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科学家发现阻断癌症转移的靶基因

2017-12-22

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导读:生物谷报道:美国科学家已经证明了一条阻止乳腺癌全身转移的途径,它通过阻断相关基因或者通过药物阻断它们。

    生物谷报道:美国科学家已经证明了一条阻止乳腺癌全身转移的途径,它通过阻断相关基因或者通过药物阻断它们。这项研究结果发表在《Nature》杂志上。
    90%的癌症死亡是由于肿瘤从基本位点扩散或转移到身体的其他部位。对科学家来说,癌症的转移过程至今仍是一个谜。他们并不能说出肿瘤是否会扩散之间的区别。以及为什么,什么时候成百上千的肿瘤细胞进入血液,或者是只有很小数量的肿瘤细胞在一个新的部位定居并开始增殖。
    纽约史隆凯特琳癌症中心的Joan Massagué博士在这个领域研究了一段时间。他和他的团队一直在观察细胞调控及他们如何使肿瘤细胞扩散到特殊组织。2005年,他们发现了许多有助于乳腺癌转移到肺的基因。在这项新的研究中,他们已经鉴定出四个特殊的基因,它们协同作用使肿瘤细胞由原位转移定居在新的位点并生长。这四个基因分别是:EREG,间质金属蛋白酶-1(MMP1),间质金属蛋白酶-2(MMP2)和环氧化酶2(COX2)。
    Massagué博士和他的团队完成了两项实验。其一他们切断基因,另一项他们用药物阻断它们。在第一项研究中,他们取人乳腺癌细胞,切断所有的四个基因后注入小白鼠体内。发现肿瘤并没有生长,肺转移的几率也大大降低。然而,当他们只是个别的阻断这些基因,结果与预期相差甚远。第二项实验他们联合用三种药物抑制基因的作用。其中两种药物已经批准应用于临床:西妥昔单抗和塞来考昔,另一种加贝酯则仍在实验中。这些药物有相同的阻断基因的作用。除外加贝酯单纯用两种被批准的药物同样可以阻断癌症的扩散。根据结果,他们预测这四个基因必须共同作用才能使肿瘤生长并扩散。他们说这些基因可能会劫持血管使它们取代健康细胞而为肿瘤细胞提供营养。接着,它们帮助肿瘤细胞进入血液,穿透肺内的血管壁,使之定居并开始增殖。
    到目前为止,Massagué博士和他的团队以小鼠对对象展开研究,他们希望尽快开展人体实验。自从这两种药物被批准用于临床,应该会加快人体实验的进程。下一阶段,目标是找出依赖于这四个基因的乳腺癌患者。然后他们可以测试在实验小鼠身上用的药是否能同样阻止人体的肺转移。
    这项研究对肿瘤转移理论有重要贡献。许多科学家相信肿瘤在达到成熟期时才开始扩散。但这项研究对这个理论提出挑战,并指出肿瘤细胞从一开始就会发生迁移。驱动原发肿瘤生长的相同的基因同样有助于肿瘤细胞移动并在任何地方定居。
    这项研究另一个潜在贡献是证明这些相同的基因与其他癌症的转移相关,至少有相似规律可循的可能性。这个是由德国雷根斯堡大学研究肿瘤转移的Christoph Klein提出的。
当这项研究对揭开肿瘤转移之谜露出一线光明时,仍有一些领域困惑着专家们。比如说,一些患者在没有找到原发肿瘤就被诊断为转移癌。没有人知道为什么不同的肿瘤扩散到不同的特定组织,就像为什么乳腺癌尤以肺和骨转移。

 

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.

 

原文出处:

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

 

作者简介:

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.

 

 

相关基因:

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

 

 

 

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