Function of heparanase in prostate tumorigenesis: potential for therapy.
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.
Lerner
Immanuel
I
Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Baraz
Leah
L
Pikarsky
Eli
E
Meirovitz
Amichay
A
Edovitsky
Evgeny
E
Peretz
Tamar
T
Vlodavsky
Israel
I
Elkin
Michael
M
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
D003094:Collagen; D004338:Drug Combinations; D005966:Glucuronidase; D007797:Laminin; D011509:Proteoglycans; D000099175:Heparanase; C059485:matrigel