Effect of Inhibition of the Lysophosphatidic Acid Receptor 1 on Metastasis and Metastatic Dormancy in Breast Cancer
Effect of Inhibition of the Lysophosphatidic Acid Receptor 1 on Metastasis and Metastatic Dormancy in Breast Cancer
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DOI：
10.1093/jnci/djs319
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发表时间：
2012-09-01
影响因子：
10.3
通讯作者：
Steeg, Patricia S.
中科院分区：
文献类型：
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作者：
Marshall, Jean-Claude A.;Collins, Joshua W.;Steeg, Patricia S.
先前的研究确定了人类非转移基因23（NME 1，下文称为Nm 23-H1）作为第一个转移抑制基因。还报道了Nm 23-H1与溶血磷脂酸受体1基因（LPAR 1，也称为EDG 2或下文中的LPA 1）的表达之间的反向关系。然而，LPA 1抑制剂对原发肿瘤大小、转移和转移休眠的影响尚未研究，使用LPA 1抑制剂Debio-0719或LPA 1短发夹RNA（shRNA）。使用4 T1自发转移小鼠模型和MDA-MB-231 T实验转移小鼠模型（每组n = 13只小鼠）研究原发肿瘤大小和转移。通过免疫组织化学和western blot检测肿瘤和细胞系中的增殖和p38细胞内信号，以研究LPA 1抑制对转移性休眠的影响。在4 T1自发转移小鼠模型中，Debio-0719抑制了4 T1细胞向肝脏的转移（对于赋形剂处理的小鼠，每个组织切片的平均值= 25.2个肝转移，对于Debio-0719处理的小鼠，每个组织切片的平均值= 6.8个肝转移，减少73.0%，P <0.001）和肺（对于赋形剂治疗的小鼠，每个组织切片平均= 6.37个病变，对于Debio-0719治疗的小鼠，每个组织切片平均= 0.73个病变，减少88.5%，P <0.001），对原发性肿瘤大小没有影响。使用MDA-MB-231 T实验性肺转移小鼠模型观察到类似的结果。LPA 1 shRNA也抑制转移，但不影响原发肿瘤的大小。在4 T1转移瘤中，而不是原发性肿瘤中，Debio-0719降低了增殖标志物Ki 67和pErk的表达，并且增加了p38应激激酶的磷酸化，指示转移性休眠。
Previous studies identified the human nonmetastatic gene 23 (NME1, hereafter Nm23-H1) as the first metastasis suppressor gene. An inverse relationship between Nm23-H1 and expression of lysophosphatidic acid receptor 1 gene (LPAR1, also known as EDG2 or hereafter LPA1) has also been reported. However, the effects of LPA1 inhibition on primary tumor size, metastasis, and metastatic dormancy have not been investigated.The LPA1 inhibitor Debio-0719 or LPA1 short hairpinned RNA (shRNA) was used. Primary tumor size and metastasis were investigated using the 4T1 spontaneous metastasis mouse model and the MDA-MB-231T experimental metastasis mouse model (n = 13 mice per group). Proliferation and p38 intracellular signaling in tumors and cell lines were determined by immunohistochemistry and western blot to investigate the effects of LPA1 inhibition on metastatic dormancy. An analysis of variance-based two-tailed t test was used to determine a statistically significant difference between treatment groups.In the 4T1 spontaneous metastasis mouse model, Debio-0719 inhibited the metastasis of 4T1 cells to the liver (mean = 25.2 liver metastases per histologic section for vehicle-treated mice vs 6.8 for Debio-0719-treated mice, 73.0% reduction, P < .001) and lungs (mean = 6.37 lesions per histologic section for vehicle-treated mice vs 0.73 for Debio-0719-treated mice, 88.5% reduction, P < .001), with no effect on primary tumor size. Similar results were observed using the MDA-MB-231T experimental pulmonary metastasis mouse model. LPA1 shRNA also inhibited metastasis but did not affect primary tumor size. In 4T1 metastases, but not primary tumors, expression of the proliferative markers Ki67 and pErk was reduced by Debio-0719, and phosphorylation of the p38 stress kinase was increased, indicative of metastatic dormancy.The data identify Debio-0719 as a drug candidate with metastasis suppressor activity, inducing dormancy at secondary tumor sites.