2012年8月23日 讯 /生物谷BIOON/ 一种溶血磷脂酸受体1（LPAR1）的抑制剂Debio-0719能通过诱导小鼠体内的癌细胞进入休眠状态来抑制肿瘤转移，相关研究论文发表在8月21日的Journal of the National Cancer Institute杂志上。
转移是癌症患者死亡率的一个主要根源。“三阴性”乳腺癌患者存在高风险的转移可能性。
此外，乳腺癌和前列腺癌是众所周知的具有可变性，比如这些类型的肿瘤可能是长期的休眠期即这种疾病是默默潜伏的。目前有关对诱导或打破肿瘤细胞休眠状态的因素了解甚少，但可以明确的是延长肿瘤细胞的休眠是肿瘤治疗的一种策略。
为了确定LPA1抑制剂对转移性细胞休眠的影响，国家癌症研究所分子药理学重点实验室Jean-Claude A. Marshall, MSc博士和同事在两种侵袭性的“三阴性”乳腺癌癌症转移模型系统即小鼠4T1乳腺癌模型和人MDA-MB-231人乳腺癌细胞模型中分析了原味肿瘤尺寸大小，远处转移情况以及它们的分子特征。结果发现Debio-0719或shRNA抑制LPA1后能显著抑制转移的形成，而不影响原发位肿瘤的大小。Debio-0719治疗的小鼠在远端器官如肺和肝中发现了肿瘤细胞，但已不具备增殖能力，呈现出休眠状态的分子标志。
作者指出，LPA1抑制剂对任一肿瘤模型中的原发位肿瘤的生长没有影响。因此，它通常不会被当作药物来开发。而他们的数据表明或许开发具有新的活性比如能诱导转移性细胞进入休眠的新化合物可能有抗肿瘤前景。（生物谷：Bioon.com）
编译自：LPA1 inhibition induces metastatic dormancy in mouse models of breast cancer
doi:10.1093/jnci/djs319
PMC:
PMID:
Effect of Inhibition of the Lysophosphatidic Acid Receptor 1 on Metastasis and Metastatic Dormancy in Breast Cancer
Jean-Claude A. Marshall, Joshua W. Collins, Joji Nakayama, Christine E. Horak, David J. Liewehr, Seth M. Steinberg, Mary Albaugh, Fernando Vidal-Vanaclocha, Diane Palmieri, Maryse Barbier, Maximilien Murone and Patricia S. Steeg
Background 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.
Methods 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.
Results 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.
Conclusion The data identify Debio-0719 as a drug candidate with metastasis suppressor activity, inducing dormancy at secondary tumor sites.
