The Extracellular Matrix in Pancreatic Cancer: Description of a Complex Network and Promising Therapeutic Options

Abstract

The stroma is a relevant player in driving and supporting the progression of pancreatic ductal adenocarcinoma (PDAC), and a large body of evidence highlights its role in hindering the efficacy of current therapies. In fact, the dense extracellular matrix (ECM) characterizing this tumor acts as a natural physical barrier, impairing drug penetration. Consequently, all of the approaches combining stroma-targeting and anticancer therapy constitute an appealing option for improving drug penetration. Several strategies have been adopted in order to target the PDAC stroma, such as the depletion of ECM components and the targeting of cancer-associated fibroblasts (CAFs), which are responsible for the increased matrix deposition in cancer. Additionally, the leaky and collapsing blood vessels characterizing the tumor might be normalized, thus restoring blood perfusion and allowing drug penetration. Even though many stroma-targeting strategies have reported disappointing results in clinical trials, the ECM offers a wide range of potential therapeutic targets that are now being investigated. The dense ECM might be bypassed by implementing nanoparticle-based systems or by using mesenchymal stem cells as drug carriers. The present review aims to provide an overview of the principal mechanisms involved in the ECM remodeling and of new promising therapeutic strategies for PDAC.

Oncogenic KRAS-Induced Protein Signature in the Tumor Secretome Identifies Laminin-C2 and Pentraxin-3 as Useful Biomarkers for the Early Diagnosis of Pancreatic Cancer

“…Furthermore, PTX3 binds selected fibroblast growth factors (FGFs), including FGF2 and FGF8b, and inhibits FGF-dependent angiogenic responses [ 76 ]. Interestingly, tissue remodeling and vascular inhibition are two conditions that bear relevance in the strong desmoplastic reaction associated with pancreatic cancer [ 77 ].…”

Pancreatic Cancer and Cellular Senescence: Tumor Microenvironment under the Spotlight

“…This matrix also acts as a physical barrier, contributing to the intra-tumoral hypoxia, compressing blood vessels, and impairing drug delivery to PDAC cells [ 44 ]. Activated PSCs have been shown to be able to remodel the ECM in PDAC, promoting an increase in tissue stiffening and in the crosslinking of collagen fibers [ 45 ]. Moreover, they can also promote the epithelial–mesenchymal transition (EMT) of tumor cells, which fosters tumor invasion and metastasization.…”

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

“…The fraction of carcinoma cells within the tumor bed is often less than 20% in patients with PDAC [31], which likely hinders biological and molecular investigations of pancreatic cancer pathogenesis. The desmoplastic stroma is comprised of heterogeneous cellular and non-cellular members, such as fibroblasts, immune cells, blood vessels, lymphatic vessels, and extracellular matrix (ECM) proteins [32]. Numerous previous studies have revealed that these stromal elements can regulate the tumor molecular mechanisms underlying various cellular functions, including proliferation, survival, senescence, apoptosis, cell motility, invasion, and metastasis [32][33][34][35][36][37].…”

“…The desmoplastic stroma is comprised of heterogeneous cellular and non-cellular members, such as fibroblasts, immune cells, blood vessels, lymphatic vessels, and extracellular matrix (ECM) proteins [32]. Numerous previous studies have revealed that these stromal elements can regulate the tumor molecular mechanisms underlying various cellular functions, including proliferation, survival, senescence, apoptosis, cell motility, invasion, and metastasis [32][33][34][35][36][37]. Furthermore, emerging evidence derived from single-cell transcriptome analyses has underscored the importance of fibroblastic subpopulations with different functional and phenotypic characteristics [38,39].…”