The Extracellular Matrix and Pancreatic Cancer: A Complex Relationship

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has an extraordinarily dense fibrotic stroma that impedes tumor perfusion and delivery of anticancer drugs. Since the extracellular matrix (ECM) comprises the bulk of the stroma, it is primarily responsible for the increased interstitial tissue pressure and stiff mechanical properties of the stroma. Besides its mechanical influence, the ECM provides important biochemical and physical cues that promote survival, proliferation, and metastasis. By serving as a nutritional source, the ECM also enables PDAC cells to survive under the nutrient-poor conditions. While therapeutic strategies using stroma-depleting drugs have yielded disappointing results, an increasing body of research indicates the ECM may offer a variety of potential therapeutic targets. As preclinical studies of ECM-targeted drugs have shown promising effects, a number of clinical trials are currently investigating agents with the potential to advance the future treatment of PDAC. Thus, the present review seeks to give an overview of the complex relationship between the ECM and PDAC.

Keywords: collagen; hyaluronan; matrisome; tissue stiffness.

Figure 1

Interactions between extracellular matrix, cancer cells, and pancreatic stellate cells. Forming a dense meshwork of collagen fibers around pancreatic ductal adenocarcinoma (PDAC) cells, the extracellular matrix (ECM) impairs tumor perfusion and penetration by anticancer drugs. On top of these mechanical effects, collagen fibers bind to cell surface receptors, activating intracellular signaling pathways that induce protumorigenic programs. Here, both the biochemical and biomechanical effects of the ECM may be amplified by collagen cross-linking and hyaluronic acid (HA). In addition to interacting with the ECM itself, PDAC cells also communicate with pancreatic stellate cells (PSCs), which steer the turnover of the ECM. DDR1, dimeric discoidin receptor 1; ECM, extracellular matrix; FAK, focal adhesion kinase; HA, hyaluronic acid; LOX, lysil oxidase; MMP, matrix metalloproteinase; PSC, pancreatic stellate cells; Pyk2, FAK-related protein tyrosine kinase; TG2, tissue transglutaminase 2; TIMP, tissue inhibitor of matrix metalloproteinases.