The PDAC Extracellular Matrix: A Review of the ECM Protein Composition, Tumor Cell Interaction, and Therapeutic Strategies

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is notorious for a dense fibrotic stroma that is interlaced with a collagen-based extracellular matrix (ECM) that plays an important role in tumor biology. Traditionally thought to only provide a physical barrier from host responses and systemic chemotherapy, new studies have demonstrated that the ECM maintains biomechanical and biochemical properties of the tumor microenvironment (TME) and restrains tumor growth. Recent studies have shown that the ECM augments tumor stiffness, interstitial fluid pressure, cell-to-cell junctions, and microvascularity using a mix of biomechanical and biochemical signals to influence tumor fate for better or worse. In addition, PDAC tumors have been shown to use ECM-derived peptide fragments as a nutrient source in nutrient-poor conditions. While collagens are the most abundant proteins found in the ECM, several studies have identified growth factors, integrins, glycoproteins, and proteoglycans in the ECM. This review focuses on the dichotomous nature of the PDAC ECM, the types of collagens and other proteins found in the ECM, and therapeutic strategies targeting the PDAC ECM.

On the Evaluation of a Novel Hypoxic 3D Pancreatic Cancer Model as a Tool for Radiotherapy Treatment Screening

“…The expression of collagen-I (i.e., an ECM protein that is abundant in the PDAC tumour microenvironment and secreted by both stroma and cancer cells [ 55 , 62 , 63 ]) was monitored in the 3D scaffolds for all conditions under study. Figure 4 shows the immuno-fluorescence images of scaffold sections along with image quantification of the percentage of collagen-I positive areas for all conditions under study ( Figure 4 ).…”

“…As previously mentioned, we also reported a correlation between increases in HIF-1a levels in our 3D scaffolds and (i) higher collagen-I deposition in hypoxic cultures and (ii) less collagen-I disruption post-radiation treatment in hypoxic cultures. Studies of tumour hypoxia have revealed not only the impact of hypoxia of pancreatic cancer progression and invasion, but the stimulation of fibrosis and angiogenesis including collagen-I expression [ 55 , 62 , 73 , 74 , 75 , 76 ]. As an abundant and important protein of ECM, the expression of collagen-I is also reported to be linked to pancreatic cancer cell survival and progression [ 62 , 73 , 74 ].…”

“…Furthermore, collagen-I gene overexpression in line with lactate dehydrogenase (which aids glycolysis in hypoxic conditions) has been identified in radio-resistant cervical cancer tissue samples [ 79 ]. In recent years, there is a growing understanding of the importance of the ECM as a key player in treatment resistance and success, particularly in the complex pancreatic cancer TME (dense desmoplasia) [ 9 , 10 , 55 , 80 , 81 ]. Generally, the ability to map collagen-I deposition along with the response to in vitro hypoxia and radiation treatment is therefore an important aspect for the accuracy of a PDAC 3D model.…”

“…In our previous work, we surface modified our scaffolds with fibronectin. Fibronectin is one of the most abundant proteins present in the ECM of the pancreatic cancer tumour microenvironment [ 55 ]. Therefore, the scaffolds were surface modified with fibronectin to enhance ECM mimicry and improve cell–cell and cell–matrix interactions.…”

Tumor Microenvironment in Pancreatic Intraepithelial Neoplasia

“…Proteoglycans are involved in altering the ECM during tumor formation through post-translational glycosylation [ 163 ]. In PDAC, the pancreatic TME is known to overproduce hyaluronic acid (HA).…”