生物谷報(bào)道：美國科學(xué)家已經(jīng)證明了一條阻止乳腺癌全身轉(zhuǎn)移的途徑，它通過阻斷相關(guān)基因或者通過藥物阻斷它們。這項(xiàng)研究結(jié)果發(fā)表在《Nature》雜志上。
90%的癌癥死亡是由于腫瘤從基本位點(diǎn)擴(kuò)散或轉(zhuǎn)移到身體的其他部位,。對科學(xué)家來說，癌癥的轉(zhuǎn)移過程至今仍是一個(gè)謎。他們并不能說出腫瘤是否會(huì)擴(kuò)散之間的區(qū)別,。以及為什么，什么時(shí)候成百上千的腫瘤細(xì)胞進(jìn)入血液,，或者是只有很小數(shù)量的腫瘤細(xì)胞在一個(gè)新的部位定居并開始增殖,。
紐約史隆凱特琳癌癥中心的Joan Massagué博士在這個(gè)領(lǐng)域研究了一段時(shí)間。他和他的團(tuán)隊(duì)一直在觀察細(xì)胞調(diào)控及他們?nèi)绾问鼓[瘤細(xì)胞擴(kuò)散到特殊組織。2005年,，他們發(fā)現(xiàn)了許多有助于乳腺癌轉(zhuǎn)移到肺的基因,。在這項(xiàng)新的研究中，他們已經(jīng)鑒定出四個(gè)特殊的基因,，它們協(xié)同作用使腫瘤細(xì)胞由原位轉(zhuǎn)移定居在新的位點(diǎn)并生長,。這四個(gè)基因分別是：EREG，間質(zhì)金屬蛋白酶-1（MMP1）,，間質(zhì)金屬蛋白酶-2（MMP2）和環(huán)氧化酶2（COX2）,。
Massagué博士和他的團(tuán)隊(duì)完成了兩項(xiàng)實(shí)驗(yàn)。其一他們切斷基因,，另一項(xiàng)他們用藥物阻斷它們,。在第一項(xiàng)研究中，他們?nèi)∪巳橄侔┘?xì)胞,，切斷所有的四個(gè)基因后注入小白鼠體內(nèi),。發(fā)現(xiàn)腫瘤并沒有生長，肺轉(zhuǎn)移的幾率也大大降低,。然而,，當(dāng)他們只是個(gè)別的阻斷這些基因，結(jié)果與預(yù)期相差甚遠(yuǎn),。第二項(xiàng)實(shí)驗(yàn)他們聯(lián)合用三種藥物抑制基因的作用,。其中兩種藥物已經(jīng)批準(zhǔn)應(yīng)用于臨床：西妥昔單抗和塞來考昔，另一種加貝酯則仍在實(shí)驗(yàn)中,。這些藥物有相同的阻斷基因的作用,。除外加貝酯單純用兩種被批準(zhǔn)的藥物同樣可以阻斷癌癥的擴(kuò)散。根據(jù)結(jié)果,，他們預(yù)測這四個(gè)基因必須共同作用才能使腫瘤生長并擴(kuò)散,。他們說這些基因可能會(huì)劫持血管使它們?nèi)〈?a href="http://hnhlg.com/news/list-54.html" target="_blank">健康細(xì)胞而為腫瘤細(xì)胞提供營養(yǎng)。接著,，它們幫助腫瘤細(xì)胞進(jìn)入血液,，穿透肺內(nèi)的血管壁，使之定居并開始增殖,。
到目前為止,，Massagué博士和他的團(tuán)隊(duì)以小鼠對對象展開研究，他們希望盡快開展人體實(shí)驗(yàn),。自從這兩種藥物被批準(zhǔn)用于臨床,，應(yīng)該會(huì)加快人體實(shí)驗(yàn)的進(jìn)程。下一階段,，目標(biāo)是找出依賴于這四個(gè)基因的乳腺癌患者,。然后他們可以測試在實(shí)驗(yàn)小鼠身上用的藥是否能同樣阻止人體的肺轉(zhuǎn)移,。
這項(xiàng)研究對腫瘤轉(zhuǎn)移理論有重要貢獻(xiàn)。許多科學(xué)家相信腫瘤在達(dá)到成熟期時(shí)才開始擴(kuò)散,。但這項(xiàng)研究對這個(gè)理論提出挑戰(zhàn),，并指出腫瘤細(xì)胞從一開始就會(huì)發(fā)生遷移。驅(qū)動(dòng)原發(fā)腫瘤生長的相同的基因同樣有助于腫瘤細(xì)胞移動(dòng)并在任何地方定居,。
這項(xiàng)研究另一個(gè)潛在貢獻(xiàn)是證明這些相同的基因與其他癌癥的轉(zhuǎn)移相關(guān),，至少有相似規(guī)律可循的可能性。這個(gè)是由德國雷根斯堡大學(xué)研究腫瘤轉(zhuǎn)移的Christoph Klein提出的,。
當(dāng)這項(xiàng)研究對揭開腫瘤轉(zhuǎn)移之謎露出一線光明時(shí),，仍有一些領(lǐng)域困惑著專家們。比如說,，一些患者在沒有找到原發(fā)腫瘤就被診斷為轉(zhuǎn)移癌,。沒有人知道為什么不同的腫瘤擴(kuò)散到不同的特定組織，就像為什么乳腺癌尤以肺和骨轉(zhuǎn)移,。
FIGURE 1. EREG, MMP1, MMP2 and COX2 cooperate to mediate primary tumour growth.
