title: Function of heparanase in prostate tumorigenesis: potential for therapy.
abstract: OBJECTIVE
  Heparanase is the predominant enzyme that cleaves heparan sulfate, the main polysaccharide in the extracellular matrix. Whereas the role of heparanase in sustaining the pathology of human cancer is well documented, its association with prostate carcinoma remains uncertain. Our research was undertaken to elucidate the significance of heparanase in prostate tumorigenesis and bone metastasis.
  
  
  METHODS
  We applied immunohistochemical analysis of tissue microarray, in vitro adhesion and invasion assays, as well as mouse models of intraosseous growth and spontaneous metastasis of prostate cancer, monitored by whole-body bioluminescent imaging. Electroporation-assisted administration of anti-heparanase small interfering RNA in vivo was applied as a therapeutic approach.
  
  
  RESULTS
  We report a highly statistically significant (P < 0.0001) prevalence of heparanase overexpression in prostate carcinomas versus noncancerous tissue, as well as strong correlation between tumor grade and the extent of heparanase expression. We observed >5-fold increase in the metastatic potential of PC-3 prostate carcinoma cells engineered to overexpress heparanase. Notably, overexpression of a secreted form of the enzyme also led to a dramatic increase in intraosseous prostate tumor growth. Local in vivo silencing of heparanase resulted in a 4-fold inhibition of prostate tumor growth, representing the first successful application of anticancer therapy based on heparanase small interfering RNA and validating the potential of heparanase as a target for prostate cancer treatment.
  
  
  CONCLUSIONS
  Heparanase directly contributes to prostate tumor growth in bone and its ability to metastasize to distant organs. Thus, anti-heparanase strategy may become an important modality in the treatment of prostate cancer patients, particularly those with bone metastases.
authors.affiliation: Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Immanuel
authors.initials: I
authors.lastname: Lerner
authors.forename: Leah
authors.initials: L
authors.lastname: Baraz
authors.forename: Eli
authors.initials: E
authors.lastname: Pikarsky
authors.forename: Amichay
authors.initials: A
authors.lastname: Meirovitz
authors.forename: Evgeny
authors.initials: E
authors.lastname: Edovitsky
authors.forename: Tamar
authors.initials: T
authors.lastname: Peretz
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.forename: Michael
authors.initials: M
authors.lastname: Elkin
mesh_terms: D001706:Biopsy; D001859:Bone Neoplasms / Q000201:enzymology / Q000473:pathology / Q000556:secondary; D002448:Cell Adhesion; D002455:Cell Division; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D003094:Collagen; D004338:Drug Combinations; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007797:Laminin; D008297:Male; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D011467:Prostate / Q000201:enzymology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D011509:Proteoglycans; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D000099175:Heparanase
chemical_list: D003094:Collagen; D004338:Drug Combinations; D005966:Glucuronidase; D007797:Laminin; D011509:Proteoglycans; D000099175:Heparanase; C059485:matrigel