Game of Bones: How Myeloma Manipulates Its Microenvironment

Abstract

Multiple myeloma is a clonal disease of long-lived plasma cells and is the second most common hematological cancer behind Non-Hodgkin's Lymphoma. Malignant transformation of plasma cells imparts the ability to proliferate, causing harmful lesions in patients. In advanced stages myeloma cells become independent of their bone marrow microenvironment and form extramedullary disease. Plasma cells depend on a rich array of signals from neighboring cells within the bone marrow for survival which myeloma cells exploit for growth and proliferation. Recent evidence suggests, however, that both the myeloma cells and the microenvironment have undergone alterations as early as during precursor stages of the disease. There are no current therapies routinely used for treating myeloma in early stages, and while recent therapeutic efforts have improved patients' median survival, most will eventually relapse. This is due to mutations in myeloma cells that not only allow them to utilize its bone marrow niche but also facilitate autocrine pro-survival signaling loops for further progression. This review will discuss the stages of myeloma cell progression and how myeloma cells progress within and outside of the bone marrow microenvironment.

Keywords: MGUS; bone marrow microenviroment; multiple myeloma; myeloma therapy; smoldering myeloma.

Figure 1

Bone marrow interactions that promote myeloma growth and survival. Myeloma cells bind to the extracellular matrix (ECM) via integrins, proteoglycans, and hyaluronan receptors. They also directly bind to bone marrow stromal cell (BMSC) such as dendritic cells (DC) via the VCAM-VLA4, ICAM-LFA1, ICAM-MUC1, and CD80/86-CD28 axes. BMSC will produce the cytokines SDF1α, IL6, APRIL, BAFF, TNFα, IGF, HGF, and VEGF. In turn, myeloma cells secrete TGFβ and VEGF for BMSC. Myeloma cells promote osteoclast activation by secreting MIP1α/β and VEGF and by promoting BMSC secretion of IL1, IL6, TNFα, RANKL, MIP1α/β, SDF1, and PTHRP. They also prevent osteoblast differentiation by downregulating RUNX2 via direct binding of the VLA-VCAM axis and secretion of DKK1 and IL3. They also secrete sFRP-2 which also suppresses osteoblast differentiation. Osteoclasts produce IL6 and CHSY1 to promote myeloma cell survival. Myeloma cells induce angiogenesis in the bone marrow by secreting HGF, bFGF, VEGF, Ang-2, cleaved syndecan-1 (SDC1), and TGFβ. They also promote BMSC secretion of HGF, VEGF, and IL8. Endothelial cells produce IL6 and IGF1 to influence myeloma cell survival. Myeloma cells promote an immunosuppressive environment by inhibiting T cell function through production of TGFβ, PD-L1, LAG3, TIM3, and IL10. They also signal to BMSC to produce IL5, IL6, TNFα, and IDO.

Figure 2

Models for leukocyte and myeloma cell extravasation. (A) Standard leukocyte multistep model of extravasation. The leukocyte in the bloodstream receives homing signals from chemokines. This is followed by weak adhesion to the endothelium and rolling along the surface. Integrins such as VLA4 and LFA1 are activated to form tight adhesion to the endothelium. The leukocyte then reorganizes its cytoskeleton and degrades the basement membrane to transmigrate through. (B) Model of myeloma extravasation out of the bone marrow. Myeloma cells downregulate receptors used for homing to the bone marrow. They alter adhesion molecules by downregulating integrins and increasing hyaluronan receptors such as CD44 and RHAMM and expression of focal adhesion kinase (FAK). The myeloma cell will secrete MMP-9 and heparanase as well as induce production of MMP-9 via endothelial cells to degrade the extracellular matrix (ECM). Heparanase secretion can cause shedding of SDC1 which also contributes to cell motility. The myeloma cell will then reorganize its cytoskeleton and migrate through the ECM.