A cross-species analysis of a mouse model of breast cancer-specific osteolysis and human bone metastases using gene expression profiling.
A cross-species analysis of a mouse model of breast cancer-specific osteolysis and human bone metastases using gene expression profiling.
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DOI：
10.1186/1471-2407-11-304
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发表时间：
2011-07-20
期刊：
影响因子：
3.8
通讯作者：
Singh RK
中科院分区：
文献类型：
--
作者：
Sadanandam A;Futakuchi M;Lyssiotis CA;Gibb WJ;Singh RK
乳腺癌是美国女性癌症相关死亡的第二大原因。在疾病的晚期，许多乳腺癌患者患有骨转移。这些转移瘤主要是溶骨的，当肿瘤细胞与骨相互作用时发生。模拟乳腺癌特异性溶骨微环境的体内模型是有限的。在此之前，我们开发了一个肿瘤-骨相互作用的小鼠模型，在该模型中，三个小鼠乳腺癌细胞系被种植到颅骨上。对该模型肿瘤的分析表明，它们表现出强烈的骨吸收、破骨细胞的诱导和肿瘤骨(TB)-界面的颅内穿透。在这项研究中，我们从这个模型中识别并使用了结核病微环境特异性基因表达特征，以扩大我们对人类疾病转移骨微环境的理解，并预测潜在的治疗靶点。在我们的小鼠溶骨模型中，我们发现了一个由934个基因组成的结核标志物，这些基因通常(在我们的3个细胞系中)和特异性(与骨骼微环境中的肿瘤单独区域相比)在TB界面上上调和下调2倍。通过比较结核信号与人类乳腺转移瘤和体外破骨细胞模型的基因表达谱，我们证明我们的模型既模拟了人类乳腺癌的骨微环境，又模拟了破骨细胞的形成。此外，我们观察到TB界面特异的各种信号通路的丰富；即转化生长因子-β和髓系自我更新通路被激活，而Wnt通路被失活。最后，我们使用TB-Signature来预测环丙沙星可能成为TB界面的抑制因子。我们的小鼠乳腺癌模型在形态和基因上与人类疾病中观察到的破骨细胞骨微环境相似。在我们的模型中，对TB界面特异性基因表达特征的表征揭示了在人类乳腺癌转移中起作用的信号机制，并预测了一种癌症介导的骨溶解的治疗抑制物。
Breast cancer is the second leading cause of cancer-related death in women in the United States. During the advanced stages of disease, many breast cancer patients suffer from bone metastasis. These metastases are predominantly osteolytic and develop when tumor cells interact with bone. In vivo models that mimic the breast cancer-specific osteolytic bone microenvironment are limited. Previously, we developed a mouse model of tumor-bone interaction in which three mouse breast cancer cell lines were implanted onto the calvaria. Analysis of tumors from this model revealed that they exhibited strong bone resorption, induction of osteoclasts and intracranial penetration at the tumor bone (TB)-interface. In this study, we identified and used a TB microenvironment-specific gene expression signature from this model to extend our understanding of the metastatic bone microenvironment in human disease and to predict potential therapeutic targets. We identified a TB signature consisting of 934 genes that were commonly (among our 3 cell lines) and specifically (as compared to tumor-alone area within the bone microenvironment) up- and down-regulated >2-fold at the TB interface in our mouse osteolytic model. By comparing the TB signature with gene expression profiles from human breast metastases and an in vitro osteoclast model, we demonstrate that our model mimics both the human breast cancer bone microenvironment and osteoclastogenesis. Furthermore, we observed enrichment in various signaling pathways specific to the TB interface; that is, TGF-β and myeloid self-renewal pathways were activated and the Wnt pathway was inactivated. Lastly, we used the TB-signature to predict cyclopenthiazide as a potential inhibitor of the TB interface. Our mouse breast cancer model morphologically and genetically resembles the osteoclastic bone microenvironment observed in human disease. Characterization of the gene expression signature specific to the TB interface in our model revealed signaling mechanisms operative in human breast cancer metastases and predicted a therapeutic inhibitor of cancer-mediated osteolysis.
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影响因子：
12.3
作者：
Herschkowitz JI;Simin K;Weigman VJ;Mikaelian I;Usary J;Hu Z;Rasmussen KE;Jones LP;Assefnia S;Chandrasekharan S;Backlund MG;Yin Y;Khramtsov AI;Bastein R;Quackenbush J;Glazer RI;Brown PH;Green JE;Kopelovich L;Furth PA;Palazzo JP;Olopade OI;Bernard PS;Churchill GA;Van Dyke T;Perou CM
通讯作者：
Perou CM
影响因子：
3.7
作者：
Hoshida Y;Brunet JP;Tamayo P;Golub TR;Mesirov JP
通讯作者：
Mesirov JP
影响因子：
5.8
作者：
Benito, M;Parker, J;Marron, JS
通讯作者：
Marron, JS
影响因子：
14.9
作者：
Barrett T;Troup DB;Wilhite SE;Ledoux P;Rudnev D;Evangelista C;Kim IF;Soboleva A;Tomashevsky M;Marshall KA;Phillippy KH;Sherman PM;Muertter RN;Edgar R
通讯作者：
Edgar R
DOI：
10.1056/nejmoa0804525
发表时间：
2008-11-06
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hoshida Y;Villanueva A;Kobayashi M;Peix J;Chiang DY;Camargo A;Gupta S;Moore J;Wrobel MJ;Lerner J;Reich M;Chan JA;Glickman JN;Ikeda K;Hashimoto M;Watanabe G;Daidone MG;Roayaie S;Schwartz M;Thung S;Salvesen HB;Gabriel S;Mazzaferro V;Bruix J;Friedman SL;Kumada H;Llovet JM;Golub TR
通讯作者：
Golub TR