Fibroblasts in Pancreatic Ductal Adenocarcinoma: Biological Mechanisms and Therapeutic Targets

Abstract

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.

FAK activity in cancer‐associated fibroblasts is a prognostic marker and a druggable key metastatic player in pancreatic cancer

“…Inter‐tumour stromal heterogeneity was reported in PDAC patients and enables patient stratification within prognosis groups (Moffitt et al , 2015; Puleo et al , 2018). Additionally, diverse subpopulations of CAFs were recently reported to co‐exist within a same PDAC tumour, being heterogeneous with regard to cell surface marker expression, cytokine production or cell signalling (Nielsen et al , 2018; Whittle & Hingorani, 2019; Norton et al , 2020). A recent publication identified, using molecular and functional analyses of several patient‐derived CAF primary cultures, four CAF sub‐groups that co‐exist within a tumour, each featuring specific phenotype and prognostic value (Neuzillet et al , 2019).…”

Cancer‐associated fibroblasts that restrain cancer progression: Hypotheses and perspectives

“…The prevailing paradigm that CAF promote cancer progression has led to several attempts to develop novel therapeutics that specifically target CAF, some of which have progressed to clinical evaluation, as summarized and discussed elsewhere . One caveat in targeting CAF, however, is described in three separate studies published approximately 5 years ago: selective genetic depletion of a proliferative α‐SMA + CAF population or pharmacological blockade of Sonic Hedgehog (Shh) signaling, which is essential for desmoplastic reaction in the tumor stroma, resulted in tumor progression in PDAC mouse models .…”

Classification of muscle-invasive bladder cancer based on tumor stromal compartment

“…[34] The e cacy of anti-angiogenic agents has been con rmed in the treatment of various cancers. [35][36][37][38] Anti-broblast therapies were in exploration, [39] it may be a novel promising treatment strategy as broblasts are the most abundant in the tumor stroma cell components.…”