Loss of SMAD4 Promotes Lung Metastasis of Colorectal Cancer by Accumulation of CCR1+ Tumor-Associated Neutrophils through CCL15-CCR1 Axis
Loss of SMAD4 Promotes Lung Metastasis of Colorectal Cancer by Accumulation of CCR1+ Tumor-Associated Neutrophils through CCL15-CCR1 Axis
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DOI：
10.1158/1078-0432.ccr-16-0520
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发表时间：
2017-02-01
影响因子：
11.5
通讯作者：
Sakai, Yoshiharu
中科院分区：
文献类型：
--
作者：
Yamamoto, Takamasa;Kawada, Kenji;Sakai, Yoshiharu
目的：我们已经报道了SMAD 4的缺失促进结直肠癌中CCL 15的表达，以通过CCL 15-CCR 1轴招募CCR 1（+）髓样细胞，这有助于侵袭和肝转移。然而，肺转移的分子机制尚未阐明。我们的目的是确定是否有类似的机制参与肺转移的结直肠cancer.Experimental设计：在小鼠模型中，我们检查SMAD 4是否可以通过CCL 15-CCR 1轴影响结直肠癌细胞向肺的转移活性。我们用免疫组化方法分析了107例结直肠癌肺转移临床标本中SMAD 4、CCL 15和CCR 1的表达。结果：在小鼠模型中，SMAD 4缺陷型结直肠癌细胞分泌的CCL 15能募集CCR 1（+）细胞，促进其向肺的转移。结直肠癌患者肺转移的免疫组织化学分析显示，CCL 15表达与SMAD 4的丢失显著相关，CCL 15阳性转移招募的CCR 1（+）细胞数量是CCL 15阴性转移的1.9倍。重要的是，与CCL 15阴性转移的患者相比，CCL 15阳性转移的患者显示出显著更短的无复发生存期（RFS），多变量分析表明，CCL 15表达是较短RFS的独立预测因子。结论：CCL 15-CCR 1轴可能成为大肠癌肺转移的治疗靶点。CCL 15可作为结直肠癌肺转移患者预后不良的生物标志物。(C)2016年AACR。
Purpose: We have reported loss of SMAD4 promotes expression of CCL15 from colorectal cancer to recruit CCR1(+) myeloid cells through the CCL15-CCR1 axis, which contributes to invasion and liver metastasis. However, the molecular mechanism of lung metastasis is yet to be elucidated. Our purpose is to determine whether similar mechanism is involved in the lung metastasis of colorectal cancer.Experimental Design: In a mouse model, we examined whether SMAD4 could affect the metastatic activity of colorectal cancer cells to the lung through the CCL15-CCR1 axis. We immunohistochemically analyzed expression of SMAD4, CCL15, and CCR1 with 107 clinical specimens of colorectal cancer lung metastases. We also characterized the CCR1(+) myeloid cells using several cell-type-specific markers.Results: In a mouse model, CCL15 secreted from SMAD4-deficient colorectal cancer cells recruited CCR1(+) cells, promoting their metastatic activities to the lung. Immunohistochemical analysis of lung metastases from colorectal cancer patients revealed that CCL15 expression was significantly correlated with loss of SMAD4, and that CCL15-positive metastases recruited approximately 1.9 times more numbers of CCR1(+) cells than CCL15-negative metastases. Importantly, patients with CCL15-positive metastases showed a significantly shorter relapse-free survival (RFS) than those with CCL15-negative metastases, and multivariate analysis indicated that CCL15 expression was an independent predictor of shorter RFS. Immunofluorescent staining showed that most CCR1(+) cells around lung metastases were tumor-associated neutrophil, although a minor fraction was granulocytic myeloid-derived suppressor cell.Conclusions: CCL15-CCR1 axis may be a therapeutic target to prevent colorectal cancer lung metastasis. CCL15 can be a bio-marker indicating poor prognosis of colorectal cancer patients with lung metastases. (C) 2016 AACR.