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

SIMPLE SUMMARY: This review depicts the principal mechanisms involved in the process of stromal desmoplasia characterizing pancreatic ductal adenocarcinoma (PDAC). The aim of this review is to point out the role of the dense extracellular matrix in worsening PDAC responsiveness to conventional therapies. In this context, a presentation of the most promising therapeutic solutions for targeting or overcoming the matrix is provided. Even though several drug compounds revealed disappointing results in clinics, other matrix factors are now becoming the focus of studies and must be further explored to develop the optimal therapeutic strategy. Bringing novel therapeutics to PDAC patients is challenging but crucial for effectively eradicating the disease and improving patient survival. 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.