Metastasis Suppressors Regulate the Tumor Microenvironment by Blocking Recruitment of Prometastatic Tumor-Associated Macrophages.
Metastasis Suppressors Regulate the Tumor Microenvironment by Blocking Recruitment of Prometastatic Tumor-Associated Macrophages.
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DOI：
10.1158/0008-5472.can-14-3394
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发表时间：
2015-10-01
期刊：
影响因子：
11.2
通讯作者：
Rosner MR
中科院分区：
文献类型：
--
作者：
Frankenberger C;Rabe D;Bainer R;Sankarasharma D;Chada K;Krausz T;Gilad Y;Becker L;Rosner MR
三阴性乳腺癌（TNBC）患者复发和转移的风险最高。因为他们不能用靶向治疗，许多人对化疗没有反应，他们代表了一个临床服务不足的群体。TNBC的特征在于转移抑制因子如Raf激酶抑制蛋白（RKIP）的表达降低，其抑制肿瘤侵袭性。转移抑制因子改变肿瘤细胞的机制已得到很好的表征;然而，它们调节肿瘤微环境的能力以及这种调节对转移抑制的重要性还不完全清楚。在这里，我们使用物种特异性RNA测序显示，RKIP在肿瘤中的表达显着降低浸润性TAM的数量和转移潜力。相对于转移性RKIP −肿瘤，从非转移性RKIP+肿瘤中分离的TAM表现出降低的驱动肿瘤细胞侵袭的能力和降低的促转移因子分泌，包括PRGN和脱落的TNFR 2。RKIP通过阻断HMGA 2调节TAM募集，导致许多巨噬细胞趋化因子（包括CCL 5）的表达减少。RKIP+肿瘤中的CCL 5过表达恢复了促转移性TAM的募集和内渗，而用CCL 5受体拮抗剂Maraviroc治疗减少了TAM浸润。这些结果强调了RKIP作为通过趋化因子如CCL 5募集TAM的调节剂的重要性。这些相互作用的临床意义通过我们证明由RKIP信号传导和促转移性TAM因子组成的特征基于生存结果显著地分离TNBC患者而得到强调。总的来说，我们的研究结果将TAM确定为转移抑制剂RKIP调节肿瘤侵袭性的先前未被怀疑的机制，并进一步表明RKIP活性降低和TAM浸润增加的TNBC患者可能对基于巨噬细胞的治疗有反应。
Triple-negative breast cancer (TNBC) patients have the highest risk of recurrence and metastasis. Because they cannot be treated with targeted therapies, and many do not respond to chemotherapy, they represent a clinically underserved group. TNBC is characterized by reduced expression of metastasis suppressors such as Raf Kinase Inhibitory Protein (RKIP), which inhibits tumor invasiveness. Mechanisms by which metastasis suppressors alter tumor cells are well characterized; however, their ability to regulate the tumor microenvironment, and the importance of such regulation to metastasis suppression is incompletely understood. Here we use species-specific RNA sequencing to show that RKIP expression in tumors markedly reduces the number and metastatic potential of infiltrating TAMs. TAMs isolated from non-metastatic RKIP+ tumors, relative to metastatic RKIP− tumors, exhibit a reduced ability to drive tumor cell invasion and decreased secretion of pro-metastatic factors including PRGN and shed TNFR2. RKIP regulates TAM recruitment by blocking HMGA2, resulting in reduced expression of numerous macrophage chemotactic factors, including CCL5. CCL5 overexpression in RKIP+ tumors restores recruitment of pro-metastatic TAMs and intravasation, while treatment with the CCL5 receptor antagonist Maraviroc reduces TAM infiltration. These results highlight the importance of RKIP as a regulator of TAM recruitment through chemokines such as CCL5. The clinical significance of these interactions is underscored by our demonstration that a signature comprised of RKIP signaling and pro-metastatic TAM factors strikingly separates TNBC patients based on survival outcome. Collectively, our findings identify TAMs as a previously unsuspected mechanism by which the metastasis suppressor RKIP regulates tumor invasiveness, and further suggest that TNBC patients with decreased RKIP activity and increased TAM infiltration may respond to macrophage-based therapeutics.