Abstract
Alterations in extracellular matrix composition and organization are known to promote tumor growth and metastatic progression in breast cancer through interactions with tumor cells as well as stromal cell populations. Macrophages display a spectrum of behaviors from tumor-suppressive to tumor-promoting, and their function is spatially and temporally dependent upon integrated signals from the tumor microenvironment including, but not limited to, cytokines, metabolites, and hypoxia. Through years of investigation, the specific biochemical cues that recruit and activate tumor-promoting macrophage functions within the tumor microenvironment are becoming clear. In contrast, the impact of biomechanical stimuli on macrophage activation has been largely underappreciated, however there is a growing body of evidence that physical cues from the extracellular matrix can influence macrophage migration and behavior. While the complex, heterogeneous nature of the extracellular matrix and the transient nature of macrophage activation make studying macrophages in their native tumor microenvironment challenging, this review highlights the importance of investigating how the extracellular matrix directly and indirectly impacts tumor-associated macrophage activation. Additionally, recent advances in investigating macrophages in the tumor microenvironment and future directions regarding mechano-immunomodulation in cancer will also be discussed.
Highlights
Macrophages are an innate immune cell type found in all tissues of the body with multiple functions
While a causal mechanistic link between biomechanical properties of the extracellular matrix (ECM) and macrophage activation has yet to be fully established in vivo, here we highlight studies that investigate the relationship and crosstalk between biophysical properties of the ECM and macrophage activation
Further investigation into downstream signaling pathways activated by integrin ligand binding and mechanical stimuli is necessary to identify potential therapeutic interventions to shift tumor-associated macrophages (TAMs) away from a tumor promoting phenotype
Summary
Macrophages are an innate immune cell type found in all tissues of the body with multiple functions. Much work has been done to characterize soluble factors present in the TME that recruit and influence macrophage behavior [14], less is known about how the mechanical properties of tumor ECM impact macrophage recruitment, activation, and cytokine secretion. The binding of these ECM proteins to adhesion receptors on the surface of macrophages promote inflammatory and tumor-promoting macrophage activation [32–34] (Figure 1A).
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