Effect of macrophages on breast cancer cell proliferation, and on expression of hormone receptors, uPAR and HER-2.
Effect of macrophages on breast cancer cell proliferation, and on expression of hormone receptors, uPAR and HER-2.
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DOI：
10.3892/ijo.2017.3996
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发表时间：
2017-07
影响因子：
5.2
通讯作者：
Erlandsson A
中科院分区：
文献类型：
--
作者：
Lindsten T;Hedbrant A;Ramberg A;Wijkander J;Solterbeck A;Eriksson M;Delbro D;Erlandsson A
恶性肿瘤（包括乳腺癌）经常被先天免疫细胞浸润，肿瘤相关巨噬细胞（TAMs）是许多肿瘤基质中的主要炎症成分。在这项研究中，我们检测了巨噬细胞标志物CD 68和CD 163以及激素受体雌激素受体α（ERα）、孕激素受体（PR）、雌激素受体β1（ERβ1）、人表皮生长因子受体2（HER-2）、基质金属蛋白酶9（MMP-9）、尿激酶型纤溶酶原激活物受体（uPAR）和增殖标记Ki 67在17例乳腺癌活检。CD 68+和CD 163+的定量评分强烈表明当前研究的活检中M2表型占主导地位。我们发现巨噬细胞水平的增加与ERα或PR呈负相关，而Ki-67或uPAR则呈正相关。HER-2、ERβ1和MMP-9的表达与巨噬细胞的水平无明显相关性。研究了由培养的人M1和M2巨噬细胞表型产生的条件培养基（CM）对T47 D乳腺癌细胞系中选定标记物的增殖和表达的影响。与体内情况相比，M1巨噬细胞的CM可抑制T47 D细胞的生长，抑制Ki 67的表达，并显著增加ERβ1 mRNA的表达。此外，根据体内情况，巨噬细胞CM降低ERα蛋白的表达，同时降低ERα或PR mRNA的表达。结论：巨噬细胞在体外具有降低肿瘤细胞ERα和PR表达的作用。在体内肿瘤环境中，巨噬细胞也有助于肿瘤细胞表达uPAR和Ki 67的增加，表明巨噬细胞参与损害乳腺癌患者的预后。
Malignant tumors, including breast cancers, are frequently infiltrated with innate immune cells and tumor-associated macrophages (TAMs) represent the major inflammatory component in stroma of many tumors. In this study, we examined the immunoreactivity of the macrophage markers CD68 and CD163 as well as the hormone receptors estrogen receptor α (ERα), progesterone receptor (PR), estrogen receptor β1 (ERβ1), human epidermal growth factor receptor 2 (HER-2), matrix metalloproteinase 9 (MMP-9), urokinase-type plasminogen activator receptor (uPAR) and the proliferations marker Ki67 in 17 breast cancer biopsies. The quantitative score for CD68+ and CD163+ strongly indicate M2 phenotype dominance in the currently investigated biopsies. We found that an increasing level of macrophages was negatively associated with ERα or PR, whereas a positive association was observed for Ki-67 or uPAR. No significant association could be seen between the level of macrophage and HER-2, ERβ1 or MMP-9 expression. Effect of conditioned media (CM) generated from cultured human M1 and M2 macrophage phenotypes were investigated on the proliferation and expression of selected markers in the T47D breast cancer cell line. We found that in contrast to the in vivo situation, in particularly the CM from M1 macrophages decreased the growth and Ki67 expression in T47D, and significantly increased ERβ1 mRNA levels. Moreover, in accordance to the in vivo situation the CM from the macrophages decreased the expression of ERα protein as well as ERα or PR mRNA. In conclusion our results show that macrophages alone have the capability to decrease the tumor cell expression of ERα and PR in vitro. In the tumor environment in vivo macrophages also contribute to an increase in tumor cell expression of uPAR and Ki67, suggesting that macrophages are involved in impairing the prognosis for breast cancer patients.