphoma (cHL) is one of the most particular lymphomas for the few tumor cells surrounded by an inflammatory microenvironment. Reed-Sternberg (RS) and Hodgkin (H) cells reprogram and evade antitumor mechanisms of the normal cells present in the microenvironment. The cells of microenvironment are essential for growth and survival of the RS/H cells and are recruited through the effect of cytokines/chemokines. We summarize recent advances in gene expression profiling (GEP) analysis applied to study microenvironment component in cHL. We also describe the main therapies that target not only the neoplastic cells but also the cellular components of the background.