The bone marrow microenvironment in multiple mieloma: cellular and molecular basis of disease progression

The growth, survival and proliferation of cancer cells are guaranteed by a crosstalk between cancer cells themselves and surrounding host cells and extracellular matrix. An intense area of research has contributed to a better understanding of the pathophysiological modification of tumor progression, e.g., the role of microenvironment. Multiple Myeloma (MM) is a malignancy of immunoglobulin-synthesizing plasma cells with symptoms mainly related to imbalance of bone homeostasis, kidney damage, anemia, impaired humoral immunity, and sometimes nervous system dysfunctions. Plasma cells home and expand in the bone marrow where cause an unbalanced bone remodelling with increased bone resorption and low bone formation that represent the typical feature in the majority of patients. MM plasma cells are thought to be responsible for the osteolytic bone lesions, which occur by increased osteoclast formation/activity and inhibition of osteoblast formation/differentiation. In physiological conditions, this process is critically regulated by the transcription factor Runx2 and by the Wnt signaling pathway. Moreover, MM plasma cells accelerate the differentiation of resident macrophages to osteoclasts. Finally, plasma cells themselves can transdifferentiate to functional osteoclasts. Another relevant aspect of the interactions of MM plasma cells with stromal cells in the bone marrow microenvironment is neovascularization, a constant hallmark of disease progression. MM plasma cells induce angiogenesis both directly, via their own factors (vascular endothelial growth factor [VEGF], fibroblast growth factor-2 [FGF-2], hepatocyte growth factor [HGF] and metalloproteinases), and indirectly via recruitment and activation of stromal inflammatory cells to secrete their own angiogenic factors. Macrophages and mast cells play an important role in this sense. They are recruited and activated by tumor plasma cells through the secretion of FGF-2, interleukin-8 (IL-8) and chemokines, such as ITAC, Mig, IP-10. When macrophages and mast cells are activated they secrete potent angiogenic factors (FGF-2, VEGF, granulocyte-colony stimulating factor [G-CSF], granulocyte macrophage-colony stimulating factor [GM-CSF]), which contribute to the tumor neovascularization. Recent evidence demonstrates the vasculogenic ability of active MM macrophages exposed to VEGF and FGF-2, the major angiogenic cytokines secreted by plasma cells, and present in the bone marrow microenvironment at four-to five-fold higher levels than in peripheral blood. Under these stimuli, bone marrow macrophages acquire endothelial cell (EC) markers and transform into cells functionally and phenotypically similar to paired bone marrow ECs (MM patient-derived endothelial cells, MMECs). So they generate capillary-like networks mimicking those of MMECs. Thus, MM macrophages contribute to build the neovessel wall via a “vasculogenic mimicry”, hence helping MM progression by this way.