[HTML][HTML] P300, a new player in mechanosensitivity and activation of cancer-associated fibroblasts

NJ Torok - Gastroenterology, 2018 - ncbi.nlm.nih.gov
NJ Torok
Gastroenterology, 2018ncbi.nlm.nih.gov
The physical properties of the extracellular environment such as matrix composition and
mechanics are key factors that determine cancer cell behavior. 1, 2 Stiffening matrix is a
result of a complex multidirectional interplay between stromal cells such as cancer-
associated fibroblasts (CAF), infiltrating immune cells, and cancer cells. Fiber realignment
and strain stiffening enable cancer cells to contract and break basement membranes,
withdraw adhesions, and form invadosomes. 3 Cells can “sense” their environment, and …
The physical properties of the extracellular environment such as matrix composition and mechanics are key factors that determine cancer cell behavior. 1, 2 Stiffening matrix is a result of a complex multidirectional interplay between stromal cells such as cancer-associated fibroblasts (CAF), infiltrating immune cells, and cancer cells.
Fiber realignment and strain stiffening enable cancer cells to contract and break basement membranes, withdraw adhesions, and form invadosomes. 3 Cells can “sense” their environment, and respond by complex mechanotransductive pathways. 4 Extracellular physical signals are known to affect integrin subunit assembly and the recruitment of several cellular constituents such as focal adhesion kinase and associated Src, eventually leading to an increasing number and activity of invadosomes. Downstream activation of the RhoA GTPase ultimately controls actin cytoskeletal dynamics and invadopodia formation. Its effector, ROCK, is able to further increase matrix stiffness via a β-catenin–mediated transcriptional program. Matrix cross-linking also has a significant role in rigidity, and it was shown that the combined inhibition of lysyl oxidase 2 (LOXL2) and the transforming growth factor β receptor I had a potent inhibitory effect on collagen accumulation, softening the matrix. 5
ncbi.nlm.nih.gov