Heparanase promotes growth, angiogenesis and survival of primary breast tumors.
Despite great strides toward diagnosis and therapy, breast cancer remains a most threatening disease in its incidence, morbidity and mortality; therefore, additional knowledge regarding the molecular mechanisms contributing to breast cancer progression, as well as new targets for drug discovery are highly needed. Heparanase is the predominant enzyme involved in cleavage of heparan sulfate, the main polysaccharide component of the extracellular matrix. Experimental and clinical data indicate that heparanase plays important roles in cancer metastasis and angiogenesis. In breast carcinoma patients, heparanase expression correlates with the metastatic potential of the tumor. The present study was undertaken to investigate the role of heparanase in local growth and angiogenesis of primary breast tumors. MCF-7 breast carcinoma cells were stable transfected with the human heparanase (H-hpa) cDNA, or empty vector (mock), and injected into the mammary pad of nude mice. MRI was applied to monitor progression of tumor growth and angiogenesis. We demonstrate that tumors produced by cells overexpressing heparanase grew faster and were 7-fold larger than tumors produced by mock transfected cells. This enhanced growth was accompanied by increased tumor vascularization and a higher degree of vessel maturation. Histological examination ascribed the differences in tumor growth to heparanase-stimulated cell proliferation and survival. In-vitro experiments reinforced heparanase role as a survival factor under stress conditions. Moreover, H-hpa tumor cells infiltrate into the adjacent stroma, promoting formation of highly vascularized fibrous bands. Our results emphasize the significance and clarify the involvement of heparanase in primary breast cancer progression by generating a supportive microenvironment that promotes tumor growth, angiogenesis and survival.
Cohen
Irit
I
Department of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
Pappo
Orit
O
Elkin
Michael
M
San
Tamara
T
Bar-Shavit
Rachel
R
Hazan
Rachel
R
Peretz
Tamar
T
Vlodavsky
Israel
I
Abramovitch
Rinat
R
D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology*; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D005966:Glucuronidase / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D014162:Transfection; D014183:Transplantation, Heterologous; D000099175:Heparanase
D005966:Glucuronidase; D000099175:Heparanase