Abstract
Background: The aggressiveness of pancreatic ductal adenocarcinoma (PDAC) is enhanced by its interactions with stromal extracellular matrix, notably with hyaluronan (HA). Our previous studies have demonstrated increased expression of genes involved in HA synthesis and degradation in PDAC, suggesting the presence of an autocrine mechanism which accelerates the production of low-molecular-weight HA. Results: A subset of PDAC (20% of cell lines and 25% of tissues) showed overexpression of multiple genes encoding both HA-synthesizing and HA-degrading enzymes, displaying a phenotype defined as an HA activated-metabolism phenotype (HAMP). Interestingly, HAMP+ cells were more susceptible to the treatment with an HA synthesis inhibitor and HA degradation inhibitor than HAMP- cells. Patients with HAMP+ tumors were significantly associated with shorter survival than those with HAMP- tumors (P = 0.049). Methods: We investigated transcriptional profiling of genes involved in HA synthesis (including HAS2 and HAS3) and degradation (including HYAL1 and KIAA1199) in a panel of PDAC cell lines and primary tissues. Response of PDAC cells to treatment with an HA synthesis inhibitor (4-methylumbelliferone) or HA degradation inhibitor (dextran sulfate) was examined by cell migration assay. Survival was determined by Kaplan–Meier curve and compared by log-rank test. Conclusions: The present study identified a novel phenotype, HAMP, characterized by activation of HA metabolism pathways, in PDAC. HAMP should be further investigated as a prognostic marker as well as a target for personalized medicine.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers worldwide, currently ranking the fourth leading cause of cancer death in Western countries and Japan
We investigated transcriptional profiling of genes involved in HA synthesis and degradation in a panel of pancreatic ductal adenocarcinoma (PDAC) cell lines and primary tissues
In an attempt to identify genes related to HA metabolism that are highly expressed in PDAC, we first examined mRNA expression levels of major genes responsible for HA synthesis (HAS1, HAS2 and HAS3) and degradation (HYAL1, HYAL2, and KIAA1199) in a panel of 7 PDAC cell lines
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers worldwide, currently ranking the fourth leading cause of cancer death in Western countries and Japan. Progression of cancer depends largely on tumor microenvironment composed of extracellular matrix (ECM), such as collagen, fibronectin, laminin, and hyaluronan (HA). These ECM components, along with a variety of stromal cells, orchestrate a host stromal response that supports invasive and metastatic processes of cancer cells [3]. We demonstrated that HA is strongly expressed in primary PDAC tissues, with a staining being detected both in tumor and stromal components [5]. The aggressiveness of pancreatic ductal adenocarcinoma (PDAC) is enhanced by its interactions with stromal extracellular matrix, notably with hyaluronan (HA). Our previous studies have demonstrated increased expression of genes involved in HA synthesis and degradation in PDAC, suggesting the presence of an autocrine mechanism which accelerates the production of low-molecular-weight HA
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