Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Genes Dev. 2011 Dec 1;25(23):2465-79. doi: 10.1101/gad.180331.111.
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.
微环境被认为能显著调节肿瘤的进展，但它在调节治疗反应中的作用还知之甚少。在这里，我们发现紫杉醇（Taxol）化疗后乳腺肿瘤中巨噬细胞浸润和组织蛋白酶蛋白酶水平增加。组织蛋白酶表达的巨噬细胞在共培养中保护紫杉醇诱导的肿瘤细胞死亡，组织蛋白酶抑制可完全逆转这种作用，部分由组织蛋白酶 B 和 S 介导。还发现巨噬细胞可防止其他化疗药物（特别是依托泊苷和阿霉素）诱导的肿瘤细胞死亡。体内联合紫杉醇和组织蛋白酶抑制显著增强了对原发性和转移性肿瘤的疗效，支持了这种作用的治疗相关性。此外，联合使用连续低剂量环磷酰胺可显著抑制肿瘤生长和转移并提高生存率。这项研究强调了靶向肿瘤及其微环境的综合重要性，并表明巨噬细胞和组织蛋白酶在削弱化疗反应中起作用。
