Abstract
Hyaluronan (HA) accumulates in pancreatic ductal adenocarcinoma (PDAC), but functional significance of HA in the aggressive phenotype remains unknown. We used different models to investigate the effect of HA on PDAC cell motility by wound healing and transwell migration assay. Changes in cell motility were examined in 8 PDAC cell lines in response to inhibition of HA production by treatment with 4-methylumbelliferone (4-MU) and to promotion by treatment with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or by co-culture with tumor-derived stromal fibroblasts. We also investigated changes in cell motility by adding exogenous HA. Additionally, mRNA expressions of hyaluronan synthases and hyaluronidases were examined using real time RT-PCR. Inhibition of HA by 4-MU significantly decreased the migration, whereas promotion of HA by TPA or co-culture with tumor-derived fibroblasts significantly increased the migration of PDAC cells. The changes in HA production by these treatments tended to be associated with changes in HAS3 mRNA expression. Furthermore, addition of exogenous HA, especially low-molecular-weight HA, significantly increased the migration of PDAC cells. These findings suggest that HA stimulates PDAC cell migration and thus represents an ideal therapeutic target to prevent invasion and metastasis.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of malignant neoplasm, which is currently the 4th leading cause of cancer-related deaths in western countries [1]
Forced production and accumulation of extracellular HA by hyaluronan synthase (HAS) 3 overexpression have been shown to promote growth of PDAC tumor in mice [18]. These findings suggest the importance of HA in the progression of PDAC; only a few studies addressed its effects on the aggressive tumor phenotype, especially cell migration, in PDAC
Treatment with 4-MU significantly inhibited the migration of PDAC cells, whereas treatment with TPA significantly enhanced the migration of PDAC cells, in both wound healing assay (Supplementary Figure S2) and transwell cell migration assay (Figure 2)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of malignant neoplasm, which is currently the 4th leading cause of cancer-related deaths in western countries [1]. The most prominent biological and pathological feature that characterizes pancreatic cancer progression is its early invasion to surrounding structures and metastasis to distant organs so that it often presents clinically at a late stage in the course of the disease and many patients lost the opportunity for curative surgical resection. There are no laboratory markers available to detect early stage PDAC. The complex tumor microenvironment and activated multiple aberrant signaling pathways always lead to chemoresistance of patients with PDAC [2]. It is important to understand the molecular basis that leads to invasion, dissemination, and metastasis of PDAC in order to provide more effective therapy
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