1] Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA [2] Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Oncogene. 2014 Apr 3;33(14):1799-808. doi: 10.1038/onc.2013.142. Epub 2013 May 6.
Heparan sulfate proteoglycans are an important and abundant component of the extracellular matrix, which undergo substantial remodeling throughout tumorigenesis via the enzymatic activity of heparanase. Heparanase has been shown to be upregulated in many human cancers; however, its specific functions in human pancreatic neuroendocrine tumors (PanNETs) and spontaneous mouse models of cancer have not been evaluated. Here, we investigated the role of heparanase in PanNETs using patient samples and the RIP1-Tag2 (RT2) PanNET-transgenic mouse model. High heparanase expression significantly correlated with more advanced tumor stage, higher tumor grade and the presence of distant metastasis in PanNET patients. We genetically manipulated heparanase levels in the RT2 model using heparanase-transgenic mice, which constitutively overexpress heparanase, and heparanase-knockout mice. Heparanase was found to have a critical role in promoting tumor invasion, through both macrophage and cancer cell sources in the tumor microenvironment. In addition, elevated heparanase levels significantly increased peritumoral lymphangiogenesis in vivo and promoted the trans-differentiation of macrophages into lymphatic endothelial cell-like structures in culture. Conversely, we found that heparanase deletion led to increased angiogenesis and pericyte coverage. Together, these data identify important roles for heparanase in regulating several critical aspects of tumorigenesis, demonstrating that heparanase represents a potential therapeutic target for PanNET patients.
硫酸乙酰肝素蛋白聚糖是细胞外基质的重要且丰富的组成部分，在肿瘤发生过程中，通过乙酰肝素酶的酶活性，其会发生大量重塑。已有研究表明，乙酰肝素酶在许多人类癌症中上调；然而，其在人类胰腺神经内分泌肿瘤（PanNETs）和自发性癌症小鼠模型中的具体功能尚未得到评估。在这里，我们使用患者样本和 RIP1-Tag2（RT2）PanNET 转基因小鼠模型研究了乙酰肝素酶在 PanNETs 中的作用。高乙酰肝素酶表达与 PanNET 患者更晚期的肿瘤分期、更高的肿瘤分级和远处转移的存在显著相关。我们使用持续过表达乙酰肝素酶的乙酰肝素酶转基因小鼠和乙酰肝素酶敲除小鼠对 RT2 模型中的乙酰肝素酶水平进行了基因操作。研究发现，乙酰肝素酶在促进肿瘤侵袭方面具有关键作用，可通过肿瘤微环境中的巨噬细胞和癌细胞来源来实现。此外，升高的乙酰肝素酶水平显著增加了体内肿瘤周围淋巴管生成，并促进了巨噬细胞向淋巴管内皮细胞样结构的转分化。相反，我们发现乙酰肝素酶缺失导致血管生成增加和周细胞覆盖增加。综上所述，这些数据确定了乙酰肝素酶在调节肿瘤发生的几个关键方面的重要作用，表明乙酰肝素酶代表了 PanNET 患者的一个潜在治疗靶点。
