Multiple Myeloma Macrophages: Pivotal Players in the Tumor Microenvironment

Abstract

Tumor microenvironment is essential for multiple myeloma (MM) growth, progression, and drug resistance through provision of survival signals and secretion of growth and proangiogenic factors. This paper examines the importance of macrophages within MM bone marrow (BM) microenvironment, referred to as MM-associated macrophages, as a potential niche component that supports tumor plasma cells. These macrophages are derived from peripheral blood monocytes recruited into the tumor. Upon activation by MM plasma cells and mesenchymal stromal cells, macrophages can release growth factors, proteolytic enzymes, cytokines, and inflammatory mediators that promote plasma cell growth and survival. Macrophages promote tumor progression through several mechanisms including angiogenesis, growth, and drug resistance. Indeed, these macrophages are essential for the induction of an angiogenic response through vasculogenic mimicry, and this ability proceeds in step with progression of the plasma cell tumors. Data suggest that macrophages play an important role in the biology and survival of patients with MM, and they may be a target for the MM antivascular management.

Modifications of the mouse bone marrow microenvironment favor angiogenesis and correlate with disease progression from asymptomatic to symptomatic multiple myeloma

“…32 Unfortunately, no information is available to date on TEMs in MM patients, but in patients with active MM and in Vk*MYC mice, macrophages are an abundant component of the BM microenvironment (data reported herein and in [33][34][35] ) where they support survival and proliferation of neoplastic plasma cells [35][36][37] and associate with increased BM vascularity and poor prognosis. 38 These macrophages are functionally, phenotypically, and morphologically different from those of patients with non-active disease and MGUS, and upon in vitro exposure to VEGF and FGF-2, they undergo a process of vascular mimicry, increasing the expression of Tie2 and VEGFR-1 molecules. 39 Thus, investigating the characteristics of TAMs and TEMs in the BM of patients before they have developed symptomatic MM might help defining the pathogenic progression of the disease.…”

Prognostic Significance of Absolute Lymphocyte Count/Absolute Monocyte Count Ratio at Diagnosis in Patients with Multiple Myeloma

“…TAMs, which constitute a significant proportion of tumor-infiltrating inflammatory cells, have been linked to the growth, angiogenesis and metastasis of a variety of cancers 7. In MM, macrophages are an abundant and important component of BM stromal cells and contribute to tumor angiogenesis 25,26. TAMs, which are continually being recruited and activated both in an autocrine manner and by cytokines secreted by myeloma cells, adapt functionally, phenotypically and morphologically to collaborate with endothelial cells in vessel formation 27.…”

Targeting the bone marrow microenvironment in multiple myeloma

“…Tumor-associated macrophages are also a rich source of potent proangiogenic cytokines and growth factors, such as vascular endothelial growth factor, IL-8, and fibroblast growth factor-2, and express a broad array of angiogenesis modulating enzymes including matrix metalloproteinases, cycloxygenase-2, and colony-stimulating factor-1 (87). Neovessel formation and angiogenesis are important pathogenic mechanisms associated with MM progression (discussed later); these observations support the hypothesis that macrophages may also support MM growth indirectly through the paracrine stimulation of MM-associated neoangiogenesis.…”