Cathepsin L secretion by host and neoplastic cells potentiates invasion.
Cathepsin L secretion by host and neoplastic cells potentiates invasion.
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DOI：
10.18632/oncotarget.27182
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发表时间：
2019-09-17
期刊：
影响因子：
--
通讯作者：
Siemann, Dietmar W
中科院分区：
文献类型：
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作者：
Dykes, Samantha S;Fasanya, Henrietta O;Siemann, Dietmar W
乳腺肿瘤内巨噬细胞的存在与转移潜能有关。这些肿瘤相关巨噬细胞通常具有促肿瘤(M2样)表型，导致分泌生长因子和蛋白酶，包括溶酶体蛋白水解酶组织蛋白酶L。由于组织蛋白酶L也经常由乳腺癌细胞分泌，并有助于肿瘤的侵袭、转移和血管生成，我们假设肿瘤相关巨噬细胞和肿瘤细胞分泌组织蛋白酶L将促进转移表型。我们的结果表明，新型组织蛋白酶L/K抑制剂KGP94和KGP207在体外能够抑制M2巨噬细胞的侵袭，并减少巨噬细胞刺激的4T1小鼠乳腺癌细胞的侵袭。KGP94和KGP207处理还降低了几个M2相关标志物的表达，提示组织蛋白酶L的活性可能在IL-4诱导的M0向M2分化中起重要作用。此外，组织蛋白酶L shRNA敲除研究表明，组织蛋白酶L来自肿瘤细胞和巨噬细胞两个群体，对肿瘤细胞的侵袭具有重要作用。因此，我们的数据表明，肿瘤细胞和巨噬细胞可能都参与了组织蛋白酶L驱动的乳腺癌转移表型。综上所述，这些研究强调了组织蛋白酶L在巨噬细胞功能中的重要性，并表明组织蛋白酶抑制策略可能通过抑制M2巨噬细胞高渗透的肿瘤的进展而在治疗上受益。
The presence of macrophages within breast tumors correlates with metastatic potential. These tumor-associated macrophages often take on a pro-tumorigenic (M2-like) phenotype resulting in the secretion of growth factors and proteases, including the lysosomal protease cathepsin L. Since cathepsin L also is frequently secreted by breast cancer cells and contributes to tumor invasion, metastasis, and angiogenesis, we hypothesized that secretion of cathepsin L by both tumor-associated macrophages and neoplastic cells would facilitate the metastatic phenotype. Our results showed that the novel cathepsin L/K inhibitors KGP94 and KGP207 could inhibit in vitro M2 macrophage invasion and reduce the macrophage-stimulated invasion of 4T1 murine breast cancer cells. KGP94 and KGP207 treatment also reduced the expression of several M2-associated markers, suggesting that cathepsin L activity may be important for IL-4-driven M0 to M2 differentiation. In addition, cathepsin L shRNA knockdown studies revealed that cathepsin L from both the tumor cell and the macrophage population is important for tumor cell invasion. Thus our data suggest that tumor cells and macrophages may both contribute to the cathepsin L-driven metastatic phenotype of breast cancer. Taken together, these studies highlight the importance of cathepsin L in macrophage functions and suggest that cathepsin inhibition strategies may be therapeutically beneficial by impairing the progression of tumors with high infiltration of M2 macrophages.