Perivascular M2 Macrophages Stimulate Tumor Relapse after Chemotherapy.
Perivascular M2 Macrophages Stimulate Tumor Relapse after Chemotherapy.
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DOI：
10.1158/0008-5472.can-14-3587
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发表时间：
2015-09-01
期刊：
影响因子：
11.2
通讯作者：
Lewis CE
中科院分区：
文献类型：
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作者：
Hughes R;Qian BZ;Rowan C;Muthana M;Keklikoglou I;Olson OC;Tazzyman S;Danson S;Addison C;Clemons M;Gonzalez-Angulo AM;Joyce JA;De Palma M;Pollard JW;Lewis CE
化疗后肿瘤复发是一个主要的临床问题，因为它通常涉及不能手术的转移性疾病。肿瘤相关巨噬细胞()在癌症的临床前模型中可以限制化疗的细胞毒效应。在这里，我们报告了化疗后TAMs(MRC1+TIE2HiCXCR4Hi)交替激活的(M2)亚群聚集在肿瘤血管周围，在那里它们促进了肿瘤的血管重建和复发，部分是通过释放VEGF-A。类似的血管周围，M2相关的亚群也存在于人类乳腺癌和化疗后的骨转移中。虽然一小部分M2 TAM也存在于低氧肿瘤区域，但当我们通过低氧诱导因子1和2从基因上消除它们对低氧的反应能力时，肿瘤复发没有受到影响。在化疗后的小鼠肿瘤中，TAMS是表达CXCR4免疫反应的主要细胞，其中MRC1+TAMS的表达水平最高，聚集在肿瘤血管周围。此外，化疗后，主要的CXCR4配体CXCL12在这些血管周围部位上调，对MRC1+TAMS具有选择性的趋化作用。有趣的是，HMOX-1，氧化应激的标志，也在化疗后血管周围区域上调。这种酶从血红素的分解中产生一氧化碳，血红素是一种已知的上调CXCL12的气体。最后，CXCR4的药物阻断选择性地减少了化疗后M2相关的TAM，特别是那些直接接触血管的TAM，从而减少了肿瘤的血管重建和再生长。我们的研究通过选择性地针对血管周围、促进复发的M2相关的细胞群，使利用化疗疗效的策略合理化。
Tumor relapse after chemotherapy-induced regression is a major clinical problem, because it often involves inoperable metastatic disease. Tumor-associated macrophages (TAM) are known to limit the cytotoxic effects of chemotherapy in preclinical models of cancer. Here, we report that an alternatively activated (M2) subpopulation of TAMs (MRC1+TIE2HiCXCR4Hi) accumulate around blood vessels in tumors after chemotherapy, where they promote tumor revascularization and relapse, in part, via VEGF-A release. A similar perivascular, M2-related TAM subset was present in human breast carcinomas and bone metastases after chemotherapy. Although a small proportion of M2 TAMs were also present in hypoxic tumor areas, when we genetically ablated their ability to respond to hypoxia via hypoxia-inducible factors 1 and 2, tumor relapse was unaffected. TAMs were the predominant cells expressing immunoreactive CXCR4 in chemotherapy-treated mouse tumors, with the highest levels expressed by MRC1+ TAMs clustering around the tumor vasculature. Furthermore, the primary CXCR4 ligand, CXCL12, was upregulated in these perivascular sites after chemotherapy, where it was selectively chemotactic for MRC1+ TAMs. Interestingly, HMOX-1, a marker of oxidative stress, was also upregulated in perivascular areas after chemotherapy. This enzyme generates carbon monoxide from the breakdown of heme, a gas known to upregulate CXCL12. Finally, pharmacologic blockade of CXCR4 selectively reduced M2-related TAMs after chemotherapy, especially those in direct contact with blood vessels, thereby reducing tumor revascularization and regrowth. Our studies rationalize a strategy to leverage chemotherapeutic efficacy by selectively targeting this perivascular, relapse-promoting M2-related TAM cell population.