Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-5900, USA.
BMC Cancer. 2011 Jul 20;11:304. doi: 10.1186/1471-2407-11-304.
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.
乳腺癌是美国女性癌症相关死亡的第二大主要原因。在疾病的晚期，许多乳腺癌患者患有骨转移。这些转移主要是溶骨性的，并且当肿瘤细胞与骨骼相互作用时发展。模仿乳腺癌特异性溶骨性骨微环境的体内模型是有限的。以前，我们开发了一种肿瘤-骨相互作用的小鼠模型，其中三种小鼠乳腺癌细胞系被植入颅骨。该模型肿瘤的分析表明，它们表现出强烈的骨吸收，破骨细胞的诱导以及肿瘤骨（TB）界面内的颅内穿透。
在这项研究中，我们从该模型中鉴定并使用了 TB 微环境特异性基因表达特征，以扩展我们对人类疾病中转移性骨微环境的理解，并预测潜在的治疗靶标。
我们鉴定了一个 TB 特征，该特征由 934 个基因组成，这些基因在我们的小鼠溶骨性模型中在 TB 界面处普遍（在我们的 3 种细胞系中）和特异性（与骨微环境中肿瘤单独区域相比）上调和下调 >2 倍。通过将 TB 特征与来自人类乳腺癌转移和体外破骨细胞模型的基因表达谱进行比较，我们证明我们的模型模拟了人类乳腺癌骨微环境和破骨细胞生成。此外，我们观察到各种信号通路在 TB 界面上的富集；也就是说，TGF-β 和髓样自我更新途径被激活，Wnt 途径被失活。最后，我们使用 TB 特征来预测环戊噻嗪作为 TB 界面的潜在抑制剂。
我们的小鼠乳腺癌模型在形态和遗传上与人类疾病中观察到的破骨细胞骨微环境相似。对我们模型中 TB 界面特有的基因表达特征的特征分析揭示了人类乳腺癌转移中起作用的信号机制，并预测了癌症介导的溶骨性的治疗抑制剂。
