Interstitial flow in and around tumor tissue affects the mechanical microenvironment to modulate tumor cell growth and metastasis. We investigated the roles of flow-induced shear stress in modulating cell cycle distribution in four tumor cell lines and the underlying mechanisms. In all four cell lines, incubation under static conditions for 24 or 48 h led to G0/G1 arrest; in contrast, shear stress (12 dynes/cm 2 ) induced G2/M arrest. The molecular basis of the shear effect was analyzed, and the presentation on molecular mechanism is focused on human MG63 osteosarcoma cells. Shear stress induced increased expressions of cyclin B1 and p21 CIP1 and decreased expressions of cyclins A, D1, and E, cyclin-dependent protein kinases (Cdk)-1, -2, -4, and -6, and p27 KIP1 as well as a decrease in Cdk1 activity. Using specific antibodies and small interfering RNA, we found that the shear-induced G2/M arrest and corresponding changes in G2/M regulatory protein expression and activity were mediated by ␣v3 and 1 integrins through bone morphogenetic protein receptor type IA-specific Smad1 and Smad5. Shear stress also down-regulated runt-related transcription factor 2 (Runx2) binding activity and osteocalcin and alkaline phosphatase expressions in MG63 cells; these responses were mediated by ␣v3 and 1 integrins through Smad5. Our findings provide insights into the mechanism by which shear stress induces G2/M arrest in tumor cells and inhibits cell differentiation and demonstrate the importance of mechanical microenvironment in modulating molecular signaling, gene expression, cell cycle, and functions in tumor cells.M echanical microenvironment plays important roles in modulating tissue development, maintenance, and remodeling and in cellular responses and functions (1). Interstitial fluid flow in and around tissue affects the mechanical microenvironment, including the shear stress and pressure force acting on the cell surface and the tethering force acting on cell-matrix connections (2). These interstitial flow-induced forces can modulate tumor metastasis and invasion as well as anticancer drug delivery (3).Although the influence of interstitial fluid flow on tumor pathobiology and drug delivery has been studied, the effect of the flow-induced shear force on tumor cells has not been much explored. Compressive forces have been shown to inhibit tumor cell growth (4) and up-regulate adhesion molecules (5). A recent study reported that tumor cell proliferation is affected by intratumoral pressure and that activation of mitogen-activated protein kinases and nuclear antigen Ki-67 is involved in this mechanical modulation (6). Although these results show that mechanical forces can modulate tumor cell responses, the detailed mechanisms by which mechanical stimuli are transduced into cellular signaling to regulate tumor cell gene expression and functions remain unclear.Integrins have been implicated as mechanosensors in many types of cells seeded on extracellular matrix (ECM) (7), but their role in modulating mechanical responses of...
A novel system for trace analysis of multiple heavy metals was developed wherein we have integrated a magnetic nano-adsorbent with a lab-on-valve system and coupled this to an inductively coupled plasma mass spectrometer. The magnetic nano-adsorbent was prepared by surface modification of iron-based magnetic nanoparticles with polyacrylic acid (MNPs-PAA). The MNPs-PAA possessing the superparamagnetic nature of MNPs could be controllably immobilized in PTFE tubing by an external magnetic force. The high surface density of PAA (3.30 Â 10 11 molecules cm À2 ) on MNPs-PAA significantly reduced the amounts of adsorbent needed for adsorption of heavy metals (Mn 2+ , Co 2+ , Cu 2+ , Zn 2+ , and Pb 2+ ). A detection limit of 0.04-0.06 mg L À1 (except 0.6 mg L À1 for Cu 2+ and Zn 2+ ), a precision smaller than 4% (RSD, n ¼ 3), and a linear range of 0.5-50 mg L À1 were obtained by directly injecting an aliquot of 20 mL fortified standard solution analyzed at 5 min per sample. The accuracy was evaluated by analyzing certified reference materials of SRM 2670a (trace elements in urine, low level) and CASS-2 (nearshore seawater reference material for trace metals). Good agreement between the measured and certified values demonstrated that the system is useful for trace analysis of multiple heavy metals in environmental and biological aqueous samples. The potential of integrating functionalized nano-materials to improve the performance of existing analytical systems as an alternative approach to green analytical chemistry is foreseen.
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