Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer.

Pancreatic ductal adenocarcinomas (PDAs) are notoriously aggressive and resistant to treatment. They distinguish themselves further by their robust fibroinflammatory, or desmoplastic, stromal reaction and degree of hypovascularity. Recent findings have revealed multiple mechanisms of stromal complicity in disease pathogenesis and resistance. In this review, we focus on altered physicomechanics as one mechanism of what we term as 'stromal resistance' in PDA. Extremely high interstitial fluid pressures and a dense extracellular matrix combine to limit the delivery and distribution of therapeutic agents. We discuss the genesis and consequences of altered fluid dynamics in PDA and strategies to restore them.

Application of nonlinear viscoelastic models to describe ligament behavior.

Recent experiments in rat medial collateral ligament revealed that the rate of stress relaxation is strain dependent and the rate of creep is stress dependent. This nonlinear behavior requires a more general description than the separable quasilinear viscoelasticity theory commonly used in tissue biomechanics. The purpose of this study was to determine whether the nonlinear theory of Schapery or the modified superposition method could adequately model the strain-dependent stress-relaxation behavior of ligaments. It is shown herein that both theories describe available nonlinear experimental ligament data well and hence can account for both elastic and viscous nonlinearities. However, modified superposition allows for a more direct interpretation of the relationship between model parameters and physical behavior, such as elastic and viscous nonlinearities, than does Schapery's theory. Hence, the modified superposition model is suggested to describe ligament data demonstrating both elastic nonlinearity and strain-dependent relaxation rate behavior. The behavior of the modified superposition model under a sinusoidal strain history is also examined. The model predicts that both elastic and viscous behaviors are dependent on strain amplitude and frequency.

Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK-ERK linkage.

Mammographically dense breast tissue is one of the greatest risk factors for developing breast carcinoma, yet the associated molecular mechanisms remain largely unknown. Importantly, regions of high breast density are associated with increased stromal collagen and epithelial cell content. We set out to determine whether increased collagen-matrix density, in the absence of stromal cells, was sufficient to promote proliferation and invasion characteristic of a malignant phenotype in non-transformed mammary epithelial cells. We demonstrate that increased collagen-matrix density increases matrix stiffness to promote an invasive phenotype. High matrix stiffness resulted in increased formation of activated three-dimensional (3D)-matrix adhesions and a chronically elevated outside-in/inside-out focal adhesion (FA) kinase (FAK)-Rho signaling loop, which was necessary to generate and maintain the invasive phenotype. Moreover, this signaling network resulted in hyperactivation of the Ras-mitogen-activated protein kinase (MAPK) pathway, which promoted growth of mammary epithelial cells in vitro and in vivo and activated a clinically relevant proliferation signature that predicts patient outcome. Hence, the current data provide compelling evidence for the importance of the mechanical features of the microenvironment, and suggest that mechanotransduction in these cells occurs through a FAK-Rho-ERK signaling network with extracellular signal-regulated kinase (ERK) as a bottleneck through which much of the response to mechanical stimuli is regulated. As such, we propose that increased matrix stiffness explains part of the mechanism behind increased epithelial proliferation and cancer risk in human patients with high breast tissue density.

Microstructural morphology in the transition region between scar and intact residual segments of a healing rat medial collateral ligament.

This study used a rat model to investigate the microstructural organization of collagen through the transition from scar to intact residual segments of a healing medial collateral ligament (MCL). Twenty-two male retired breeder Sprague-Dawley rats were randomly separated into two groups. Eleven underwent surgical transections of both MCLs and were allowed unrestricted cage activity until euthanized two weeks post surgery. The remaining eleven rats were used as normal controls. All 44 MCLs were harvested including intact femoral and tibial insertions and prepared for scanning electron microscopy (SEM) imaging. At harvest the scar region in the healing ligaments was more translucent than the normal tissue. Ligaments were viewed from femoral to tibial insertions at magnifications of 100X through 20,000X. Tissue away from the scar region in the transected MCLs was indistinguishable from normal tissue in uninjured ligaments. Collagen fibers and fibrils in these tissues were more aligned along the longitudinal axis of the ligament than in the scar tissue. Continuity of collagen fibers and fibrils were consistently observed from the residual portions of the transected ligament through the scar region. Bifurcations/fusions, but no anastomoses, in fibers and fibrils were observed in both normal and scar tissues of ligaments. Qualitatively, bifurcations were encountered more frequently in scar tissue. In the transition region, larger diameter fibers from the residual tissue bifurcated into smaller diameter fibrils in the scar. This connection between larger diameter and smaller diameter fibers and fibrils indicates that bifurcations/fusions are likely to be the dominant way in which force is transmitted from a region with larger fibrils (residual ligament) into and through a region with smaller fibrils (scar).