Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma: An Update on Heterogeneity and Therapeutic Targeting

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related morbidity and mortality in the western world, with limited therapeutic strategies and dismal long-term survival. Cancer-associated fibroblasts (CAFs) are key components of the pancreatic tumor microenvironment, maintaining the extracellular matrix, while also being involved in intricate crosstalk with cancer cells and infiltrating immunocytes. Therefore, they are potential targets for developing therapeutic strategies against PDAC. However, recent studies have demonstrated significant heterogeneity in CAFs with respect to their origins, spatial distribution, and functional phenotypes within the PDAC tumor microenvironment. Therefore, it is imperative to understand and delineate this heterogeneity prior to targeting CAFs for PDAC therapy.

The Desmoplastic Stroma of Pancreatic Cancer: Multilayered Levels of Heterogeneity, Clinical Significance, and Therapeutic Opportunities

“…PSCs have long been considered a principal source of CAFs in PDACs. However, previous studies in various tumor types have indicated multiple cell origins for CAFs, including resident fibroblasts, bone marrow-derived mesenchymal stem cells, adiposederived stem cells, mesothelial cells, endothelial cells, and epithelial cells [90,[100][101][102][103][104]. A recent study has suggested a pro-tumorigenic contribution of PSC-derived CAFs, although PSC-derived CAFs are a minor subset of the total CAFs present in PDAC tissues [105].…”

Editorial: Mechanisms of Inflammation and Fibrosis Interplays in the Digestive Diseases

“…Therefore, there existed discrepancies between the results obtained using cultured PSCs and those obtained by Hedgehog inhibitors or targeting α -SMA in genetically engineered mouse models. It is also noteworthy that the several clinical trials assessing the effectiveness of PSC-targeting therapies failed to show effectiveness ( Vaish et al, 2021 ). The clinical trial evaluating efficacy of IPI-926 with gemcitabine has been halted due to unexpected shortening of survival in patients with advanced pancreatic cancer, who received combination therapy.…”

Multimodal Therapies against Pancreatic Ductal Adenocarcinoma: A Review on Synergistic Approaches toward Ultimate Nanomedicine Treatments

“…[571,576] These studies had the double effect of improving PDAC therapy by enhancing drug delivery into the tumor site while elucidating the complex and dual role of CAFs in desmoplasia. [577] They involved, among many other mechanisms, [503] the use of polymeric micelle-based nanoformulations to inhibit SHH pathway, [576] nab-paclitaxel to target SPARC glycoprotein, [578] miRNA inhibitors to reprogram CAFs, [579] and anti-microRNA as part of peptide-based nanocomplexes aimed at inhibiting PSC differentiation into CAFs. [580] PSCs, as stated above, are the main responsible for the increased ECM production which ultimately provokes reduced intratumoral perfusion and nanotherapeutic delivery.…”