Elevated serum heparanase‐1 levels in patients with pancreatic carcinoma are associated with poor survival

Abstract

BACKGROUND It has previously been shown that heparanase‐1 (HPR1), an endoglycosidase, is up‐regulated in pancreatic carcinoma. The purpose of this study was to test whether serum HPR1 levels in pancreatic carcinoma patients are elevated, and whether higher serum HPR1 levels are associated with a shortened survival. METHODS Serum HPR1 levels in 40 healthy donors, 31 pancreatic carcinoma patients, and 11 patients treated with gemcitabine were measured by a novel enzyme‐linked immunoadsorbent assay. HPR1 expression in tumors was analyzed by immunohistochemical staining. Patient overall survival time was determined according to the Kaplan–Meier method, and their difference was evaluated by the log‐rank test. A P value < 0.05 was considered statistically significant. RESULTS The mean serum HPR1 activity in pancreatic carcinoma patients was 439 ± 14 units/mL, compared with 190 ± 4 units/mL in the control serum samples from healthy donors. Serum HPR1 levels were significantly higher in patients with HPR1‐positive tumors (660 ± 62 units/mL) compared with those with HPR1‐negative tumors (241 ± 14 units/mL). The mean survival of 19 pancreatic carcinoma patients with serum HPR1 activity > 300 units/mL was 7.9 ± 0.2 months, whereas the mean survival of 12 patients with serum HPR1 activity < 300 units/mL was 13.3 ± 0.6 months. A Kaplan–Meier plot of the patient survival curve followed by log‐rank test revealed that patients in the high serum HPR1 group had a significantly shorter survival compared with those in the low serum HPR1 group. Mean serum HPR1 activity decreased by 64% in 11 pancreatic carcinoma patients after 2 weeks of treatment with gemcitabine. CONCLUSIONS Serum HPR1 activity in pancreatic carcinoma patients was found to be significantly elevated, in particular in those with HPR1‐positive tumors. Increased serum HPR1 activity was associated with a shorter survival in patients with pancreatic carcinoma patients. Cancer 2006. © 2005 American Cancer Society.

A Three-Gene Signature for Outcome in Soft Tissue Sarcoma

“…HB-EGF is able to bind to EGF receptors, the main target of the tyrosine kinase inhibitors (11), with a higher affinity than EGF itself and has recently been discussed as a potential molecular target (12,13). Heparanase (HPSE) functions as an endoglycosidase that cleaves heparan sulfate chains of proteoglycans (14,15). Enclosed in the heparan sulfate glycosaminoglycans are growth factors and angiogenic factors, like basic fibroblast growth factor (bFGF) and HB-EGF that are released upon degradation with HPSE (16).…”

Reactive oxygen species mediate high glucose-induced heparanase-1 production and heparan sulphate proteoglycan degradation in human and rat endothelial cells: a potential role in the pathogenesis of atherosclerosis

“…HPR1 activity assay Endothelial cells grown for 48 h in the media containing 5 or 30 mmol/l glucose were collected and analysed for HPR1 activity in cell lysates according to a novel ELISA protocol established in this laboratory [18,22,24,25].…”

“…Immunohistochemistry analysis of HPR1 content The sections of paraffin-embedded arteries were analysed for HPR1 content by immunohistochemistry staining with a monoclonal antibody (ImClone) against HPR1 as previously described [25,29,34], except that antigen retrieval was conducted by microwave-heating the slides in 6 mol/l urea for 30 min. At least three sections of aortic artery from normal or diabetic rats were stained and graded.…”

PG545, an Angiogenesis and Heparanase Inhibitor, Reduces Primary Tumor Growth and Metastasis in Experimental Pancreatic Cancer

“…This occurs through the regulation of several heparin-bound growth factors such as VEGF, fibroblast growth factor (FGF)-1, FGF-2, EGF, and hepatocyte growth factor (HGF), all of which are known to promote carcinogenesis (16,17). Heparanase is known to participate in the progression of PDAC, and elevated levels of heparanase in patients with PDAC correlate with worse overall survival (18,19). Heparanase expression is elevated in patients with dedifferentiated histology of the primary tumor and correlated with increased incidence of lymph node metastasis suggesting the importance of heparanase in tumor progression (20).…”