a, LM2 cells were infected with retrovirus encoding a control hairpin, or with shRNAs targeting EREG, MMP1, MMP2 or COX2. For combination knockdown retrovirus, multiple hairpin vectors were transfected as pools into viral packaging cell lines. Infected cells were selected and EREG knockdown was determined by quantitative (q)RT–PCR, COX2 analysed via western blot, and secreted MMP1 and MMP2 measured by ELISA. Shown are levels of each gene product in the parental MDA-MB-231 cell line from which LM2 cells were selected, as well as LM2 control, single (sh) and quadruple knockdown (4-sh) cells. n = 3; error bars represent 95% confidence interval for qRT–PCR analysis and standard errors of the mean (s.e.m.) for ELISA. b, 1 106 cells of control, single knockdowns, or the indicated combination knockdown samples were inoculated into the fourth mammary fat pads of immunodeficient mice. Length and width of palpable tumours were measured, and tumour volumes calculated at the indicated time points. Left: effects of single gene knockdown; right: control compared to combination knockdown cells. n = 6; error bars indicate s.e.m.; asterisk, P < 0.05; double asterisk, P < 0.01; triple asterisk, P < 0.001; calculated using a two-tailed Student's t-test for tumour volumes at the last time point, compared to control. c, Automated immunohistochemistry for phospho-histone 3 and cleaved caspase-3 detection was performed on tumours obtained from the various combination knockdown cell lines. Shown are representative images at an original magnification of 20. d, Quantification of cleaved caspase-3 staining using Image J software. n = 15; error bars indicate s.e.m.; single asterisk, P < 0.01; double asterisk, P < 0.001; calculated using a two-sided Wilcoxon rank-sum test, compared to levels in control tumours.
原文出處：
Mediators of vascular remodelling co-opted for sequential steps in lung metastasis
Gaorav P. Gupta, Don X. Nguyen, Anne C. Chiang, Paula D. Bos, Juliet Y. Kim, Cristina Nadal, Roger R. Gomis, Katia Manova-Todorova, Joan Massagué
SUMMARY: Metastasis entails numerous biological functions that collectively enable cancerous cells from a primary site to disseminate and overtake distant organs. Using genetic and pharmacological
Nature 446, 765 - 770 (12 Apr 2007) Article
Abstract | Full Text | PDF | Rights and permissions | Save this link
作者簡介：
Joan Massagué, PhD
Dr. Massagué, a renowned cell biologist, is investigating TGF-beta factors, a group of hormones that control the formation and regeneration of tissues all the way from embryonic life to adulthood. Breakdowns in TGF-beta factor activity cause serious birth defects and cancer in adults. To find ways to prevent and treat such disorders, Dr. Massagué and his group are determining the molecular processes by which the TGF-beta factors exert their control on the growth and behavior of diverse cell types.
View Joan Massagué's laboratory research at Sloan-Kettering Institute.
相關(guān)基因：
EREG
Official Symbol: EREG and Name: epiregulin [Homo sapiens]
Other Aliases: ER
Chromosome: 4; Location: 4q13.3
MIM: 602061
GeneID: 2069
MMP1
Official Symbol: MMP1 and Name: matrix metallopeptidase 1 (interstitial collagenase) [Homo sapiens]
Other Aliases: CLG, CLGN
Other Designations: fibroblast collagenase; interstitial collagenase; matrix metalloprotease 1; matrix metalloproteinase 1; matrix metalloproteinase 1 (interstitial collagenase)
Chromosome: 11; Location: 11q22.3
MIM: 120353
GeneID: 4312
MMP2
Official Symbol: MMP2 and Name: matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase) [Homo sapiens]
Other Aliases: CLG4, CLG4A, MMP-II, MONA, TBE-1
Other Designations: 72kD type IV collagenase; collagenase type IV-A; matrix metalloproteinase 2; matrix metalloproteinase 2 (gelatinase A, 72kD gelatinase, 72kD type IV collagenase); matrix metalloproteinase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase); matrix metalloproteinase-II; neutrophil gelatinase
Chromosome: 16; Location: 16q13-q21
MIM: 120360
GeneID: 4313
