Desmoplasia in pancreatic ductal adenocarcinoma: insight into pathological function and therapeutic potential

Abstract

Extensive desmoplasia is a prominent feature of the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Initially, studies demonstrated that desmoplasia promotes proliferation, invasion and chemoresistance in PDAC cells. While these findings suggested the therapeutic potential of targeting desmoplasia in PDAC, more recent studies utilizing genetically-engineered mouse models of PDAC, which lack key components of desmoplasia, demonstrated accelerated progression of PDAC. This contrast calls into question the paradigm that desmoplasia unilaterally promotes PDAC progression and the premise of desmoplasia-targeted therapy. This review briefly examines the major reports of the tumor-promoting and -restraining roles of desmoplasia in PDAC with commentary on the gaps in our current understanding of desmoplasia in PDAC. Additionally, we discuss the studies demonstrating the heterogeneous and multifaceted nature of desmoplasia in PDAC and advocate for future areas of research to thoroughly address the various facets of desmoplasia in PDAC, reconcile seemingly contradictory reports of the role of desmoplasia in PDAC progression, and discover aspects of desmoplasia that are therapeutically actionable.

Integrated transcriptome meta-analysis of pancreatic ductal adenocarcinoma and matched adjacent pancreatic tissues

“…Further analysis showed that most of the proteins encoded by the identified up/ down-regulated genes are components of the extracellular matrix, which is in line with the fact that PDAC has a characteristically abundant desmoplastic stroma (Cannon et al, 2018). Moreover, the gene ontology analysis revealed that the identified up-regulated genes in PDAC generally encode extracellular matrix (ECM) structural elements together with the proteins with collagen and integrin-binding properties.…”

Force-exerting perpendicular lateral protrusions in fibroblastic cell contraction

“…Strategies to ablate the culprit CAFs have indeed reduced stroma, yet offered no benefit to pancreatic ductal adenocarcinoma (PDAC) patients 55 , or in some cases even dangerously promoted cancer progression 56 , 57 . Thus, there is growing appreciation for “stroma normalization”, i.e.…”

Signaling in the Physiology and Pathophysiology of Pancreatic Stellate Cells – a Brief Review of Recent Advances

“…et al, 2019). The inhibition of stroma-cancer cell interactions is currently attracting a lot of interest as a promising strategy that may sensitize PDAC to therapy and increase the 5-year survival rate of patients suffering from this disease (Cannon et al, 2018).…”