Fibroblasts in Pancreatic Ductal Adenocarcinoma: Biological Mechanisms and Therapeutic Targets

The desmoplastic reaction of pancreas cancer may begin as a wound healing response to the nascent neoplasm, but it soon creates an insidious shelter that can sustain the growing tumor and rebuff therapy. Among the many cell types subverted by transformed epithelial cells, fibroblasts are recruited and activated to lay a foundation of extracellular matrix proteins and glycosaminoglycans that alter tumor biophysics and signaling. Their near-universal presence in pancreas cancer and ostensible support of disease progression make fibroblasts attractive therapeutic targets. More recently, however, it has also become apparent that diverse subpopulations of fibroblasts with distinct phenotypes and secretomes inhabit the stroma, and that targeted depletion of particular fibroblast subsets could either provide substantial therapeutic benefit or accelerate disease progression. An improved characterization of these fibroblast subtypes, along with their potential relationships to tumor subtypes and mutational repertoires, is needed in order to make anti-fibroblast therapies clinically viable.