Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer.
Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer.
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DOI：
10.1007/s10549-017-4311-8
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发表时间：
2017-08
影响因子：
3.8
通讯作者：
Joshi A
中科院分区：
文献类型：
--
作者：
Flister MJ;Tsaih SW;Stoddard A;Plasterer C;Jagtap J;Parchur AK;Sharma G;Prisco AR;Lemke A;Murphy D;Al-Gizawiy M;Straza M;Ran S;Geurts AM;Dwinell MR;Greene AS;Bergom C;LaViolette PS;Joshi A
肿瘤微环境（TME）的多个方面影响乳腺癌，但TME的遗传修饰剂在很大程度上是未知的，包括那些改变肿瘤血管形成和功能的基因。为了发现宿主TME修饰物，我们开发了一种称为同源/同源异种移植模型（CXM）的系统。在CXM中，将人乳腺癌细胞原位植入遗传工程改造的同源异种移植宿主菌株中，所述宿主菌株源自对乳腺癌具有不同易感性的两种亲本菌株。由于异种移植宿主菌株的遗传背景不同，而接种的肿瘤细胞相同，因此任何表型变异都是由于被取代的染色体（同源）或亚染色体区域（同源）上的TME特异性修饰剂所致。在这里，我们评估了植入SSIL 2 R γ和SS.BN3IL2Rγ CXM菌株的肿瘤的生长、血管生成和血管功能的TME调节剂。与SSIL 2 R γ（亲本对照）相比，植入SS.BN3IL2Rγ（同源）的乳腺癌异种移植物具有显著的肿瘤生长抑制，尽管SS.BN3IL2Rγ肿瘤中血管密度的矛盾增加。我们假设SS.BN3IL2Rγ肿瘤的生长减少可能是由于非生产性血管生成。为了测试这种可能性，通过动态对比增强磁共振成像（DCE-MRI）、微型计算机断层扫描（micro-CT）和原代血液内皮细胞的离体分析来检查SSIL 2 R γ和SS.BN3IL2Rγ肿瘤血管功能;所有这些都显示与SSIL 2 R γ相比SS.BN3IL2Rγ肿瘤中的血管功能改变。基因表达分析还显示SS.BN3IL2Rγ肿瘤中血管信号网络失调，其中DLL 4差异表达并共定位于通过同源定位鉴定的宿主TME修饰基因座（Chr 3：95- 131 Mb）。总的来说，这些数据表明RNO 3上的宿主遗传修饰剂诱导非生产性血管生成，其通过DLL 4途径抑制肿瘤生长。
Multiple aspects of the tumor microenvironment (TME) impact breast cancer, yet the genetic modifiers of the TME are largely unknown, including those that modify tumor vascular formation and function. To discover host TME modifiers, we developed a system called the Consomic/Congenic Xenograft Model (CXM). In CXM, human breast cancer cells are orthotopically implanted into genetically-engineered consomic xenograft host strains that are derived from two parental strains with different susceptibilities to breast cancer. Because the genetic backgrounds of the xenograft host strains differ, whereas the inoculated tumor cells are the same, any phenotypic variation is due to TME-specific modifier(s) on the substituted chromosome (consomic) or subchromosomal region (congenic). Here, we assessed TME modifiers of growth, angiogenesis, and vascular function of tumors implanted in the SSIL2Rγ and SS.BN3IL2Rγ CXM strains. Breast cancer xenografts implanted in SS.BN3IL2Rγ (consomic) had significant tumor growth inhibition compared with SSIL2Rγ (parental control), despite a paradoxical increase in the density of blood vessels in the SS.BN3IL2Rγ tumors. We hypothesized that decreased growth of SS.BN3IL2Rγ tumors might be due to nonproductive angiogenesis. To test this possibility, SSIL2Rγ and SS.BN3IL2Rγ tumor vascular function was examined by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), micro-computed tomography (micro-CT), and ex vivo analysis of primary blood endothelial cells; all of which revealed altered vascular function in SS.BN3IL2Rγ tumors compared with SSIL2Rγ. Gene expression analysis also showed a dysregulated vascular signaling network in SS.BN3IL2Rγ tumors, among which DLL4 was differentially expressed and co-localized to a host TME modifier locus (Chr3: 95–131Mb) that was identified by congenic mapping. Collectively, these data suggest that host genetic modifier(s) on RNO3 induce nonproductive angiogenesis that inhibits tumor growth through the DLL4 pathway.
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影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
8.3
作者：
Flister, Michael J.;Hoffman, Matthew J.;Moreno, Carol
通讯作者：
Moreno, Carol
DOI：
10.1073/pnas.0611177104
发表时间：
2007-02-27
影响因子：
11.1
作者：
Suchting, Steven;Freitas, Catarina;Eichmann, Anne
通讯作者：
Eichmann, Anne
影响因子：
8.3
作者：
Hoffman, Matthew J.;Flister, Michael J.;Moreno, Carol
通讯作者：
Moreno, Carol