Tumor-Recruited Neutrophils and Neutrophil TIMP-Free MMP-9 Regulate Coordinately the Levels of Tumor Angiogenesis and Efficiency of Malignant Cell Intravasation
Tumor-Recruited Neutrophils and Neutrophil TIMP-Free MMP-9 Regulate Coordinately the Levels of Tumor Angiogenesis and Efficiency of Malignant Cell Intravasation
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DOI：
10.1016/j.ajpath.2011.05.031
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发表时间：
2011-09-01
影响因子：
6
通讯作者：
Deryugina, Elena I.
中科院分区：
文献类型：
--
作者：
Bekes, Erin M.;Schweighofer, Bernhard;Deryugina, Elena I.
肿瘤相关中性粒细胞通过提供基质金属蛋白酶 9 (MMP-9) 来促进新血管形成，基质金属蛋白酶 9 是一种在遗传和生化方面与诱导血管生成相关的蛋白酶。然而，炎性中性粒细胞及其独特的 proMMP-9 在肿瘤血管生成和肿瘤细胞传播的协调调节中的具体作用尚未得到解决。我们证明，由人纤维肉瘤和前列腺癌的高度播散性变体形成的原发性肿瘤会募集升高水平的浸润性 MMP-9 阳性中性粒细胞，并同时表现出增强的血管生成和内渗水平。通过白细胞介素 8 (IL-8) 中和对中性粒细胞流入的特异性抑制导致肿瘤血管生成和内渗的协同减少，而纯化的中性粒细胞 proMMP-9 可以挽救这两种情况。然而，如果中性粒细胞proMMP-9（天然缺乏金属蛋白酶组织抑制剂（TIMP））与TIMP-1复合物或与TIMP-2混合物一起递送，则蛋白酶无法挽救抗IL8治疗的抑制作用，表明proMMP-9的无TIMP状态对于促进肿瘤血管生成和血管内渗至关重要。我们的研究结果将肿瘤相关中性粒细胞及其不含 TIMP 的 proMMP-9 与侵袭性肿瘤细胞诱导新血管形成的能力直接联系起来，新血管可作为肿瘤细胞传播的管道。因此，与中性粒细胞浸润相关的癌症的治疗可能受益于早期阶段特异性靶向中性粒细胞 MMP-9，以防止随后的肿瘤血管生成和肿瘤转移。 （Am J Pathol 2011，179：1455-1470；DO！：10.1016/j.ajpath.2011.05.031）
Tumor-associated neutrophils contribute to neovascularization by supplying matrix metalloproteinase-9 (MMP-9), a protease that has been genetically and biochemically linked to induction of angiogencsis. Specific roles of inflammatory neutrophils and their distinct proMMP-9 in the coordinate regulation of tumor angiogenesis and tumor cell dissemination, however, have not been addressed. We demonstrate that the primary tumors formed by highly disseminating variants of human fibrosarcoma and prostate carcinoma recruit elevated levels of infiltrating MMP-9-positive neutrophils and concomitantly exhibit enhanced levels of angiogenesis and intravasation. Specific inhibition of neutrophil influx by interleukin 8 (IL-8) neutralization resulted in the coordinated diminishment of tumor angiogenesis and intravasation, both of which were rescued by purified neutrophil proMMP-9. However, if neutrophil proMMP-9, naturally devoid of tissue inhibitor of metalloproteinases (TIMP), was delivered in complex with TIMP-1 or in a mixture with TIMP-2, the protease failed to rescue the inhibitory effects of anti-IL8 therapy, indicating that the TIMP-free status of proMMP-9 is critical for facilitating tumor angiogenesis and intravasation. Our findings directly link tumor-associated neutrophils and their TIMP-free proMMP-9 with the ability of aggressive tumor cells to induce the formation of new blood vessels that serve as conduits for tumor cell dissemination. Thus, treatment of cancers associated with neutrophil infiltration may benefit from specific targeting of neutrophil MMP-9 at early stages to prevent ensuing tumor angiogenesis and tumor metastasis. (Am J Pathol 2011, 179:1455-1470; DO!: 10.1016/j.ajpath.2011.05.031)