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.
Highlights
With a 5-year survival of 10%, pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer deaths in the United States and is projected to become the second leading cause of cancer deaths in the United States by 2030 [1, 2]
extracellular matrix (ECM) collagens interact with signaling integrins expressed on the surface of Pancreatic ductal adenocarcinoma (PDAC) cells
The ECM plays an important role in PDAC tumor growth, metastasis, and therapy resistance
Summary
With a 5-year survival of 10%, pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer deaths in the United States and is projected to become the second leading cause of cancer deaths in the United States by 2030 [1, 2]. ECM collagens interact with signaling integrins expressed on the surface of PDAC cells. Integrins mediate the interactions between TME cell-types and ECM proteins like proteoglycans and glycoproteins. Secreted protein acidic and rich in cysteine (SPARC) is another major glycoprotein in the PDAC stroma that modulates ECM organization by directly binding to collagens I, III, IV, and V [88, 89]. In the presence of tumor cells, PSCs assume an “activated” state in which they excessively deposit ECM proteins; become elongated in shape; and demonstrate increased expression of aSMA, collagens, immune-modulating, and other tumor-promoting genes [96]. The additional cross-linked collagen and stiff ECM, prompted by TG2 and/or LOX, activates yesassociated protein (YAP) and the transcriptional coactivator with a PDZ-binding motif (TAZ) that enhances cell proliferation [105]. I/II Active, not recruiting III Terminated (sponsor decision) II Completed II Completed I/II Completed
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