Clin Cancer Res. ：在HER2阴性乳腺癌中鉴定出HER2阳性干细胞

MedSci编者按：这一研究与以往发现肿瘤具有异质性是一致的，肿瘤在不同的发展阶段，以及不同的治疗阶段，都不段在变化，包括表面标志物，甚至突变状况，都随时可能发生改变，这些改变给肿瘤的治疗带来困难，尤其为靶向治疗提出了新的挑战。当然，本研究由HER2阴性向阳性转变，同样HER2阳性的乳腺癌也有可能会转变为HER2阴性肿瘤。

在一项新的研究中,来自美国加州大学戴维斯分校、密歇根大学癌症综合研究中心、爱荷华大学霍顿综合癌症研究中心(Holden Comprehensive Cancer Center at the University of Iowa)、埃默里大学医学院和德州大学MD安德森癌症中心的研究人员在最为常见类型的乳腺癌中发现新的但又自相矛盾的特征.这些研究发现有助于深入人们认识这种疾病如何能够躲避治疗,从而可能改善乳腺癌诊断和治疗.

在加州大学戴维斯分校放射肿瘤科转化研究主任Jian Jian Li的领导下,研究人员研究了之前被认为缺乏HER2蛋白的乳腺癌,其中已知HER2过表达与癌症复发相关联.令人吃惊的是,研究人员在这种肿瘤中发现一小群侵袭性的抗治疗的HER2阳性乳腺癌干细胞(breast cancer stem cells, BCSCs).相关研究结果将发表在2012年12月15日那期Clinical Cancer Research期刊上,论文标题为“HER2-Associated Radioresistance of Breast Cancer Stem Cells Isolated from HER2-Negative Breast Cancer Cells”.Jian Jian Li是论文通信作者.

Li说,“这些BCSCs极其抵抗传统治疗,因而能够导致病人癌症复发.尽管将化疗、放疗或者甚至手术摘除用于治疗,但是这种癌症仍然复发.这些研究发现改变我们对乳腺癌的认识,这是因为如今我们知道靶向HER2的治疗方法能够有效地治疗HER2阴性乳腺癌.”

过去十年来,科学家和临床医生已更好地理解不同类型的乳腺癌在细胞水平上如何产生差异.一种乳腺癌是否含有HER2、雌激素受体蛋白、孕酮受体蛋白或者全部含有这三种蛋白或者都不含有任何其中一种蛋白能够对这种肿瘤的侵袭性、病人总体预后和治疗选择产生巨大的影响.

人们经常使用靶向HER2蛋白的药物如抗体药物赫塞汀(Herceptin)或拉帕替尼(Tykerb)来治疗HER2阳性乳腺癌,并且取得较好的结果.然而,直到最近,人们实在没有理由利用这些靶向HER2蛋白的治疗方法来治疗患有HER2阴性乳腺癌的病人.

在这项研究中,研究人员从经过化疗治疗的HER2阴性乳腺癌中分离出HER2阳性BCSCs.他们也分析了指示癌症侵袭性和作为BCSCs标记物的细胞表面蛋白CD44和CD24.

研究人员发现HER2阳性、CD44阳性、CD24阴性/较低CD4水平的BCSCs是更为侵袭性的,而且高度对抗化疗治疗.进行赫塞汀或小分子干扰RNA(short interfering RNA, siRNA)处理则显着性地降低这些特征.他们在57.1%的原发性肿瘤和84.6%的复发性肿瘤中发现HER2阳性、CD44阳性的BCSCs.

除了鉴定出这种之前未曾发现的HER2阳性干细胞群体之外,进一步研究有助于人们深入认识这些BCSCs如何维持它们对抗治疗的能力.包括HER2和STAT3在内的复杂蛋白网络调节肿瘤转移、程序性细胞死亡和其他功能.因此,这些细胞在所有的传统抗癌疗法中存活下来.

Li说,“我们认为这项研究在科学和临床上具有重大的意义.如今我们能够更好地理解这些BCSCs如何抵抗化疗和其他治疗方法.”

尽管最近的研究已证实患有HER2阴性乳腺癌的病人确实能够有益于靶向HER2的疗法,但是在这项研究之前,没有人理解其中的机制.这项研究详细地证实靶向HER2的疗法能够潜在地改善治疗HER2阴性乳腺癌的结果.

这项研究不仅有助于为治疗HER2阴性乳腺癌病人提供新的治疗选择,而且也提供一种新的诊断途径.诸如CD44的标记物可能有助于临床医生在表面上是HER2阴性的乳腺癌中鉴定出侵袭性的HER2阳性BCSCs.

Li说,“这可能为治疗很难治疗的晚期骨癌、肺癌或脑癌中的HER2阳性干细胞提供可能.”

拓展阅读：

NEJM：肿瘤内异质性和分支进化揭示肿瘤的复杂性

NEJM：肿瘤具有高度遗传异质性

doi: 10.1158/1078-0432.CCR-12-1436
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PMID:

HER2-Associated Radioresistance of Breast Cancer Stem Cells Isolated from HER2-Negative Breast Cancer Cells

Nadire Duru1, Ming Fan1, Demet Candas1, Cheikh Menaa1, Hsin-Chen Liu1, Danupon Nantajit1, Yunfei Wen6, Kai Xiao2, Angela Eldridge1,3, Brett A. Chromy3,5, Shiyong Li7, Douglas R. Spitz8, Kit S. Lam2,4, Max S. Wicha9, and Jian Jian Li1,4

Purpose: To understand the role of HER2-associated signaling network in breast cancer stem cells (BCSC) using radioresistant breast cancer cells and clinical recurrent breast cancers to evaluate HER2-targeted therapy as a tumor eliminating strategy for recurrent HER2−/low breast cancers. Experimental Design: HER2-expressing BCSCs (HER2+/CD44+/CD24−/low) were isolated from radiation-treated breast cancer MCF7 cells and in vivo irradiated MCF7 xenograft tumors. Tumor aggressiveness and radioresistance were analyzed by gap filling, Matrigel invasion, tumor-sphere formation, and clonogenic survival assays. The HER2/CD44 feature was analyzed in 40 primary and recurrent breast cancer specimens. Protein expression profiling in HER2+/CD44+/CD24−/low versus HER2−/CD44+/CD24−/low BCSCs was conducted with two-dimensional difference gel electrophoresis (2-D DIGE) and high-performance liquid chromatography tandem mass spectrometry (HPLC/MS-MS) analysis and HER2-mediated signaling network was generated by MetaCore program. Results: Compared with HER2-negative BCSCs, HER2+/CD44+/CD24−/low cells showed elevated aldehyde dehydrogenase (ALDH) activity and aggressiveness tested by Matrigel invasion, tumor sphere formation, and in vivo tumorigenesis. The enhanced aggressive phenotype and radioresistance of the HER2+/CD44+/CD24−/low cells were markedly reduced by inhibition of HER2 via siRNA or Herceptin treatments. Clinical breast cancer specimens revealed that cells coexpressing HER2 and CD44 were more frequently detected in recurrent (84.6%) than primary tumors (57.1%). In addition, 2-D DIGE and HPLC/MS-MS of HER2+/CD44+/CD24−/low versus HER2−/CD44+/CD24−/low BCSCs reported a unique HER2-associated protein profile including effectors involved in tumor metastasis, apoptosis, mitochondrial function, and DNA repair. A specific feature of HER2–STAT3 network was identified. Conclusion: This study provides the evidence that HER2-mediated prosurvival signaling network is responsible for the aggressive phenotype of BCSCs that could be targeted to control the therapy-resistant HER2−/low breast cancer.