The Development of a Novel Therapeutic Strategy to Target Hyaluronan in the Extracellular Matrix of Pancreatic Ductal Adenocarcinoma

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.

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

“…A positive effect of 4-MU treatment was also reported on the sensitivity of fibrosarcoma cells to radiotherapy (Saga et al, 2017). Under the trade name Hychromone, 4-MU is already marketed in Asia and Europe as a choleretic agent (reviewed in Kudo et al, 2017). As clinical experience with this drug already exists, application in a different cancer treatment setting could be probably enhanced.…”

Effects of oxymatrine on the adhesion of human hepatoma cell line QGY-7703 and the expression of integrin β1

“…Liver cancer metastasis is an extremely complex "multi-step" process, liver cancer cells leave the primary tumor and invaded into blood vessels and lymphatic vessels through the extracellular matrix (extracellular matrix, ECM), then the metastases was formed [16]. In this process, the combination of hepatoma cells and ECM is the initial step of invasive growth and distant metastasis of hepatocarcinoma cells [17]. A recent study showed that OM inhibits hepatocyte apoptosis by suppressing the TLR4/PI3K/Akt/GSK-3β signalling pathway [18].…”

Remodeling the Tumor Microenvironment Sensitizes Breast Tumors to Anti-Programmed Death-Ligand 1 Immunotherapy

“…Accumulation of HA in the TME has previously been shown to increase tumor interstitial pressure, inducing vascular collapse, which was associated with a decreased exposure of tumor cells to chemotherapy. Conversely, removal of HA in the TME can reverse these physiologic characteristics and, ultimately, improve accessibility of the tumor cells to chemotherapy in various mouse models of pancreatic ductal adenocarcinoma (15,(26)(27)(28)(29). Furthermore, it was shown that depletion of HA can lead to an increased accumulation of CD8 þ T cells in tumors of a mouse model of ovarian cancer (30).…”