Deletion of cathepsin H perturbs angiogenic switching, vascularization and growth of tumors in a mouse model of pancreatic islet cell cancer.
Deletion of cathepsin H perturbs angiogenic switching, vascularization and growth of tumors in a mouse model of pancreatic islet cell cancer.
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DOI：
10.1515/bc.2010.080
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发表时间：
2010-08
影响因子：
3.7
通讯作者：
Joyce JA
中科院分区：
文献类型：
--
作者：
Gocheva V;Chen X;Peters C;Reinheckel T;Joyce JA
蛋白酶可以调节肿瘤发展的许多方面，因为它们的作用，包括细胞外基质的降解、趋化因子的蛋白水解加工和其他酶的活化，影响许多关键的肿瘤发生过程。一类蛋白酶的成员，半胱氨酸组织蛋白酶，已收到越来越多的认识，他们参与癌症的发展，和许多临床研究报告之间的相关性升高的组织蛋白酶水平和恶性进展。这也是组织蛋白酶H的情况，半胱氨酸组织蛋白酶家族的成员，其作为预后标志物的效用已被广泛分析。然而，关于其在肿瘤发展和进展中的特定功能的信息有限。为了进一步了解这种蛋白酶在癌症中的作用，我们将组织蛋白酶H缺陷小鼠与胰岛癌发生的RIP 1-Tag 2模型杂交。组织蛋白酶H的缺失显著损害了癌前增生性胰岛的血管生成转换，并导致随后形成的肿瘤数量减少。此外，组织蛋白酶H缺失RT 2小鼠的肿瘤负荷显著降低，与血管缺陷和细胞凋亡增加相关。因此，我们在这里证明，第一次，重要的肿瘤促进作用的组织蛋白酶H在体内使用小鼠模型的人类癌症。
Proteases can regulate many aspects of tumor development as their actions, which include degradation of the extracellular matrix, proteolytic processing of chemokines and activation of other enzymes, influence a number of key tumorigenic processes. Members of one protease class, the cysteine cathepsins, have received increasing recognition for their involvement in cancer development, and numerous clinical studies have reported correlations between elevated cathepsin levels and malignant progression. This is also the case for cathepsin H, a member of the cysteine cathepsin family, and its utility as a prognostic marker has been analyzed extensively. However, there is limited information available on its specific functions in tumor development and progression. To gain further insight into the role of this protease in cancer, we crossed cathepsin H deficient mice to the RIP1-Tag2 model of pancreatic islet carcinogenesis. Deletion of cathepsin H significantly impaired angiogenic switching of the pre-malignant hyperplastic islets and resulted in a reduction in the subsequent number of tumors that formed. Moreover, the tumor burden in cathepsin H null RT2 mice was significantly reduced, in association with defects in the blood vasculature and increased apoptosis. Thus, we demonstrate here, for the first time, important tumor promoting roles for cathepsin H in vivo using a mouse model of human cancer.