2012年8月23日 訊 /生物谷BIOON/ 一種溶血磷脂酸受體1（LPAR1）的抑制劑Debio-0719能通過誘導(dǎo)小鼠體內(nèi)的癌細(xì)胞進(jìn)入休眠狀態(tài)來抑制腫瘤轉(zhuǎn)移,，相關(guān)研究論文發(fā)表在8月21日的Journal of the National Cancer Institute雜志上,。
轉(zhuǎn)移是癌癥患者死亡率的一個主要根源,。“三陰性”乳腺癌患者存在高風(fēng)險的轉(zhuǎn)移可能性,。
此外,，乳腺癌和前列腺癌是眾所周知的具有可變性,，比如這些類型的腫瘤可能是長期的休眠期即這種疾病是默默潛伏的,。目前有關(guān)對誘導(dǎo)或打破腫瘤細(xì)胞休眠狀態(tài)的因素了解甚少,，但可以明確的是延長腫瘤細(xì)胞的休眠是腫瘤治療的一種策略,。
為了確定LPA1抑制劑對轉(zhuǎn)移性細(xì)胞休眠的影響,，國家癌癥研究所分子藥理學(xué)重點(diǎn)實(shí)驗(yàn)室Jean-Claude A. Marshall, MSc博士和同事在兩種侵襲性的“三陰性”乳腺癌癌癥轉(zhuǎn)移模型系統(tǒng)即小鼠4T1乳腺癌模型和人MDA-MB-231人乳腺癌細(xì)胞模型中分析了原味腫瘤尺寸大小，遠(yuǎn)處轉(zhuǎn)移情況以及它們的分子特征,。結(jié)果發(fā)現(xiàn)Debio-0719或shRNA抑制LPA1后能顯著抑制轉(zhuǎn)移的形成,，而不影響原發(fā)位腫瘤的大小。Debio-0719治療的小鼠在遠(yuǎn)端器官如肺和肝中發(fā)現(xiàn)了腫瘤細(xì)胞,，但已不具備增殖能力,，呈現(xiàn)出休眠狀態(tài)的分子標(biāo)志。
作者指出,，LPA1抑制劑對任一腫瘤模型中的原發(fā)位腫瘤的生長沒有影響,。因此，它通常不會被當(dāng)作藥物來開發(fā),。而他們的數(shù)據(jù)表明或許開發(fā)具有新的活性比如能誘導(dǎo)轉(zhuǎn)移性細(xì)胞進(jìn)入休眠的新化合物可能有抗腫瘤前景,。（生物谷：Bioon.com）
編譯自：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.
