乳腺癌是美國婦女癌癥死亡的第二大原因,。許多這樣的死亡發(fā)生在還只是初步診斷為侵襲性或轉(zhuǎn)移性癌癥之時。大量的研究證實,，一種稱作NEDD9的蛋白質(zhì)參與調(diào)控了細(xì)胞遷移,、分裂及存活,，與多種癌癥的腫瘤侵襲及轉(zhuǎn)移有關(guān),。
近日來自Fox Chase癌癥中心的研究人員發(fā)現(xiàn),，NEDD9通過控制引起腫瘤的祖細(xì)胞生長，在乳腺癌形成的早期階段發(fā)揮了令人驚奇的作用,。研究結(jié)果在線發(fā)表在1月14日的《癌基因》（Oncogene）雜志上,，有可能為乳腺癌婦女開發(fā)出基于腫瘤中的NEDD9水平的個體化治療新策略。
論文的資深作者是Fox Chase癌癥中心的副首席執(zhí)行官及副主席Erica A. Golemis博士,。“多年來,，人們一直認(rèn)為NEDD9與晚期階段的腫瘤轉(zhuǎn)移和侵襲相關(guān)。本研究第一次揭示了NEDD9在乳腺癌的腫瘤發(fā)生中起重要的作用,，并且將這一起始過程與祖細(xì)胞關(guān)聯(lián)到一起,，”論文的主要作者、Golemis實驗室博士后研究員Joy Little說,。
在這項研究中,，Little,、Golemis及合作者將無NEDD9基因的小鼠與形成HER2+乳腺腫瘤的轉(zhuǎn)基因小鼠進行交配,，發(fā)現(xiàn)這些小鼠大多對抗腫瘤形成。只有18%的小鼠形成了乳腺腫瘤,，相比之下具有功能性NEDD9基因的小鼠則有80%的形成了乳腺腫瘤,。過去的研究發(fā)現(xiàn)NEDD9水平增高可以促進腫瘤侵襲性，而在新研究中研究人員發(fā)現(xiàn)NEDD9喪失對于腫瘤轉(zhuǎn)移影響不大,，表明在這一特殊背景下它并非是這一過程的必要條件,。腫瘤一旦形成，缺乏NEDD9的小鼠腫瘤生長迅速,，表明它或是在腫瘤生長的晚期階段起不太重要的作用,，或是腫瘤發(fā)生了代償性改變，使得它們繞過了對NEDD9的需求,。
更為重要的是,，研究人員發(fā)現(xiàn)與具有功能性NEDD9基因的小鼠相比，缺失NEDD9的小鼠乳腺中的祖細(xì)胞群數(shù)量顯著減少,。來自NEDD9缺失小鼠的祖細(xì)胞不太可能在培養(yǎng)物中形成三維微球體,，而增殖速率則與來自對照小鼠的祖細(xì)胞相同,。Nedd9缺失也使得祖細(xì)胞對于低劑量的兩種腫瘤抑制藥物更為敏感。這兩種藥物分別是獲得FDA批準(zhǔn)的Src抑制劑dasatinib,，以及當(dāng)前正在癌癥治療臨床實驗中進行測試的一種FAK抑制劑,。這些結(jié)果表明這些類型的藥物可以更有效控制低水平NEDD9乳腺癌腫瘤。
Little 說：“最終,，利用活檢,，你或許能夠讀取出一個腫瘤所具有的所有突變，每一個突變都有可能表明某一線治療是否會對一種特定的腫瘤起作用,。如果在一種特定的腫瘤中NEDD9水平較高,，我們有可能能夠確定它是否會對某些抑制劑更加的敏感。”
為了跟進這項工作,，研究人員計劃進一步研究NEDD9控制腫瘤形成的機制,，并調(diào)查NEDD9是否在其他的癌癥中起相似的作用。(生物谷Bioon.com)
doi:10.1038/onc.2012.607
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PMID:
A requirement for Nedd9 in luminal progenitor cells prior to mammary tumorigenesis in MMTV-HER2/ErbB2 mice
J L Little, V Serzhanova, E Izumchenko, B L Egleston, E Parise, A J Klein-Szanto, G Loudon, M Shubina, S Seo, M Kurokawa, M F Ochsand E A Golemis
Overexpression of the NEDD9/HEF1/Cas-L scaffolding protein is frequent, and drives invasion and metastasis in breast, head and neck, colorectal, melanoma, lung and other types of cancer. We have examined the consequences of genetic ablation of Nedd9 in the MMTV-HER2/ERBB2/neu mouse mammary tumor model. Unexpectedly, we found that only a limited effect on metastasis in MMTV-neu;Nedd9−/− mice compared with MMTV-neu;Nedd9+/+mice, but instead a dramatic reduction in tumor incidence (18 versus 80%), and a significantly increased latency until tumor appearance. Orthotopic reinjection and tail-vein injection of cells arising from tumors, coupled with in vivo analysis, indicated tumors arising in MMTV-neu;Nedd9−/− mice had undergone mutational selection that overcame the initial requirement for Nedd9. To better understand the defects in early tumor growth, we compared mammary progenitor cell pools from MMTV-neu;Nedd9−/− versus MMTV-neu;Nedd9+/+ mice. The MMTV-neu;Nedd9−/− genotype selectively reduced both the number and colony-forming potential of mammary luminal epithelial progenitor cells, while not affecting basal epithelial progenitors. MMTV-neu;Nedd9−/− mammospheres had striking defects in morphology and cell polarity. All of these defects were seen predominantly in the context of the HER2/neu oncogene, and were not associated with randomization of the plane of mitotic division, but rather with depressed expression the cell attachment protein FAK, accompanied by increased sensitivity to small molecule inhibitors of FAK and SRC. Surprisingly, in spite of these significant differences, only minimal changes were observed in the gene expression profile of Nedd9−/− mice, indicating critical Nedd9-dependent differences in cell growth properties were mediated via post-transcriptional regulation of cell signaling. Coupled with emerging data indicating a role for NEDD9 in progenitor cell populations during the morphogenesis of other tissues, these results indicate a functional requirement for NEDD9 in the growth of mammary cancer progenitor cells.
