Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases to affect humans, regardless of whether patients receive multimodal therapy (including surgery, radiotherapy, and chemotherapy). This resistance to intervention is currently considered to be caused by the desmoplastic change of the extracellular matrix (ECM) in PDAC tissues, which is characterized by the accumulation of cancer-associated fibroblasts, collagen, proteoglycan, and hyaluronan. Among these ECM components, hyaluronan has attracted interest because various studies have indicated that hyaluronan-rich PDAC is correlated with the progressive properties of cancer cells, both in experimental and clinical settings. Hence, the reduction of hyaluronan in cancer tissue may represent a novel therapeutic approach for PDAC. 4-methylumbelliferone (4-MU) is a derivative of coumarin that was reported to suppress the synthesis of hyaluronan in cultured human skin fibroblasts in 1995. As an additional study, our group firstly reported that 4-MU reduced the hyaluronan synthesis of mouse melanoma cells and exerted anti-cancer activity. Subsequently, we have showed that 4-MU inhibited liver metastasis in mice inoculated with human pancreatic cancer cells. Thereafter, 4-MU has been accepted as an effective agent for hyaluronan research and is expected to have clinical applications. This review provides an overview of the interaction between PDAC and hyaluronan, the properties of 4-MU as a suppressor of the synthesis of hyaluronan, and the perspectives of PDAC treatment targeting hyaluronan.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer-related deaths in the US
The administration of intensive chemotherapy can prolong the survival time by 2–6 months [4,5,6,7]. These difficulties in PDAC treatment are partly due to the desmoplastic change of the extracellular matrix (ECM), which is characterized by the accumulation of cancer-associated fibroblasts (CAF) and increased fibrous ECM components, including collagen, proteoglycans, and hyaluronan [8]
PDAC patients who were treated with PEGPH20 had several adverse events, 5
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer-related deaths in the US. The administration of intensive chemotherapy can prolong the survival time by 2–6 months [4,5,6,7] These difficulties in PDAC treatment are partly due to the desmoplastic change of the extracellular matrix (ECM), which is characterized by the accumulation of cancer-associated fibroblasts (CAF) and increased fibrous ECM components, including collagen, proteoglycans, and hyaluronan [8]. This remodeling of the microenvironment surrounding the cancer cells contributes to the elevation of the internal pressure in the cancerous tissue [9]. The control of hyaluronan is a considered to be a promising approach in efforts to treat this irremediable disease
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