ATRA modulates mechanical activation of TGF-beta by pancreatic stellate cells

作者：Sarper Muge; Cortes Ernesto; Lieberthal Tyler J; Hernandez Armando del Rio^*

来源：Scientific Reports, 2016, 6(1): 27639.

DOI：10.1038/srep27639

The hallmark of pancreatic ductal adenocarcinoma (PDAC) is abundant desmoplasia, which is orchestrated by pancreatic stellate cells (PSCs) and accounts for the majority of the stroma surrounding the tumour. Healthy PSCs are quiescent, but upon activation during disease progression, they adopt a myofibroblast-contractile phenotype and secrete and concomitantly reorganise the stiff extracellular matrix (ECM). Transforming growth factor beta (TGF-beta) is a potent activator of PSCs, and its activation requires spatiotemporal organisation of cellular and extracellular cues to liberate it from an inactive complex with latent TGF-beta binding protein (LTBP). Here we study the mechanical activation of TGF-beta by PSCs in vitro by investigating LTBP-1 organisation with fibrillar fibronectin and show that all trans-retinoic acid (ATRA), which induces PSC quiescence, down-regulates the ability of PSCs to mechanically organise LTBP-1 and activate TGF-beta through a mechanism involving myosin II dependent contractility. Therefore, ATRA inhibits the ability of PSCs to mechanically release active TGF-beta, which might otherwise act in an autocrine manner to sustain PSCs in an active state and a tumour-favouring stiff microenvironment.

• 出版日期2016-7-4