Heparan sulfate is required for prostate cancer initiation and progression

Prostate cancer (PCa) is one of the most prevalent forms of malignancy and the second most common cause of cancer-related death in men. The failure in treatment of this disease is our inability to prevent and control PCa growth and metastasis. A better understanding of the mechanisms underlying PCa pathogenesis will greatly enhance our effort to cure this life-threatening disease. Heparan sulfate (HS) is a linear, sulfated polysaccharide, and expresses abundantly in prostate and PCa tissues. Intriguingly, the HS content and sulfation modifications appear to increase when the prostate becomes malignance, suggesting that HS may critically modulate PCa pathogenesis. In current study, we specifically ablated Ext1, the enzyme that initiates HS biosynthesis, in mouse prostate at late development stage. The Ext1 ablation does not affect prostate development and function; instead, it protects the mice from tumorigenesis and invasion in a spontaneous PCa mouse model. Tissue staining showed that the Ext1 deficiency attenuated PCa cell proliferation, increased apoptosis, and blocked PCa stem/progenitor cell differentiation and epithelial-mesenchymal transition. The Ext1 deficiency PCa tissues also showed significant attenuation of fibrinosis, inflammation, MMP-9 activity and hypoxia. In summary, our studies demonstrate that HS functions via multiple mechanisms to promote PCa tumorigenesis and invasion, and also reveal that targeting HS may represent a novel and effective approach to cure PCa.