Macrophages and mesenchymal stromal cells support survival and proliferation of multiple myeloma cells

Abstract

Summary Multiple myeloma (MM) is characterized by almost exclusive tropism of malignant cells for the bone marrow (BM) milieu. The survival and proliferation of malignant plasma cells have been shown to rely on interactions with nonmalignant stromal cells, in particular mesenchymal stromal cells (MSCs), in the BM microenvironment. However, the BM microenvironment is composed of a diverse array of cell types. This study examined the role of macrophages, an abundant component of BM stroma, as a potential niche component that supports malignant plasma cells. We investigated the proliferation of MM tumour cell lines when cultured alone or together with MSCs, macrophages, or a combination of MSCs and macrophages, using the carboxyfluorescein succinimidyl ester assay. Consistently, we observed increased proliferation of MM cell lines in the presence of either MSCs or macrophages compared to cell line-only control. Furthermore, the combined co-culture of MSCs plus macrophages induced the greatest degree of proliferation of myeloma cells. In addition to increased proliferation, MSCs and macrophages decreased the rate of apoptosis of myeloma cells. Our in vitro studies provide evidence that highlights the role of macrophages as a key component of the BM microenvironment facilitating the growth of malignant plasma cells in MM.

TPL2 kinase regulates the inflammatory milieu of the myeloma niche

“…27,28 In a previous study from our group, we analyzed the transcriptional profile of myeloma-associated monocytes/macrophages to determine their state of activation/polarization. 24 Our work demonstrated that monocytes/macrophages acquire a strongly pro-inflammatory transcriptional profile in the myeloma microenvironment. The transcriptional upregulation of IL-1b was very striking, although transcriptional upregulation of IL-10, IL-6, and TNF-a were also significant.…”

“…20,21 Durie and coauthors highlighted the importance of macrophages as a potential source of paracrine inflammatory cytokines in myeloma in an early study. 22 Later work, including work from our laboratory, [23][24][25][26] demonstrated that macrophages support myeloma cells in the niche through both contact-mediated and noncontact-mediated mechanisms. 27,28 In a previous study from our group, we analyzed the transcriptional profile of myeloma-associated monocytes/macrophages to determine their state of activation/polarization.…”

“…The transcriptional upregulation of IL-1b was very striking, although transcriptional upregulation of IL-10, IL-6, and TNF-a were also significant. 24 However, it was still not clear whether monocytic lineage cells were the major drivers of cytokine production in the myeloma niche. The identity of signals that activate monocytic cells in myeloma bone marrow (BM) also remained enigmatic.…”

Pathogenic Long-Lived Plasma Cells and Their Survival Niches in Autoimmunity, Malignancy, and Allergy

“…Additionally, MMCs attract HNCs such as osteoclast progenitors or immature dendritic cells (69) through secretion of chemokines such as CCL3 (MIP-1a) (70). Moreover, macrophages form a multicomponent niche with stromal cells and extend MMC survival compared with stromal cells alone (71). Via abundant expression of CD28, MMCs promote survival of CD80/86 + myeloid cells in their microenvironment and stimulate IL-6 production in these cells (72).…”

NF-Kβ Activation in U266 Cells on Mesenchymal Stem Cells

“…22 Also, myeloma cells have been connected to stromal cells and endothelial cells within the BM through direct cell-tocell contacts or indirectly, through soluble factors. [23][24][25] Importantly, in numerous researches, the survival and proliferation of malignant plasma cells rely on their interactions with nonmalignant stromal cells, in particular MSCs, in the BM microenvironment.…”