RÉSUMÉ
Aberrant angiogenesis is a hallmark of cancer and is critically associated with tumor progression. Perivascular cells are essential components of blood vessels, and the role of tumor perivascular cell-derived extracellular vesicles (TPC-EVs) in angiogenesis remains elusive. In the present study, using genetic mouse models and pharmacological inhibitors, we found that ablation of perivascular cells inhibited angiogenesis in allografted colorectal cancer tumors. Further studies demonstrated that TPC-EVs promoted the proliferation, migration, invasion, viability, and tube formation of HUVECs. They also facilitated vessel spouting in rat aortic rings and induced neovascularization in chick chorioallantoic membranes (CAMs). Silencing of Gas6 or blockade of the Axl pathway suppressed TPC-EV-induced angiogenesis in vitro and ex vivo. Moreover, inhibition of the Gas6/Axl signaling pathway impaired TPC-EV-mediated angiogenesis in vivo. Our findings present a deeper insight into the biological functions of TPCs and TPC-EVs in tumor angiogenesis and demonstrate that TPC-EV-derived Gas6 could be an attractive and innovative regulator of tumor angiogenesis.
Sujet(s)
Tumeurs colorectales/génétique , Vésicules extracellulaires/génétique , Protéines et peptides de signalisation intercellulaire/génétique , Néovascularisation pathologique/génétique , Protéines proto-oncogènes/génétique , Récepteurs à activité tyrosine kinase/génétique , Animaux , Aorte/croissance et développement , Aorte/anatomopathologie , Mouvement cellulaire/génétique , Prolifération cellulaire/génétique , Survie cellulaire/génétique , Poulets , Chorioallantoïde/enzymologie , Chorioallantoïde/anatomopathologie , Tumeurs colorectales/anatomopathologie , Régulation de l'expression des gènes tumoraux/génétique , Cellules endothéliales de la veine ombilicale humaine , Humains , Souris , Invasion tumorale/génétique , Invasion tumorale/anatomopathologie , Néovascularisation pathologique/anatomopathologie , Tumeurs des cellules épithélioïdes périvasculaires/génétique , Tumeurs des cellules épithélioïdes périvasculaires/anatomopathologie , Rats , Axl Receptor Tyrosine KinaseRÉSUMÉ
Four new isocoumarins (1-4), along with three known ones (5-7), were isolated from the 70% ethanol extract of the whole body of the traditional Chinese insect medicine, American cockroach (Periplaneta americana). The structures with absolute configurations of new compounds were elucidated by extensive spectroscopic methods in combination with X-ray diffraction experiment and CD analyses. Compounds 3-5 showed significant cytotoxic activities in HepG2 and MCF-7 cells with IC50 values in the ranges 6.41-23.91 µM and 6.67-39.07 µM, respectively.