To b(ortezomib) or not to be: the stroma's the thing.

The proteasome inhibitor bortezomib has been widely used to treat patients with multiple myeloma (MM). However, some patients show primary or secondary resistance. In recent work published in The Journal of Pathology, Beyar-Katz et al demonstrate that bortezomib treatment stimulates a host inflammatory response, which in turn promotes MM cell migration, viability, and proliferation. These effects appear to be mediated by pro-inflammatory M1-like stromal macrophages partly via secretion of cytokine IL-16. These unexpected findings imply that the binary M1/M2 definition of macrophages may not accurately describe the complexity and heterogeneity of macrophages associated with MM tumour growth and progression, and further suggest that bortezomib treatment stimulates host-driven tumour-promoting activity in addition to its cytotoxic activity, thus leading to potential bortezomib resistance in MM patients. Understanding the underlying mechanisms may identify novel targets to overcome or prevent bortezomib resistance.