ANTXR1, a stem cell-enriched functional biomarker, connects collagen signaling to cancer stem-like cells and metastasis in breast cancer.
ANTXR1, a stem cell-enriched functional biomarker, connects collagen signaling to cancer stem-like cells and metastasis in breast cancer.
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DOI：
10.1158/0008-5472.can-13-1080
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发表时间：
2013-09-15
期刊：
影响因子：
11.2
通讯作者：
Nakshatri H
中科院分区：
文献类型：
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作者：
Chen D;Bhat-Nakshatri P;Goswami C;Badve S;Nakshatri H
癌症干细胞样细胞被认为有助于肿瘤复发。炭疽毒素受体ANTXR 1已被鉴定为正常干细胞和乳腺癌干细胞样细胞的功能性生物标志物。原代干细胞富集的基底细胞（CD 49 f +/EpCAM−/Lin−）与成熟的管腔细胞相比表达更高水平的ANTXR 1。乳腺癌细胞的CD 49 f +/EpCAM-、CD 44 +/EpCAM-、CD 44 +/CD 24-或ALDEFLUOR阳性亚群富集ANTXR 1表达。与CD 44 +/CD 24 −/ANTXR 1 −细胞相比，CD 44 +/CD 24 −/ANTXR 1+细胞显示出增强的自我更新（通过乳腺球测定法测量）。ANTXR 1通过其天然配体C5 A（胶原VI α3的片段）激活，增加了乳腺球试验中的干细胞自我更新和Wnt信号传导，包括Wnt受体LRP 6的表达、GSK 3 α/β的磷酸化和Wnt靶基因的表达升高。RNAi介导的ANTXR 1沉默增强了管腔富集基因的表达，但减少了Wnt信号传导，包括减少LRP 6和ZEB 1表达、自我更新、侵袭、致瘤性和转移。ANTXR 1沉默也降低了HSPA 1A的表达，HSPA 1A在转移性乳腺癌干细胞中过表达。对公共数据库的分析显示，ANTXR 1在髓样乳腺癌中扩增，在雌激素受体阴性乳腺癌中过度表达，结果最差。此外，ANTXR 1是乳腺癌中10%最高过表达的基因之一，并与胶原VI共表达。因此，ANTXR 1：C5 A相互作用在肿瘤微环境中桥接胶原蛋白切割和重塑的网络，将其连接到干性信号网络，从而驱动转移进展。
Cancer stem-like cells are thought to contribute to tumor recurrence. The anthrax toxin receptor ANTXR1 has been identified as a functional biomarker of normal stem cells and breast cancer stem-like cells. Primary stem cell-enriched basal cells (CD49f+/EpCAM−/Lin−) expressed higher levels of ANTXR1 compared to mature luminal cells. CD49f+/EpCAM−, CD44+/EpCAM−, CD44+/CD24− or ALDEFLUOR-positive subpopulations of breast cancer cells were enriched for ANTXR1 expression. CD44+/CD24−/ANTXR1+ cells displayed enhanced self-renewal as measured by mammosphere assay compared to CD44+/CD24−/ANTXR1− cells. Activation of ANTXR1 by its natural ligand C5A, a fragment of collagen VI α3, increased stem cell self-renewal in mammosphere assays and Wnt signaling including the expression of the Wnt receptor LRP6, phosphorylation of GSK3α/β and elevated expression of Wnt target genes. RNAi-mediated silencing of ANTXR1 enhanced the expression of luminal-enriched genes but diminished Wnt signaling including reduced LRP6 and ZEB1 expression, self-renewal, invasion, tumorigenicity and metastasis. ANTXR1 silencing also reduced the expression of HSPA1A, which is overexpressed in metastatic breast cancer stem cells. Analysis of public databases revealed ANTXR1 amplification in medullary breast carcinoma and overexpression in estrogen receptor-negative breast cancers with the worst outcome. Further, ANTXR1 is among the 10% most overexpressed genes in breast cancer and is co-expressed with collagen VI. Thus, ANTXR1:C5A interactions bridge a network of collagen cleavage and remodeling in the tumor microenvironment, linking it to a stemness signaling network drives metastatic progression.