Osteoprotegerin (OPG) expression by breast cancer cells in vitro and breast tumours in vivo -: a role in tumour cell survival?
Osteoprotegerin (OPG) expression by breast cancer cells in vitro and breast tumours in vivo -: a role in tumour cell survival?
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DOI：
10.1007/s10549-005-2419-8
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发表时间：
2005-08-01
影响因子：
3.8
通讯作者：
Eaton, CL
中科院分区：
文献类型：
--
作者：
Holen, I;Cross, SS;Eaton, CL
据报道，除了在骨转换中的作用外，保护骨素 (OPG) 还可以结合并抑制肿瘤坏死因子相关凋亡诱导配体 (TRAIL)。 TRAIL 通过侵入单核细胞在肿瘤中产生，诱导对该细胞因子敏感的肿瘤细胞凋亡。因此，肿瘤细胞产生的 OPG 将成为一种新机制，癌细胞可以借此逃避宿主防御并获得生长优势。在这项研究中，我们表明乳腺癌细胞产生的 OPG 通过抑制 TRAIL 诱导的细胞凋亡来增强肿瘤细胞的存活。使用 PCR 和 ELISA 检查体外生长的乳腺癌细胞 (MDA-MB 436/231) 的 OPG 表达，并确定这些细胞对 TRAIL 的敏感性。通过在存在或不存在 OPG 的情况下将 MDA-MB 436 细胞暴露于 TRAIL，然后评估核形态，研究 OPG 对 TRAIL 诱导的细胞凋亡的影响。我们发现产生的 OPG 水平足以抑制 TRAIL 诱导的细胞凋亡，表明 OPG 可能在肿瘤细胞存活中发挥作用。我们还通过免疫组织化学检查了选定的乳腺肿瘤 (n=400) 中 OPG 的表达模式，并将 OPG 表达与每个肿瘤的临床病理数据相关。发现 OPG 表达与肿瘤分级的增加呈负相关。据我们所知，这些结果首次证明 OPG 可以作为乳腺癌细胞的内分泌生存因子，并报告了 OPG 在大量人类乳腺肿瘤中的表达模式。
In addition to its role in bone turnover, osteoprotegerin (OPG) has been reported to bind to and inhibit Tumour necrosis factor-related apoptosis inducing ligand (TRAIL). TRAIL is produced in tumours by invading monocytes, inducing apoptosis in neoplastic cells sensitive to this cytokine. OPG production by tumour cells would therefore be a novel mechanism whereby cancer cells evade host defences and gain a growth advantage. In this study we show that OPG produced by breast cancer cells enhances tumour cell survival by inhibiting TRAIL-induced apoptosis. OPG expression by breast cancer cells (MDA-MB 436/231) grown in vitro was examined using PCR and ELISA, and the sensitivity of these cells to TRAIL was determined. The effects of OPG on TRAIL induced apoptosis was investigated by exposing MDA-MB 436 cells to TRAIL, in the presence or absence of OPG, followed by assessment of nuclear morphology. We found that the levels of OPG produced were sufficient to inhibit TRAIL-induced apoptosis, suggesting that OPG may play a role in tumour cell survival. We also examined the expression pattern of OPG in a selection of breast tumours (n=400) by immunohistochemistry, and related OPG expression to the clinico-pathological data for each tumour. OPG expression was found to be negatively correlated with increasing tumour grade. To our knowledge these results are the first to demonstrate that OPG can act as an endocrine survival factor for breast cancer cells, as well as reporting the expression patterns of OPG in a large cohort of human breast tumours.