Tumor-Endothelial Interaction Links the CD44+/CD24- Phenotype with Poor Prognosis in Early-Stage Breast Cancer
Tumor-Endothelial Interaction Links the CD44+/CD24- Phenotype with Poor Prognosis in Early-Stage Breast Cancer
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DOI：
10.1593/neo.09670
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发表时间：
2009-10-01
期刊：
影响因子：
4.8
通讯作者：
Rochlitz, Christoph
中科院分区：
文献类型：
--
作者：
Buess, Martin;Rajski, Michal;Rochlitz, Christoph
材料和方法：肿瘤-内皮细胞相互作用在癌症中的基因组效应尚未得到很好的表征。为了研究这种相互作用在乳腺癌中，我们建立了一个离体共培养模型与人类良性和恶性乳腺上皮细胞与内皮细胞，以确定相关的基因表达变化，使用DNA微阵列。研究结果：对共培养的最突出的反应是在与正常乳腺上皮细胞共培养中不存在的乳腺癌共培养物的子集中诱导M期细胞周期基因。在单一培养中，含有干细胞样CD 44（+）/CD 24（-）标记的肿瘤细胞的M期细胞周期基因的表达低于CD 44（-）/CD 24（+）细胞，并且在CD 44（+）/CD 24（-）共培养中，这些基因被诱导。早期乳腺癌的预处理基因表达谱允许评估体内体外效应。来自共培养物的基因集的表达为将肿瘤分离成两组提供了基础。在单因素分析中，M期细胞周期基因表达水平高的早期肿瘤（n = 137）无转移生存率显著较低（P = 1.8e - 5，10年时50%）和总生存率（P = 5e - 9，10年时52%）比低表达肿瘤（n = 158;无转移生存率，73%;总生存率，84%）。结论：我们的研究结果表明，内皮细胞与表达CD 44（+）/CD 24（-）标记的肿瘤细胞的相互作用表明低增殖潜力，这可能解释了CD 44（+）/CD 24（-）标记与预后不良的高度增殖性肿瘤的意外和矛盾的联系。
MATERIALS AND METHODS: The genomic effects of tumor-endothelial interactions in cancer are not yet well characterized. To study this interaction in breast cancer, we set up an ex vivo coculture model with human benign and malignant breast epithelial cells with endothelial cells to determine the associated gene expression changes using DNA microarrays. RESULTS: The most prominent response to coculture was the induction of the M-phase cell cycle genes in a subset of breast cancer cocultures that were absent in cocultures with normal breast epithelial cells. In monoculture, tumor cells that contained the stem cell-like CD44(+)/CD24(-) signature had a lower expression of the M-phase cell cycle genes than the CD44(-)/CD24(+) cells, and in the CD44(+)/CD24(-) cocultures, these genes were induced. Pretreatment gene expression profiles of early-stage breast cancers allowed evaluating in vitro effects in vivo. The expression of the gene set derived from the coculture provided a basis for the segregation of the tumors into two groups. In a univariate analysis, early-stage tumors with high expression levels (n = 137) of the M-phase cell cycle genes had a significantly lower metastasis-free survival rate (P = 1.8e - 5, 50% at 10 years) and overall survival rate (P = 5e - 9, 52% at 10 years) than tumors with low expression (n = 158; metastasis-free survival, 73%; overall survival, 84%). CONCLUSIONS: Our results suggest that the interaction of endothelial cells with tumor cells that express the CD44(+)/CD24(-) signature, which indicates a low proliferative potential, might explain the unexpected and paradoxical association of the CD44(+)/CD24(-) signature with highly proliferative tumors that have an unfavorable prognosis.