Prognostic Impact of Hyaluronan and Its Regulators in Pancreatic Ductal Adenocarcinoma

Abstract

BackgroundAlthough pancreatic ductal adenocarcinoma is characterized by an abundant stroma enriched with hyaluronan (HA), the prognostic impact of HA and its regulators remains unknown.MethodsUsing immunohistochemistry, expression patterns of HA and its regulators, including a synthesizing enzyme (HAS2), and a degrading enzyme (HYAL1) were investigated in patients who received surgical resection. The prognostic significance of these markers and other clinicopathological variables was determined using univariate and multivariate analyses. The HA levels were determined quantitatively by enzyme-linked immunosorbent assay (ELISA).ResultsWe found that strong expressions of HA (P=0.008) and HAS2 (P=0.022) were significantly associated with shorter survival time after surgery. By contrast, weak expression of HYAL1 was significantly associated with poor survival (P=0.001). In multivariate analysis, tumor stage (hazard ratio (HR)=2.76, 95% confidence interval (CI): 1.14-6.66 P=0.024), strong HA expression (HR=6.04, 95%CI: 1.42-25.69 P=0.015), and weak HYAL1 expression (HR=3.16, 95%CI: 1.19-8.40 P=0.021) were independent factors predicting poor survival. ELISA revealed higher concentration of HA in pancreatic cancer tissues than in normal pancreatic tissues (P=0.001).ConclusionThese findings suggest, for the first time, that HA and its regulators may have prognostic impact in patients with pancreatic cancer.

Is hyaluronan deposition in the stroma of pancreatic ductal adenocarcinoma of prognostic significance?

“…The fact that HA expression was seen in large tumours more often than in small tumours is consistent with the aforementioned observations as the synthesis of large amounts of ECM is obviously mandatory during tumour progression in PDAC [3,21,22]. The results of our present study are contrast with those of a recent study published by Cheng and colleagues who were able to show a strong correlation between HA expression and patients' overall survival although larger tumours were correlated with higher HA expression in our series [6]. However, different methodologies were used in our study.…”

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

“…Several studies have reported that the excessive accumulation of hyaluronan in cancer tissues is associated with the worse prognosis after surgery in breast [20], gastric [21], and colorectal [22] cancer. In the case of pancreatic adenocarcinoma, the quantitative analysis of the hyaluronan content in resected cancerous tissue revealed that the level was 4–12 times that in normal pancreatic tissues [23,24,25]. This also has a clinical impact on the poor overall survival rate after surgery.…”

175 The Ets-Transcription Factor Etv1 Regulates Stromal Expansion and Metastasis in Pancreatic Cancer

“…41 Indeed, Has2 has been associated with poorer survival in human PDAC. 42 We found Etv1 overexpression was associated with Has2 increase by 4 fold ( Figure 5A). In silico screening demonstrated 3 putative Ets binding sites in the Has2 promoter ( Figure 5B).…”

“…10 High amounts of HA and expression of Has2 in PDAC have been associated with shorter survival after resection, but the molecular mechanisms that lead to increased expression of HA in PDAC have not been elucidated. 42 It has been demonstrated that abundance of HA and other ECM components results in increased interstitial fluid pressure within the tumor that leads to compression of intratumoral blood vessels and represents a barrier to perfusion, diffusion, and convection of chemotherapeutic agents as well as small molecule therapeutics. 10 We have identified Etv1 as a transcriptional activator of Has2 expression, resulting in remarkably increased HA deposition within the PDAC stroma that in turn leads to larger tumors and is accompanied by a more metastatic phenotype.…”