Cells within tissues are continuously exposed to physical forces including hydrostatic pressure, shear stress, and compression and tension forces. Cells dynamically adapt to force by modifying their behaviour and remodelling their microenvironment. They also sense these forces through mechanoreceptors and respond by exerting reciprocal actomyosin- and cytoskeletal-dependent cell-generated force by a process termed 'mechanoreciprocity'. Loss of mechanoreciprocity has been shown to promote the progression of disease, including cancer. Moreover, the mechanical properties of a tissue contribute to disease progression, compromise treatment and might also alter cancer risk. Thus, the changing force that cells experience needs to be considered when trying to understand the complex nature of tumorigenesis.

/pdf/a-tense-situation-forcing-tumour-progression-4myf9i89al.pdf

A Tense Situation: Forcing Tumour Progression

Dynamic remodeling of the extracellular matrix (ECM) is essential for development, wound healing and normal organ homeostasis. Life-threatening pathological conditions arise when ECM remodeling becomes excessive or uncontrolled. In this Perspective, we focus on how ECM remodeling contributes to fibrotic diseases and cancer, which both present challenging obstacles with respect to clinical treatment, to illustrate the importance and complexity of cell-ECM interactions in the pathogenesis of these conditions. Fibrotic diseases, which include pulmonary fibrosis, systemic sclerosis, liver cirrhosis and cardiovascular disease, account for over 45% of deaths in the developed world. ECM remodeling is also crucial for tumor malignancy and metastatic progression, which ultimately cause over 90% of deaths from cancer. Here, we discuss current methodologies and models for understanding and quantifying the impact of environmental cues provided by the ECM on disease progression, and how improving our understanding of ECM remodeling in these pathological conditions is crucial for uncovering novel therapeutic targets and treatment strategies. This can only be achieved through the use of appropriate in vitro and in vivo models to mimic disease, and with technologies that enable accurate monitoring, imaging and quantification of the ECM.

/pdf/remodeling-and-homeostasis-of-the-extracellular-matrix-5bwgfdcscl.pdf

Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer

Cardiac fibroblasts: at the heart of myocardial remodeling.

Cardiac fibrosis: Cell biological mechanisms, molecular pathways and therapeutic opportunities.

Because of its dynamic nature, the composition and structure of the myocardial collagen network can be reversibly modified to adapt to transient cardiac injuries In response to persistent injury, however, irreversible, maladaptive changes of the network occur leading to fibrosis, mostly characterized by the excessive interstitial and perivascular deposition of collagen types I and III fibers It is now becoming apparent that myocardial fibrosis directly contributes to adverse myocardial remodeling and the resulting alterations of left ventricular (LV) anatomy and function present in the major types of cardiac diseases The enzyme lysyl oxidase (LOX) is a copper-dependent extracellular enzyme that catalyzes lysine-derived cross-links in collagen and elastin LOX-mediated cross-linking of collagen types I and III fibrils leads to the formation of stiff collagen types I and III fibers and their subsequent tissue deposition Evidence from experimental and clinical studies shows that the excess of LOX is associated with an increased collagen cross-linking and stiffness It is thus conceivable that LOX upregulation and/or overactivity could underlie myocardial fibrosis and altered LV mechanics and contribute to the compromise of LV function in cardiac diseases This review will consider the molecular aspects related to the regulation and actions of LOX, namely, in the context of collagen synthesis In addition, it will address the information related to the role of myocardial LOX in heart failure and the potential benefits of controlling its expression and function

https://www.physiology.org/doi/pdf/10.1152/ajpheart.00335.2010

Role of lysyl oxidase in myocardial fibrosis: from basic science to clinical aspects.

Objective Dilated cardiomyopathy (DCM) represents a large subset of patients with congestive heart failure (HF), and myocardial fibrosis has been shown to be associated with this process. Lysyl oxidase (LOX), a key enzyme, plays a potential role in the biogenesis of connective tissue matrices by catalyzing crosslinks in collagen and elastin. However, the mechanisms involved in the remodeling process during HF are not clearly understood. The present work was aimed to determine the changes in collagen phenotypes, MMPs, TIMPs, and LOX, in DCM and non-failing human hearts. Moreover, the role of TGFβ in the induction of type III collagen in cardiac fibroblast is determined. Method Protein and RNA expression were quantified by Western and RT-PCR analysis; collagen phenotypes were determined by SDS-PAGE. Results Our data demonstrated that in all DCM hearts, the collagen concentration was significantly elevated compared to that of the NF hearts associated with an increase in Type I (18%) and Type III (33%) collagen. The content of MMP-2 and MMP-9 were increased significantly in all DCM hearts compared to NF hearts. Transcriptional level of LOX, TIMP 1, and 2 were significantly upregulated in DCM hearts. In addition, a significant increase in the transcript levels of cytokines, notably IFN, IL-6, TNF-α, and TGF-β superfamily was observed in all DCM hearts. Addition of TGFβ to cardiac fibroblasts caused a dose dependent increase in type III collagen. Conclusion Altogether, our data suggest an alteration of collagen, MMPs, various cytokines and particularly, LOX participates, in part, in the remodeling of the heart leading to cardiac dysfunction and HF.

P. Sivakumar

Papers

Upregulation of lysyl oxidase and MMPs during cardiac remodeling in human dilated cardiomyopathy