Feeling Stress: The Mechanics of Cancer Progression and Aggression.

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.

Vascular senescence and ageing: a role for the MEOX proteins in promoting endothelial dysfunction.

In the vascular system, ageing is accompanied by the accrual of senescent cells and is associated with an increased risk of vascular disease. Endothelial cell (EC) dysfunction is a hallmark of vascular disease and is characterized by decreased angiogenic potential, reduced nitric oxide bioavailability, impaired vasodilation, increased production of ROS, and enhanced inflammation. In ECs, the major producer of nitric oxide is the endothelial nitric oxide synthase (eNOS) enzyme that is encoded by the NOS3 gene. NOS3/eNOS function is tightly regulated at both the transcriptional and post-transcriptional levels to maintain normal vascular function. A key transcriptional regulator of eNOS expression is p53, which has been shown to play a central role in mediating cellular senescence and thereby vascular dysfunction. Herein, we show that, in ECs, the MEOX homeodomain transcription factors decrease the expression of genes involved in angiogenesis, repress eNOS expression at the mRNA and protein levels, and increase the expression of p53. These findings support a role for the MEOX proteins in promoting endothelial dysfunction.

Fighting the force: Potential of homeobox genes for tumor microenvironment regulation.

Tumor cells exist in a constantly evolving stromal microenvironment composed of vasculature, immune cells and cancer-associated fibroblasts, all residing within a dynamic extracellular matrix. In this review, we examine the biochemical and biophysical interactions between these various stromal cells and their matrix microenvironment. While the stroma can alter tumor progression via multiple mechanisms, we emphasize the role of homeobox genes in detecting and modulating the mechanical changes in the microenvironment during tumor progression.

The Ski-Zeb2-Meox2 pathway provides a novel mechanism for regulation of the cardiac myofibroblast phenotype.

Cardiac fibrosis is linked to fibroblast-to-myofibroblast phenoconversion and proliferation but the mechanisms underlying this are poorly understood. Ski is a negative regulator of TGF-ß-Smad signaling in myofibroblasts, and might redirect the myofibroblast phenotype back to fibroblasts. Meox2 could alter TGF-ß-mediated cellular processes and is repressed by Zeb2. Here, we investigated whether Ski diminishes the myofibroblast phenotype by de-repressing Meox2 expression and function through repression of Zeb2 expression. We show that expression of Meox1 and Meox2 mRNA and Meox2 protein is reduced during phenoconversion of fibroblasts to myofibroblasts. Overexpression of Meox2 shifts the myofibroblasts into fibroblasts, whereas the Meox2 DNA-binding mutant has no effect on myofibroblast phenotype. Overexpression of Ski partially restores Meox2 mRNA expression levels to those in cardiac fibroblasts. Expression of Zeb2 increased during phenoconversion and Ski overexpression reduces Zeb2 expression in first-passage myofibroblasts. Furthermore, expression of Meox2 is decreased in scar following myocardial infarction, whereas Zeb2 protein expression increases in the infarct scar. Thus Ski modulates the cardiac myofibroblast phenotype and function through suppression of Zeb2 by upregulating the expression of Meox2. This cascade might regulate cardiac myofibroblast phenotype and presents therapeutic options for treatment of cardiac fibrosis.

Adipokines and the cardiovascular system: mechanisms mediating health and disease.

This review focuses on the role of adipokines in the maintenance of a healthy cardiovascular system, and the mechanisms by which these factors mediate the development of cardiovascular disease in obesity. Adipocytes are the major cell type comprising the adipose tissue. These cells secrete numerous factors, termed adipokines, into the blood, including adiponectin, leptin, resistin, chemerin, omentin, vaspin, and visfatin. Adipose tissue is a highly vascularised endocrine organ, and different adipose depots have distinct adipokine secretion profiles, which are altered with obesity. The ability of many adipokines to stimulate angiogenesis is crucial for adipose tissue expansion; however, excessive blood vessel growth is deleterious. As well, some adipokines induce inflammation, which promotes cardiovascular disease progression. We discuss how these 7 aforementioned adipokines act upon the various cardiovascular cell types (endothelial progenitor cells, endothelial cells, vascular smooth muscle cells, pericytes, cardiomyocytes, and cardiac fibroblasts), the direct effects of these actions, and their overall impact on the cardiovascular system. These were chosen, as these adipokines are secreted predominantly from adipocytes and have known effects on cardiovascular cells.