Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer
Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer
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DOI：
10.1101/gad.180331.111
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发表时间：
2011-12-01
影响因子：
10.5
通讯作者：
Joyce, Johanna A.
中科院分区：
文献类型：
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作者：
Shree, Tanaya;Olson, Oakley C.;Joyce, Johanna A.
众所周知，微环境对肿瘤进展具有重要的调节作用，但其在调节治疗反应中的作用却知之甚少。本研究发现，紫杉醇化疗后乳腺肿瘤中巨噬细胞浸润和组织蛋白酶水平升高。在共培养中，表达cathepsin的巨噬细胞对紫杉醇诱导的肿瘤细胞死亡具有保护作用，这种作用被cathepsin抑制完全逆转，部分由cathepsin B和s介导。巨噬细胞还被发现对其他化疗药物（特别是依托泊苷和阿霉素）诱导的肿瘤细胞死亡具有保护作用。紫杉醇联合组织蛋白酶抑制在体内显著增强了对原发性和转移性肿瘤的疗效，支持这种效果的治疗相关性。此外，持续使用低剂量环磷酰胺可显著抑制肿瘤生长和转移，提高生存率。这项研究强调了肿瘤及其微环境的综合靶向的重要性，并暗示巨噬细胞和组织蛋白酶在减弱化疗反应中的作用。
The microenvironment is known to critically modulate tumor progression, yet its role in regulating treatment response is poorly understood. Here we found increased macrophage infiltration and cathepsin protease levels in mammary tumors following paclitaxel (Taxol) chemotherapy. Cathepsin-expressing macrophages protected against Taxol-induced tumor cell death in coculture, an effect fully reversed by cathepsin inhibition and mediated partially by cathepsins B and S. Macrophages were also found to protect against tumor cell death induced by additional chemotherapeutics, specifically etoposide and doxorubicin. Combining Taxol with cathepsin inhibition in vivo significantly enhanced efficacy against primary and metastatic tumors, supporting the therapeutic relevance of this effect. Additionally incorporating continuous low-dose cyclophosphamide dramatically impaired tumor growth and metastasis and improved survival. This study highlights the importance of integrated targeting of the tumor and its microenvironment and implicates macrophages and cathepsins in blunting chemotherapeutic response.