Using an in-vivo syngeneic spontaneous metastasis model identifies ID2 as a promoter of breast cancer colonisation in the brain
Using an in-vivo syngeneic spontaneous metastasis model identifies ID2 as a promoter of breast cancer colonisation in the brain
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DOI：
10.1186/s13058-018-1093-9
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发表时间：
2019-01-14
影响因子：
7.4
通讯作者：
Isacke, Clare M.
中科院分区：
文献类型：
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作者：
Kijewska, Magdalena;Viski, Carmen;Isacke, Clare M.
背景乳腺癌的脑转移与患者预后差和治疗选择有限有关。在这项研究中，我们试图通过分析小鼠乳腺癌细胞自发转移的原发性肿瘤在免疫活性同源host.Methods4T1小鼠乳腺癌亚系原发性肿瘤和自发脑和肺转移的BALB/c小鼠进行全基因组表达谱，以确定新的监管机构的脑转移。两个差异表达的基因，Id 2和Aldh 3a 1，在体内模型中使用小鼠和人癌细胞系进行验证。在乳腺癌患者的数据集中研究了无远处转移生存率和无脑转移复发生存率的临床相关性。骨形态发生蛋白（BMP）7在调节Id 2的表达和促进细胞存活的作用进行了研究，在二维和三维的体外assays.ResultsIn自发转移模型，表达的Id 2和Aldh 3a 1是显着高于4 T1脑衍生的亚系相比，亚系从肺转移瘤或原发肿瘤。表达下调损害细胞在脑实质中定殖的能力，而4 T1和人MDA-MB-231细胞中的异位表达促进心内接种后向脑的传播，但对肺定殖的效率没有影响。这两种基因在雌激素受体（ER）阴性乳腺癌中高度表达，并且在这个预后不良的亚组中，表达增加与无远处转移生存率降低相关。ID 2表达也与脑转移无复发生存率降低相关。从机制上讲，与肺相比，在脑组织中以显著更高水平存在的BMP 7上调ID 2表达，并且在BMP 7撤回后，这种升高的表达得以保留。最后，我们证明，无论是异位表达ID 2或BMP 7诱导ID 2表达保护肿瘤细胞从anoikis.ConclusionsThis研究确定ID 2作为一个关键的调节乳腺癌转移到大脑。我们的数据支持一个模型，其中已经扩散到大脑的乳腺癌细胞响应星形胶质细胞分泌的BMP 7上调ID 2表达，这有助于支持转移性扩张。此外，升高的ID 2表达鉴定了在脑中发展转移性复发的风险增加的乳腺癌患者。
BackgroundDissemination of breast cancers to the brain is associated with poor patient outcome and limited therapeutic options. In this study we sought to identify novel regulators of brain metastasis by profiling mouse mammary carcinoma cells spontaneously metastasising from the primary tumour in an immunocompetent syngeneic host.Methods4T1 mouse mammary carcinoma sublines derived from primary tumours and spontaneous brain and lung metastases in BALB/c mice were subject to genome-wide expression profiling. Two differentially expressed genes, Id2 and Aldh3a1, were validated in in-vivo models using mouse and human cancer cell lines. Clinical relevance was investigated in datasets of breast cancer patients with regards to distant metastasis-free survival and brain metastasis relapse-free survival. The role of bone morphogenetic protein (BMP)7 in regulating Id2 expression and promoting cell survival was investigated in two-dimensional and three-dimensional in-vitro assays.ResultsIn the spontaneous metastasis model, expression of Id2 and Aldh3a1 was significantly higher in 4T1 brain-derived sublines compared with sublines from lung metastases or primary tumour. Downregulation of expression impairs the ability of cells to colonise the brain parenchyma whereas ectopic expression in 4T1 and human MDA-MB-231 cells promotes dissemination to the brain following intracardiac inoculation but has no impact on the efficiency of lung colonisation. Both genes are highly expressed in oestrogen receptor (ER)-negative breast cancers and, within this poor prognosis sub-group, increased expression correlates with reduced distant metastasis-free survival. ID2 expression also associates with reduced brain metastasis relapse-free survival. Mechanistically, BMP7, which is present at significantly higher levels in brain tissue compared with the lungs, upregulates ID2 expression and, after BMP7 withdrawal, this elevated expression is retained. Finally, we demonstrate that either ectopic expression of ID2 or BMP7-induced ID2 expression protects tumour cells from anoikis.ConclusionsThis study identifies ID2 as a key regulator of breast cancer metastasis to the brain. Our data support a model in which breast cancer cells that have disseminated to the brain upregulate ID2 expression in response to astrocyte-secreted BMP7 and this serves to support metastatic expansion. Moreover, elevated ID2 expression identifies breast cancer patients at increased risk of developing metastatic relapse in the brain.