科学家鉴别出乳腺癌发生的细胞起源

  癌症生物学中的一个关键问题就是理解控制肿瘤异质性的机制，这或许可以帮助确定哪种肿瘤的异质性会影响患者预后的效果。近日刊登在国际杂志Nture上的一项研究论文中，来自比利时布鲁塞尔自由大学等处的科学家通过研究揭开了PIK3CA诱导的乳腺肿瘤的细胞起源，研究者表示，癌细胞的起源或许可以控制肿瘤的异质性，而且其海河多种类型的乳腺肿瘤及患者预后直接相关。
  乳腺癌是女性最常见的癌症，人类的乳腺癌根据其组织学和分子特性分为不同的亚型，包括细胞腔型、ERBB2型及基底样肿瘤等，PIK3CA和p53基因是人类乳腺癌最为常见的突变基因，而且其和不同的乳腺癌分子亚型直接相关。
  这项研究中研究人员利用先进的遗传小鼠模型进行研究鉴别出了PIK3CA和p53基因诱发的乳腺肿瘤的细胞起源，研究者表示，依赖于细胞起源，PIK3CA和p53基因的突变就会诱导不同类型乳腺肿瘤的产生；细胞腔型肿瘤细胞通常会引发恶性乳腺癌，而让研究者非常惊讶的是，基底样细胞中致癌的Pik3ca会诱导细胞腔型肿瘤的产生，同时Pik3ca的表达还会引发肿瘤异质性及恶性肿瘤的发生。
  通过分析先于肿瘤形成的步骤，研究者Alexandra Van Keymeulen及其同时发现，致癌性Pik3ca的表达会重新激活成体干细胞中多向性分化程序，这就类似于不成熟的胚胎发育阶段；经历向致癌Pik3ca表达细胞命运的细胞的分子特性往往就可以阐明新形成细胞的癌基因诱导的重编程过程，同时还可以帮助鉴别基因表达的特性。
  不同细胞命运开关的特性可以帮助预测乳腺癌的起源、肿瘤类型及乳腺癌患者的预后情况，而研究者发现，本文研究不仅可以阐明控制乳腺癌肿瘤异质性的癌细胞起源，还可以帮助解释肿瘤起始阶段的基因表达特性或可帮助预测肿瘤的类型及患者的预后情况。
  最后研究者表示，本文研究鉴别出了Pik3ca诱导的肿瘤发生的细胞起源，并且解释了致癌的Pik3ca可以帮助激活一种多潜能的遗传程序，从而就为未来阐明肿瘤异质性发生的原因提供思路，当前研究对于控制肿瘤的异质性非常关键，也对后期开发新型策略来阻断PIK3CA诱导的乳腺癌提供了新的思路。（转化医学网360zhyx.com）
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转化医学网推荐的原文摘要：

Reactivation of multipotency by oncogenic PIK3CA induces breast tumour heterogeneity
Nature       doi:10.1038/nature14665
Alexandra Van Keymeulen, May Yin Lee, Marielle Ousset, Sylvain Brohée, Sandrine Rorive, Rajshekhar R. Giraddi, Aline Wuidart, Gaëlle Bouvencourt, Christine Dubois, Isabelle Salmon, Christos Sotiriou, Wayne A. Phillips & Cédric Blanpain
Breast cancer is the most frequent cancer in women and consists of heterogeneous types of tumours that are classified into different histological and molecular subtypes1, 2. PIK3CA and P53 (also known as TP53) are the two most frequently mutated genes and are associated with different types of human breast cancers3. The cellular origin and the mechanisms leading to PIK3CA-induced tumour heterogeneity remain unknown. Here we used a genetic approach in mice to define the cellular origin of Pik3ca-derived tumours and the impact of mutations in this gene on tumour heterogeneity. Surprisingly, oncogenic Pik3caH1047R mutant expression at physiological levels4 in basal cells using keratin (K)5-CreERT2 mice induced the formation of luminal oestrogen receptor (ER)-positive/progesterone receptor (PR)-positive tumours, while its expression in luminal cells using K8-CReERT2 mice gave rise to luminal ER+PR+ tumours or basal-like ER−PR− tumours. Concomitant deletion of p53 and expression of Pik3caH1047R accelerated tumour development and induced more aggressive mammary tumours. Interestingly, expression of Pik3caH1047R in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumours. Transcriptional profiling of cells that underwent cell fate transition upon Pik3caH1047R expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3caH1047R expression in basal and luminal cells, which correlated with the cell of origin, tumour type and different clinical outcomes. Altogether our study identifies the cellular origin of Pik3ca-induced tumours and reveals that oncogenic Pik3caH1047R activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumour initiation, setting the stage for future intratumoural heterogeneity. These results have important implications for our understanding of the mechanisms controlling tumour heterogeneity and the development of new strategies to block PIK3CA breast cancer initiation.