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.
Highlights
By 2030, pancreatic ductal adenocarcinoma (PDAC) will be the second leading cause of cancer-associated deaths in the United States, yet patients continue to face a dismal prognosis owing to early local and distant spread of tumor [1,2,3]
This review aims to summarize current evidence for the role of the extracellular matrix (ECM) in PDAC and to highlight potentially targetable pathways
One of the mechanisms by which collagens contribute to PDAC biology is by functioning as signaling molecules, or ligands, for integrin receptors on the surface of PDAC cells [52]
Summary
By 2030, pancreatic ductal adenocarcinoma (PDAC) will be the second leading cause of cancer-associated deaths in the United States, yet patients continue to face a dismal prognosis owing to early local and distant spread of tumor [1,2,3]. In addition to directly affecting the biology of PDAC cells, both the mere amount of ECM and water retention by ECM glycoproteins result in high interstitial fluid pressure, thereby impairing tumor perfusion and delivery of antitumor drugs [9,10] This effect is further aggravated by reduced tumor vessel density, making cytotoxic therapy of PDAC extraordinarily challenging [9]. Once PSCs become activated, the equilibrium shifts, causing the accumulation of large amounts of ECM proteins [11,13] This transition from quiescent to activated PSC is accompanied by significant morphological changes in the cytosol and cell shape. By analyzing ongoing clinical trials of ECM-targeted therapy, future clinical therapeutic options are discussed
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