癌癥往往會在腫瘤擴散到其他組織后發(fā)動致命一擊,。一項發(fā)表在《科學(xué)》（Science）雜志網(wǎng)絡(luò)版上的研究為人們了解這一被稱為轉(zhuǎn)移的過程提供了最新的認識,。研究人員報告說,，線粒體脫氧核糖核酸（DNA）突變能夠刺激轉(zhuǎn)移,，但這一過程同時能夠被藥物所逆轉(zhuǎn)——至少在小鼠身上是這樣,。
線粒體是從母親那里繼承的一種微小的細胞器官,，其作用相當(dāng)于細胞的發(fā)電站,。線粒體擁有自己的DNA,，名為mtDNA。10年前,，癌癥研究人員注意到,，腫瘤細胞中的mtDNA往往會產(chǎn)生突變——其水平大大高于正常組織。這部分緣于mtDNA并沒有被蛋白質(zhì)所包圍,，因此更容易受到損傷,。一些研究人員推測，mtDNA可能導(dǎo)致了癌癥,。但也有人認為,，變異僅僅是癌癥的一個副產(chǎn)品；他們強調(diào),，那些患有線粒體疾病的人并沒有顯著的癌癥傾向,，同時患癌癥的風(fēng)險并非來自于母親，因此不能肯定線粒體與癌癥的形成有關(guān),。
為了研究mtDNA突變在癌癥中扮演的角色,，日本筑波大學(xué)的Jun-Ichi Hayashi研究小組與合作者將兩種小鼠腫瘤細胞中的mtDNA進行了交換—— 一種細胞會發(fā)生轉(zhuǎn)移而另一種則不會。當(dāng)研究人員用這種雜交細胞對小鼠實施皮下注射后,，這些細胞逐漸發(fā)育為腫瘤并最終擴散到肺,。與注射了來自較少轉(zhuǎn)移傾向的細胞mtDNA的小鼠相比，那些體內(nèi)攜帶轉(zhuǎn)移細胞mtDNA的小鼠形成了更多的肺腫瘤,，這意味著mtDNA便是最終的罪魁禍?zhǔn)?。然而mtDNA似乎與最初的腫瘤形成無關(guān)——當(dāng)研究人員將來自轉(zhuǎn)移細胞的mtDNA交換到正常細胞中后，后者并沒有形成腫瘤,。
轉(zhuǎn)移細胞的mtDNA似乎通過兩種突變——能夠?qū)е戮€粒體過度生產(chǎn)活性氧,，這是一種會損害DNA的有毒分子——來完成它們的罪惡行徑。當(dāng)研究人員向小鼠的飲用水中加入一種吸收這些分子的藥物后，這些被皮下注射了轉(zhuǎn)移細胞的小鼠幾乎沒有形成新的腫瘤,。
英國紐卡斯?fàn)柎髮W(xué)的線粒體研究人員Robert Taylor指出,，這篇論文是“一項技術(shù)絕技”，他同時指出,，抗氧化劑能夠抑制轉(zhuǎn)移的事實為未來的研究帶來了希望,。然而，美國波士頓大學(xué)Dana-Farber癌癥研究所的Kornelia Polyak強調(diào),，用抗氧化劑治療癌癥的臨床測試產(chǎn)生了混雜的結(jié)果,，并且讓接受化學(xué)療法的病人使用抗氧化劑將影響治療效果。（來源：科學(xué)時報 群芳）
生物谷推薦原始出處：
（Science）,，DOI: 10.1126/science.1156906,，Kaori Ishikawa，Jun-Ichi Hayashi
ROS-Generating Mitochondrial DNA Mutations Can Regulate Tumor Cell Metastasis
Kaori Ishikawa 1, Keizo Takenaga 2, Miho Akimoto 3, Nobuko Koshikawa 4, Aya Yamaguchi 5, Hirotake Imanishi 5, Kazuto Nakada 6, Yoshio Honma 3, Jun-Ichi Hayashi 5*
1 Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.; TARA Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.; Japan Society for the Promotion of Science (JSPS), 8 Ichiban-cho, Chiyoda-ku, Tokyo 102-8472, Japan.
2 Division of Chemotherapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba 260-8717, Japan.; Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan.
3 Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan.
4 Division of Chemotherapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba 260-8717, Japan.
5 Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
6 Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.; TARA Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
* To whom correspondence should be addressed.
Jun-Ichi Hayashi , E-mail: [email protected]
These authors contributed equally to this work.
Mutations in mitochondrial DNA (mtDNA) occur at high frequency in human tumors, but whether these mutations alter tumor cell behavior has been unclear. We used cytoplasmic hybrid (cybrid) technology to replace the endogenous mtDNA in a mouse tumor cell line that was poorly metastatic with mtDNA from a cell line that was highly metastatic – and vice versa. Using assays of metastasis in mice, we found that the recipient tumor cells acquired the metastatic potential of the transferred mtDNA. The mtDNA conferring high metastatic potential contained G13997A and 13885insC mutations in the gene encoding NADH dehydrogenase subunit 6 (ND6). These mutations produced a deficiency in respiratory complex I activity and were associated with overproduction of reactive oxygen species (ROS). Pretreatment of the highly metastatic tumor cells with ROS scavengers suppressed their metastatic potential in mice. These results indicate that mtDNA mutations can contribute to tumor progression by enhancing the metastatic potential of tumor cells.
