This effect is mediated by up-regulation of specific genes related to a myo/contractile phenotype. After transdifferentiation, PF-6463922 research buy PTFs expressed α-smooth muscle actin (α-SMA) and enhanced proliferation, migration, and invasion of HCC cells occur. A pan-LPA inhibitor (α-bromomethylene phosphonate [BrP]-LPA), or autotaxin gene silencing, inhibited this PTF transdifferentiation and the consequent enhanced proliferation, migration, and invasion of HCC cells. In vivo, PTFs coinjected with HCC cells underwent transdifferentiation and promoted tumor progression. Treatment with BrP-LPA blocked transdifferentiation of PTFs, down-regulated

myofibroblast-related genes, and slowed HCC growth and progression. Patients with larger and metastatic HCC and shorter survival displayed higher serum levels of LPA. Analysis of microdissected tissues indicated that stroma is the main target of the LPA paracrine loop in HCC. As a consequence, α-SMA–positive cells were more widespread in tumoral compared with paired peritumoral stroma. Conclusion:

Our data indicate that LPA accelerates HCC progression by recruiting PTFs and promoting their transdifferentiation into myofibroblasts. Inhibition of LPA could prove effective in blocking transdifferentiation of myofibroblasts and tumor progression. (HEPATOLOGY 2011;) In Western Rapamycin countries, hepatocellular carcinoma (HCC) develops in patients with liver cirrhosis and is the final stage of a disease that can last Tau-protein kinase for many years.1, 2 It is generally accepted that HCC originates from hepatocytes but grows and advances while fully embedded in a surrounding microenvironment with a rich content of myofibroblasts, fibroblasts, and other cell

types due to the underlying cirrhosis. Liver myofibroblasts, derived from quiescent fibroblasts and hepatic stellate cells activated by the chronic injury, can be recognized by their expression of α-smooth muscle actin (α-SMA).3, 4 Myofibroblasts have been detected at the advancing edge of several different malignancies as the predominant phenotype in the cancer-associated fibroblast (CAF) population.5 Although the origin of CAFs is still controversial, their immunophenotypical characterization, which primarily includes α-SMA and excludes epithelial and endothelial common markers, is widely accepted.3, 6, 7 CAFs differ from peritumoral tissue fibroblasts (PTFs) not in terms of somatic mutations but rather molecular and functional differences in modulating neighboring cancer cells.8, 9 However, the paracrine cross-talk between HCC and stromal fibroblasts such as CAFs or PTFs is still poorly understood. HCC is recognized as a highly heterogeneous tumor because of its complex multistep pathogenesis, which is further complicated by the preexisting liver cirrhosis. For this reason, the identification of a proper biological target is essential in order to design suitable molecular-oriented therapy.