Host Response to Short-term, Single-Agent Chemotherapy Induces Matrix Metalloproteinase-9 Expression and Accelerates Metastasis in Mice
Host Response to Short-term, Single-Agent Chemotherapy Induces Matrix Metalloproteinase-9 Expression and Accelerates Metastasis in Mice
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DOI：
10.1158/0008-5472.can-11-0629
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发表时间：
2011-11-15
期刊：
影响因子：
11.2
通讯作者：
Shaked, Yuval
中科院分区：
文献类型：
--
作者：
Gingis-Velitski, Svetlana;Loven, David;Shaked, Yuval
越来越多的证据表明，骨髓来源的细胞（BMDC）有助于肿瘤的生长，血管生成和转移。在对癌症治疗的急性反应中，几种类型的BMDC被迅速动员到肿瘤中。虽然这种宿主对治疗的反应可以促进肿瘤再生长，但其对转移的贡献尚未被探索。为了只关注化疗对宿主的影响，我们研究了非荷瘤小鼠。来自用紫杉醇化疗处理的动物的血浆诱导肿瘤细胞的血管生成、迁移和侵袭沿着宿主细胞定植。吉西他滨化疗的影响较小。来自BMDC的条件培养基和来自化疗处理的小鼠的血浆各自通过诱导基质金属蛋白酶9（MMP 9）和上皮向间质转化来促进肿瘤细胞的转移特性。在静脉注射刘易斯肺癌细胞的小鼠中，紫杉醇治疗加速了转移，而吉西他滨或溶剂则不能，其方式可以被MMP 9抑制剂阻断。此外，与BMDC重组的嵌合小鼠，其中MMP 9活性减弱，不支持癌细胞的加速转移，所述癌细胞在引入宿主动物之前用化疗预处理。总之，我们的研究结果说明了一些化疗如何发挥促转移作用，可能会混淆治疗结果。Cancer Res; 71（22）; 6986-96.（C）2011年《非洲标准化评论》。
Mounting evidence suggests that bone marrow-derived cells (BMDC) contribute to tumor growth, angiogenesis, and metastasis. In acute reactions to cancer therapy, several types of BMDCs are rapidly mobilized to home tumors. Although this host reaction to therapy can promote tumor regrowth, its contribution to metastasis has not been explored. To focus only on the effects of chemotherapy on the host, we studied non-tumor-bearing mice. Plasma from animals treated with the chemotherapy paclitaxel induced angiogenesis, migration, and invasion of tumor cells along with host cell colonization. Lesser effects were seen with the chemotherapy gemcitabine. Conditioned medium from BMDCs and plasma from chemotherapy-treated mice each promoted metastatic properties in tumor cells by inducing matrix metalloproteinase-9 (MMP9) and epithelial-to-mesenchymal transition. In mice in which Lewis lung carcinoma cells were injected intravenously, treatment with paclitaxel, but not gemcitabine or vehicle, accelerated metastases in a manner that could be blocked by an MMP9 inhibitor. Moreover, chimeric mice reconstituted with BMDC where MMP9 activity was attenuated did not support accelerated metastasis by carcinoma cells that were pretreated with chemotherapy before their introduction to host animals. Taken together, our findings illustrate how some chemotherapies can exert prometastatic effects that may confound treatment outcomes. Cancer Res; 71(22); 6986-96. (C)2011 AACR.