Function of heparanase in prostate turnorigenesis: Potential for therapy
Function of heparanase in prostate turnorigenesis: Potential for therapy
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DOI：
10.1158/1078-0432.ccr-07-1866
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发表时间：
2008-02-01
影响因子：
11.5
通讯作者：
Elkin, Michael
中科院分区：
文献类型：
--
作者：
Lerner, Immanuel;Baraz, Leah;Elkin, Michael
目的：乙酰肝素酶是切割细胞外基质中主要多糖硫酸乙酰肝素的主要酶。尽管乙酰肝素酶在维持人类癌症病理学中的作用已得到充分证实，但其与前列腺癌的关系仍不确定。我们的研究进行了阐明乙酰肝素酶在前列腺肿瘤发生和骨转移的意义。实验设计：我们应用免疫组织化学分析的组织芯片，体外粘附和侵袭试验，以及小鼠模型的骨内生长和自发性转移的前列腺癌，监测全身生物发光成像。电穿孔辅助管理的抗乙酰肝素酶小干扰RNA在体内被施加作为一种治疗approach.Results：我们报告一个高度统计学显著（P < 0.0001）的患病率乙酰肝素酶过度表达的前列腺癌与非癌组织，以及肿瘤分级和乙酰肝素酶表达的程度之间的强相关性。我们观察到过表达乙酰肝素酶的PC-3前列腺癌细胞的转移潜力增加> 5倍。值得注意的是，分泌型酶的过度表达也导致骨内前列腺肿瘤生长的急剧增加。体内局部沉默乙酰肝素酶可抑制前列腺肿瘤生长4倍，这代表了基于乙酰肝素酶小干扰RNA的抗癌疗法的首次成功应用，并验证了乙酰肝素酶作为前列腺癌治疗靶点的潜力。结论：乙酰肝素酶直接促进前列腺肿瘤在骨中的生长及其转移到远处器官的能力。因此，抗乙酰肝素酶策略可能成为治疗前列腺癌患者，特别是骨转移患者的重要方式。
Purpose: 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.Experimental Design: 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.