Macrophage infiltration and its prognostic relevance in clear cell renal cell carcinoma
Macrophage infiltration and its prognostic relevance in clear cell renal cell carcinoma
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DOI：
10.1111/j.1349-7006.2011.01945.x
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发表时间：
2011-07-01
期刊：
影响因子：
5.7
通讯作者：
Takeya, Motohiro
中科院分区：
文献类型：
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作者：
Komohara, Yoshihiro;Hasita, Horlad;Takeya, Motohiro
大多数恶性肿瘤都有大量巨噬细胞浸润的迹象。在这项研究中，我们研究了一个抗炎巨噬细胞表型（M2）在透明细胞肾细胞癌（RCC）使用CD 163和CD 204作为标记。免疫组化显示CD 163（+）细胞数量与年龄、性别、核分级和TNM分期相关。在单因素分析中，CD 163（+）细胞高浸润与不良临床预后显著相关，但在多因素分析中无相关性。我们还进行了体外研究，以检查巨噬细胞和癌细胞之间的细胞-细胞相互作用。RCC细胞系的培养上清液诱导巨噬细胞向M2表型极化。巨噬细胞与癌细胞的共培养显著诱导了癌细胞中信号转导和转录激活因子3（Stat 3）的激活。RCC细胞与巨噬细胞的直接共培养导致癌细胞中Stat 3比使用Transwell室皿的间接共培养更强的活化。由于RCC细胞在细胞表面表达膜型巨噬细胞集落刺激因子（mM-CSF），我们认为这种mM-CSF在直接的细胞-细胞相互作用中起重要作用。通过巨噬细胞中M-CSF受体（M-CSFR）的下调和M-CSFR的抑制剂，抑制了与巨噬细胞共培养诱导的癌细胞中Stat 3的活化。总之，CD 163（+）肿瘤相关巨噬细胞的研究将有助于评估ccRCC患者的临床预后。由mM-CSF和M-CSFR结合介导的细胞-细胞相互作用可能有助于癌细胞活化。（Cancer Sci 2011; 102：1424-1431）
Most malignant tumors evidence infiltration of many macrophages. In this study, we investigated an anti-inflammatory macrophage phenotype (M2) in clear cell renal cell carcinoma (RCC) using CD163 and CD204 as markers. Immunostaining showed a correlation between the number of CD163(+) cells and age, sex, nuclear grade, and TNM classification. High infiltration of CD163(+) cells was significantly associated with poor clinical prognosis in univariate analysis but not in multivariate analysis. We also carried out in vitro studies to examine cell-cell interactions between macrophages and cancer cells. Culture supernatants from RCC cell lines induced polarization of macrophages toward the M2 phenotype. Coculture of macrophages with cancer cells significantly induced activation of signal transducers and activators of transcription-3 (Stat3) in the cancer cells. Direct coculture of RCC cells with macrophages led to stronger activation of Stat3 in the cancer cells than did indirect coculture using Transwell chamber dishes. Because RCC cells expressed membrane-type macrophage colony-stimulating factor (mM-CSF) on the cell surface, we suggested that this mM-CSF plays an important role in direct cell-cell interactions. Stat3 activation in cancer cells that was induced by coculture with macrophages was suppressed by downregulation of the M-CSF receptor (M-CSFR) in macrophages and by an inhibitor of M-CSFR. In conclusion, investigation of CD163(+) tumor-associated macrophages would be useful for assessment of the clinical prognosis of patients with ccRCC. Cell-cell interactions mediated by mM-CSF and M-CSFR binding could contribute to cancer cell activation. (Cancer Sci 2011; 102: 1424-1431)