Breast cancer and metabolic syndrome linked through the plasminogen activator inhibitor-1 cycle

Plasminogen activator inhibitor-1 (PAI-1) is a physiological inhibitor of urokinase (uPA), a serine protease known to promote cell migration and invasion. Intuitively, increased levels of PAI-1 should be beneficial in down-regulating uPA activity, particularly in cancer. By contrast, in vivo, increased levels of PAI-1 are associated with a poor prognosis in breast cancer. This phenomenon is termed the “PAI-1 paradox”. Many factors are responsible for the upregulation of PAI-1 in the tumor micro-environment. We hypothesize that there is a breast cancer predisposition to a more aggressive stage when PAI-1 is upregulated as a consequence of Metabolic Syndrome (MetS). MetS exerts a detrimental effect on the breast tumor microenvironment that supports cancer invasion. People with MetS have an increased risk of coronary heart disease, stroke, peripheral vascular disease and hyper-insulinemia. Recently, MetS has also been identified as a risk factor for breast cancer. We hypothesize the existence of the “PAI-1 cycle”. Sustained by MetS, adipocytokines alter PAI-1 expression to promote angio-genesis, tumor-cell migration and procoagulant micro-particle formation from endothelial cells, which generates thrombin and further propagates PAI-1 synthesis. All of these factors culminate in a chemotherapy-resistant breast tumor microenvironment. The PAI-1 cycle may partly explain the PAI-1 paradox. In this hypothesis paper, we will discuss further how MetS upregulates PAI-1 and how an increased level of PAI-1 can be linked to a poor prognosis

A mathematical model of the dynamics of cytosolic free calcium in cultured vascular endothelial cells responding to shear stress

Ph.D.Robert M. Nere

Termination of Ca2+ release during Ca2+ sparks in rat ventricular myocytes

Confocal Ca2+ imaging was used to measure spontaneous release events (Ca2+ sparks) in fluo-3-loaded isolated rat ventricular myocytes.The microscopic Ca2+ release flux underlying Ca2+ sparks was derived by adapting the methods used previously to describe macroscopic Ca2+ release from cell-averaged Ca2+ transients.The magnitude of the local release fluxes varied from 2 to 5 μm ms−1, depending on SR Ca2+ loading conditions. Following spontaneous activation, the release flux rapidly decayed (τ = 6–12 ms). The rate of termination of release flux was found to be directly related to the magnitude of the flux (r2 = 0.88).The rate of termination of local release flux was slowed in the presence of FK506, a compound that is known to reduce inactivation of SR Ca2+ channels in vitro.These results suggest that termination of release flux during sparks is not due to a spontaneous stochastic decay process or local depletion of Ca2+ from the SR, but rather involves an active extinguishing mechanism such as Ca2+-dependent inactivation or adaptation