Bone Marrow Microenvironment and the Progression of Multiple Myeloma

Abstract

The BM microenvironment in MM, in terms of adhesive features, is well organized to entrap circulating precursors with BM-seeking properties and is able to produce cytokines that offer them the optimal conditions for local growth and final differentiation. Likewise, the malignant B cell clone is equipped with adhesion molecules which enable the cell to establish close contacts with BM stromal cells. Furthermore a number of cytokines are released including IL-1 beta and M-CSF activating BM stromal cells to produce other cytokines, such as IL-6, that stimulate the proliferation of plasma cells. Finally, most cytokines produced locally, including IL-1 beta, TNF-beta, M-CSF, IL-3 and IL-6, also have OAF properties, explaining why the expansion of the B cell clone parallels the activation and numerical increase of the osteoclast population.

IL-3 expression by myeloma cells increases both osteoclast formation and growth of myeloma cells

“…[34][35][36][37][38] Our results demonstrate that IL-3 levels are increased in marrow plasma samples from the majority of patients with MM whom we tested. Consistent with our results, Merico et al 28 reported that IL-3 is the only cytokine consistently increased in serum samples from MM patients while IL-1␤, IL-4, IL-6, IL-7, IL-8, and tumor necrosis factor-␣ (TNF-␣) are not increased.…”

Gene profiling of a myeloma cell line reveals similarities and unique signatures among IL-6 response, N-ras-activating mutations, and coculture with bone marrow stromal cells

“…Although normal plasma cells accumulate in the lamina propria of the gut, MM plasma cells rarely develop in this site, providing evidence that the BM provides a unique niche for the clone to proliferate. 7 Indeed, several groups have demonstrated that the BM is a major source of IL-6, and myeloma cells can induce BM stroma (BMS) to produce this cytokine on cell interaction. 8 We and others have shown that MM/BMS cell (BMSC) interactions drive ANBL-6 cells to proliferate and also alter their therapeutic response in vitro.…”

Expression and function of toll‐like receptors in multiple myeloma patients: toll‐like receptor ligands promote multiple myeloma cell growth and survival via activation of nuclear factor‐κB

“…The BM microenvironment is known to contribute substantially to the malignant growth and survival of MM cells (Caligaris-Cappio et al, 1992;Hallek et al, 1998). In fact, bone marrow stromal cells (BMSCs), in particular, provide a number of cytokines that might contribute to the growth of myeloma cells.…”