Author/Authors :
Samuel، نويسنده , , Michael S. and Lopez، نويسنده , , Jose I. and McGhee، نويسنده , , Ewan J. and Croft، نويسنده , , Daniel R. and Strachan، نويسنده , , David and Timpson، نويسنده , , Paul and Munro، نويسنده , , June and Schrِder، نويسنده , , Ewald and Zhou، نويسنده , , Jing and Brunton، نويسنده , , Valerie G. and Barker، نويسنده , , Nick and Clevers، نويسنده , , Hans and Sansom، نويسنده , , Owen J. and Anderson، نويسنده , , Kurt I. and Weaver، نويسنده , , Valerie M. and Olson، نويسنده , , Michael F.، نويسنده ,
Abstract :
Summary
and associated stroma manifest mechanical properties that promote cancer. Mechanosensation of tissue stiffness activates the Rho/ROCK pathway to increase actomyosin-mediated cellular tension to re-establish force equilibrium. To determine how actomyosin tension affects tissue homeostasis and tumor development, we expressed conditionally active ROCK2 in mouse skin. ROCK activation elevated tissue stiffness via increased collagen. β-catenin, a key element of mechanotranscription pathways, was stabilized by ROCK activation leading to nuclear accumulation, transcriptional activation, and consequent hyperproliferation and skin thickening. Inhibiting actomyosin contractility by blocking LIMK or myosin ATPase attenuated these responses, as did FAK inhibition. Tumor number, growth, and progression were increased by ROCK activation, while ROCK blockade was inhibitory, implicating actomyosin-mediated cellular tension and consequent collagen deposition as significant tumor promoters.
