Abstract
The tumor microenvironment is a dynamic landscape in which the physical and mechanical properties evolve dramatically throughout cancer progression. These changes are driven by enhanced tumor cell contractility and expansion of the growing tumor mass, as well as through alterations to the material properties of the surrounding extracellular matrix (ECM). Consequently, tumor cells are exposed to a number of different mechanical inputs including cell–cell and cell-ECM tension, compression stress, interstitial fluid pressure and shear stress. Oncogenes engage signaling pathways that are activated in response to mechanical stress, thereby reworking the cell's intrinsic response to exogenous mechanical stimuli, enhancing intracellular tension via elevated actomyosin contraction, and influencing ECM stiffness and tissue morphology. In addition to altering their intracellular tension and remodeling the microenvironment, cells actively respond to these mechanical perturbations phenotypically through modification of gene expression. Herein, we present a description of the physical changes that promote tumor progression and aggression, discuss their interrelationship and highlight emerging therapeutic strategies to alleviate the mechanical stresses driving cancer to malignancy.
Highlights
The tumor microenvironment is a dynamic landscape composed of cancer cells surrounded by the extracellular matrix (ECM) and a host of stromal cells, including fibroblasts, immune cells, blood and lymphatic vascular cells, and other tissue-specific cells
Tumor cells are exposed to a number of different mechanical stimuli including cell–cell and cell-ECM tension, compression stress from the expanding tumor mass, interstitial fluid pressure, and shear stress
Positive feedback exists between these stimuli and the responses they elicit (Figure 4), such as increased cellular actomyosin contractility and ECM stiffening, which exacerbates tumor progression and aggression
Summary
The tumor microenvironment is a dynamic landscape composed of cancer cells surrounded by the extracellular matrix (ECM) and a host of stromal cells, including fibroblasts, immune cells, blood and lymphatic vascular cells, and other tissue-specific cells (e.g., adipocytes). From transformation of the normal tissue, on through progression of the primary tumor to invasion, dissemination, and metastasis, the physical context of the tumor changes dramatically (Kumar and Weaver, 2009). These changes to the tumor microenvironment are driven by enhanced tumor cell contractility, expansion of the growing tumor mass, and alterations to the material properties of the surrounding ECM. Active tumor cell engagement with this mechanically-evolving microenvironment results in changes to cytoskeletal structure, cellular shape, differentiation, survival/death, proliferation, adhesion, and migration which can drive tumor progression and aggression (Butcher et al, 2009; Yu et al, 2011). We present a description of the mechanical stresses that promote tumor progression and aggression, discuss their interrelationship, and highlight emerging therapeutic strategies to alleviate the mechanical stresses driving cancer to malignancy
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