Expression of versican isoforms V0/V1 by pancreatic cancer associated fibroblasts increases fibroblast proliferation

Abstract

BackgroundVersican is a large extracellular matrix (ECM) proteoglycan with four isoforms V0-3. Elevated V0/V1 levels in breast cancer and glioma regulate cell migration and proliferation, but the role of versican in pancreatic ductal adenocarcinoma (PDAC) remains unclear. MethodsIn this study, we evaluated the expression levels of versican isoforms, as well as their cellular source and interacting partners, in vivo, in human and mouse primary and metastatic PDAC tumours and in vitro, in pancreatic tumour cells and fibroblasts using immunostaining, confocal microscopy and qPCR techniques. We also investigated the effect of versican expression on fibroblast proliferation and migration using genetic and pharmacological approaches. ResultsWe found that versican V0/V1 is highly expressed by cancer-associated fibroblasts (CAFs) in mouse and human primary and metastatic PDAC tumours. Our data also show that exposing fibroblasts to tumour-conditioned media upregulates V0 and V1 expressions, while Verbascoside (a CD44 inhibitor) downregulates V0/V1 expression. Importantly, V0/V1 knockdown significantly inhibits fibroblast proliferation. Mechanistically, we found that inhibiting hyaluronan synthesis does not affect versican co-localisation with CD44 in fibroblasts. ConclusionCAFs express high levels of versican V0/V1 in primary and liver metastatic PDAC tumours and versican V0/V1 supports fibroblast proliferation.