Abstract
Simple SummaryThis 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.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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a very dramatic clinical course and is the third largest cause of cancer-related deaths in the US, with a 5-year survival rate of lower than 10% [1]
PDAC stroma is hypovascularized, presenting tortuous, compressed and poorly functional blood vessels. This phenotype is determined by different factors that can be extrinsic to blood vessels or intrinsic to blood vessels [18]
Aside from describing the principal mechanisms and key players involved in the extracellular matrix (ECM) remodeling, we focus our discussion on the existing or future therapeutic strategies to overcome the dense ECM of PDAC
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a very dramatic clinical course and is the third largest cause of cancer-related deaths in the US, with a 5-year survival rate of lower than 10% [1]. Modified (m)FOLFIRINOX was further obtained by removing the 5-fluorouracil bolus from the regimen and became the preferred adjuvant therapy for patients with PDAC who had undergone surgical resection and had not received neoadjuvant chemotherapy [9]. Despite these treatments, the drug resistance of PDAC still leads to extremely poor outcomes. PDAC stroma is hypovascularized, presenting tortuous, compressed and poorly functional blood vessels This phenotype is determined by different factors that can be extrinsic to blood vessels (related to the physical and chemical properties of the ECM) or intrinsic to blood vessels (related to endothelial cell activation and tumor angiogenesis) [18]. Aside from describing the principal mechanisms and key players involved in the ECM remodeling, we focus our discussion on the existing or future therapeutic strategies to overcome the dense ECM of PDAC
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