Mol Can Res：科学家揭示调节乳腺癌细胞发生失巢凋亡的分子机制

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Mol Can Res：科学家揭示调节乳腺癌细胞发生失巢凋亡的分子机制
  Q. b( J" J2 Q6 f2 r5 s来源：生物谷 2014-05-12 08:55* _  T- ~7 Y+ Q! _2 g/ E

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5 Z0 Y/ l$ V; a2 U2014年5月11日 讯 /生物谷BIOON/ --近日，刊登在国际杂志Molecular Cancer Research上的一篇研究论文中，来自美国圣母大学的研究人员通过研究揭示了和癌相关的成纤维细胞(carcinoma-associated fibroblasts，CAFs)在肿瘤生物学中所扮演的角色。
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$ E+ Z( I) C% d* w% |癌相关的成纤维细胞(carcinoma-associated fibroblasts，CAFs) 是肿瘤和宿主之间界面的一种微环境，最近一系列研究都表明CAFs可以通过不同的机制引发肿瘤恶化发生，但是截至目前研究者并没有完全搞清楚CAFs促进肿瘤扩散生长的机制。" |# i) U$ o, @/ h

  m/ |1 U0 x- W. R* y0 l这项研究中，研究者Schafer和其同事通过研究揭示了CAFs在通过分泌胰岛素样生长因子结合蛋白（IGFBPs）阻断失巢凋亡中发挥的作用，失巢凋亡现象是一种细胞死亡的过程，该过程可以抑制肿瘤细胞向较远的位点发生扩散。研究者表示，通过利用IGFBPs的精确分子机制可以抑制失巢凋亡的发生，从而促进抗细胞死亡蛋白Mcl-1稳定。
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' h. n, F; K) ?3 Y" H: R研究者Schafer表示，当肿瘤微环境中的细胞都被激活用以促进肿瘤恶化时，我们所研究的这种机制就会自动发生，基于此开发出的抑制IGFBPs的疗法将被用于减缓乳腺癌的扩散。研究者表示，未来还需要前期的临床试验来更好地帮助我们理解IGFBPs作为靶点开发新型靶向疗法的意义，这样才能够确定肿瘤恶化过程中疗法的准确攻击靶点以及对IGFBPs抑制的有效性。（生物谷Bioon.com）
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( B$ t* n' o2 B" ]: o7 e! mdoi:10.1158/1541-7786.MCR-14-0090 4 @, P2 A$ _( {$ T. G) w
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CAF-Secreted IGFBPs Regulate Breast Cancer Cell Anoikis , F2 |( N# R& }; @- K! b* V4 B. c

9 R7 ]# `- H2 q3 Y7 ?3 d% ^Kelsey J. Weigel1, Ana Jakimenko1, Brooke A. Conti1, Sarah E. Chapman3, William J. Kaliney4, W. Matthew Leevy1,3, Matthew M. Champion2, and Zachary T. Schafer1
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Carcinoma-associated fibroblasts (CAFs) are now widely appreciated for their contributions to tumor progression. However, the ability of CAFs to regulate anoikis, detachment-induced cell death, has yet to be investigated. Here, a new role for CAFs in blocking anoikis in multiple cell lines, facilitating luminal filling in three-dimensional cell culture, and promoting anchorage-independent growth is defined. In addition, a novel mechanism underlying anoikis inhibition is discovered. Importantly, it was demonstrated that CAFs secrete elevated quantities of insulin-like growth factor–binding proteins (IGFBPs) that are both necessary for CAF-mediated anoikis inhibition and sufficient to block anoikis in the absence of CAFs. Furthermore, these data reveal a unique antiapoptotic mechanism for IGFBPs: the stabilization of the antiapoptotic protein Mcl-1. In aggregate, these data delineate a novel role for CAFs in promoting cell survival during detachment and unveil an additional mechanism by which the tumor microenvironment contributes to cancer progression. These results also identify IGFBPs as potential targets for the development of novel chemotherapeutics designed to eliminate detached cancer cells. Implications: The ability of CAF-secreted IGFBPs to block anoikis in breast cancer represents a novel target for the development of therapeutics aimed at specifically eliminating extracellular matrix–detached breast cancer cells. Mol Cancer Res; 1–12. ©2014 AACR.' _" \/ K7 I; q; p: {/ I" \

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