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Bone Marrow Stromal Cells-Induced Drug Resistance in Multiple Myeloma.

ABSTRACT: Multiple myeloma is a B-cell lineage cancer in which neoplastic plasma cells expand in the bone marrow and pathophysiological interactions with components of microenvironment influence many biological aspects of the malignant phenotype, including apoptosis, survival, proliferation, and invasion. Despite the therapeutic progress achieved in the last two decades with the introduction of a more effective and safe new class of drugs (i.e., immunomodulators, proteasome inhibitors, monoclonal antibodies), there is improvement in patient survival, and multiple myeloma (MM) remains a non-curable disease. The bone marrow microenvironment is a complex structure composed of cells, extracellular matrix (ECM) proteins, and cytokines, in which tumor plasma cells home and expand. The role of the bone marrow (BM) microenvironment is fundamental during MM disease progression because modification induced by tumor plasma cells is crucial for composing a "permissive" environment that supports MM plasma cells proliferation, migration, survival, and drug resistance. The "activated phenotype" of the microenvironment of multiple myeloma is functional to plasma cell proliferation and spreading and to plasma cell drug resistance. Plasma cell drug resistance induced by bone marrow stromal cells is mediated by stress-managing pathways, autophagy, transcriptional rewiring, and non-coding RNAs dysregulation. These processes represent novel targets for the ever-increasing anti-MM therapeutic armamentarium.

SUBMITTER: Ria R

PROVIDER: S-EPMC7013615 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Bone Marrow Stromal Cells-Induced Drug Resistance in Multiple Myeloma.

Ria Roberto R Vacca Angelo A

International journal of molecular sciences 20200117 2

Multiple myeloma is a B-cell lineage cancer in which neoplastic plasma cells expand in the bone marrow and pathophysiological interactions with components of microenvironment influence many biological aspects of the malignant phenotype, including apoptosis, survival, proliferation, and invasion. Despite the therapeutic progress achieved in the last two decades with the introduction of a more effective and safe new class of drugs (i.e., immunomodulators, proteasome inhibitors, monoclonal antibodi ...[more]

PMID: 31963513

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Project description:INTRODUCTION: Recent studies indicate that bone marrow stromal cells (BMSCs) derived from patients with multiple myeloma (MM) differ from those of healthy donors in their expression of extracellular matrix compounds and in cytokine production. It is not known whether these abnormalities are primary or are acquired by BMSCs on contact with MM cells. MATERIALS AND METHODS: Interleukin (IL)-6, IL-11, IL-10, and tumor necrosis factor (TNF)-alpha production by CD166+ mesenchymal BMSCs and the CD38+/CD138+ RPMI8226 myeloma cell line cultivated in vitro in monocultures or co-cultivated under cell-to-cell contact or non-contact conditions in the presence of a tissue culture insert were measured. Intracellular cytokines were measured by flow cytometry analysis as the percentage of cytokine-producing cells or by mean fluorescence intensity as the level of cytokine expression in cells. Additionally, ELISA was used to measure IL-6, soluble IL-6 receptor (sIL-6R), IL-11, IL-10, TNF-alpha, B-cell-activating factor of the TNF family (BAFF), hepatocyte growth factor (HGF), and osteopontin (OPN) production in the supernatants of the cultures and co-cultures. RESULTS: A higher ability of the BMSCs of MM patients than in controls was detected to produce IL-6, IL-10, TNF-alpha, OPN, and especially HGF and BAFF in response to the RPMI8226 cells. Moreover, the BMSCs of the MM patients significantly enhanced the production of sIL-6R by the RPMI8226 cells. DISCUSSION: Cytokines over-expressed by BMSCs of MM patients can function as growth factors for myeloma cells (IL-6, IL-10, HGF), migration stimulatory factors for tumor plasma cells (TNF-alpha, HGF), adhesion stimulatory factors (HGF, BAFF and OPN), stimulators of osteoclastogenesis (IL-6, TNF-alpha), and angiogenic factors (TNF-alpha). The results of this experiment strongly suggest that the BMSCs from MM patients differed in spontaneous and myeloma cell-induced production of cytokines, especially of HGF and BAFF, and these abnormalities were both primary and acquired by the BMSCs on contact with the MM cells. This in turn suggests the presence of an undefined, autocrine stimulation pathway resulting in a prolonged production of cytokines even in long-term cultures in vitro and in vivo. These abnormalities might provide optimal conditions for the proliferation and differentiation of residual tumor cells or their precursors in the affected bone marrow.

Project description:Simple Summary Mitochondrial transfer plays a crucial role in the acquisition of drug resistance in multiple myeloma, but its exact mechanism is not yet clear; moreover, overcoming the drug resistance that it causes is also a major challenge. Our research on primary myeloma cell cultures reveals that mitochondrial transfer is bi-directional between bone marrow stromal cells and myeloma cells, occurring via tunneling nanotubes and partial cell fusion with extreme increases under the influence of chemotherapeutic drugs, whereupon survival and adenosine triphosphate levels increase, while mitochondrial superoxide levels decrease in myeloma cells. These changes and the elevation of superoxide levels in stromal cells are proportional to the amount of incorporated mitochondria derived from the other cell type and to the concentration of the used drug. Although the inhibition of mitochondrial transfer is limited between stromal and myeloma cells, the supportive effect of stromal cells can be effectively averted by influencing the tumor metabolism with an inhibitor of oxidative phosphorylation in addition to chemotherapeutics. Abstract Recently, it has become evident that mitochondrial transfer (MT) plays a crucial role in the acquisition of cancer drug resistance in many hematologic malignancies; however, for multiple myeloma, there is a need to generate novel data to better understand this mechanism. Here, we show that primary myeloma cells (MMs) respond to an increasing concentration of chemotherapeutic drugs with an increase in the acquisition of mitochondria from autologous bone marrow stromal cells (BM-MSCs), whereupon survival and adenosine triphosphate levels of MMs increase, while the mitochondrial superoxide levels decrease in MMs. These changes are proportional to the amount of incorporated BM-MSC-derived mitochondria and to the concentration of the used drug, but seem independent from the type and mechanism of action of chemotherapeutics. In parallel, BM-MSCs also incorporate an increasing amount of MM cell-derived mitochondria accompanied by an elevation of superoxide levels. Using the therapeutic antibodies Daratumumab, Isatuximab, or Elotuzumab, no similar effect was observed regarding the MT. Our research shows that MT occurs via tunneling nanotubes and partial cell fusion with extreme increases under the influence of chemotherapeutic drugs, but its inhibition is limited. However, the supportive effect of stromal cells can be effectively avoided by influencing the metabolism of myeloma cells with the concomitant use of chemotherapeutic agents and an inhibitor of oxidative phosphorylation.

Dataset Information

Bone Marrow Stromal Cells-Induced Drug Resistance in Multiple Myeloma.

Publications

Bone Marrow Stromal Cells-Induced Drug Resistance in Multiple Myeloma.

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