Alcalá Sonia, Martinelli Paola, Hermann Patrick C, Heeschen Christopher, Sainz Bruno
Department of Biochemistry, Universidad Autónoma de Madrid (UAM), Madrid, Spain.
Department of Cancer Biology, Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM), CSIC-UAM, Madrid, Spain.
Stem Cells Int. 2019 May 2;2019:1378639. doi: 10.1155/2019/1378639. eCollection 2019.
Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer-related mortality. Cancer stem cells (CSCs) have been shown to be the drivers of pancreatic tumor growth, metastasis, and chemoresistance, but our understanding of these cells is still limited by our inability to efficiently identify and isolate them. While a number of markers capable of identifying pancreatic CSCs (PaCSCs) have been discovered since 2007, there is no doubt that more markers are still needed. The anthrax toxin receptor 1 (ANTXR1) was identified as a functional biomarker of triple-negative breast CSCs, and PDAC patients stratified based on expression levels showed increased mortality and enrichment of pathways known to be necessary for CSC biology, including TGF-, NOTCH, Wnt/-catenin, and IL-6/JAK/STAT3 signaling and epithelial to mesenchymal transition, suggesting that ANTXR1 may represent a putative PaCSC marker. In this study, we show that ANTXR1 cells are not only detectable across a panel of 7 PDAC patient-derived xenograft primary cultures but ANTXR1 expression significantly increased in CSC-enriched 3D sphere cultures. Importantly, ANTXR1 cells also coexpressed other known PaCSC markers such as CD44, CD133, and autofluorescence, and ANTXR1 cells displayed enhanced CSC functional and molecular properties, including increased self-renewal and expression of pluripotency-associated genes, compared to ANTXR1 cells. Thus, this study validates ANTXR1 as a new PaCSC marker and we propose its use in identifying CSCs in this tumor type and its exploitation in the development of CSC-targeted therapies for PDAC.
胰腺导管腺癌（PDAC）目前是癌症相关死亡的第四大主要原因。癌症干细胞（CSCs）已被证明是胰腺肿瘤生长、转移和化疗耐药的驱动因素，但我们对这些细胞的了解仍因无法有效识别和分离它们而受到限制。自2007年以来，虽然已经发现了一些能够识别胰腺癌症干细胞（PaCSCs）的标志物，但毫无疑问，仍需要更多的标志物。炭疽毒素受体1（ANTXR1）被确定为三阴性乳腺癌癌症干细胞的功能性生物标志物，根据表达水平分层的PDAC患者显示死亡率增加，以及癌症干细胞生物学所必需的通路富集，包括TGF-、NOTCH、Wnt/β-连环蛋白和IL-6/JAK/STAT3信号传导以及上皮-间质转化，这表明ANTXR1可能代表一种假定的PaCSC标志物。在本研究中，我们表明ANTXR1细胞不仅在一组7种源自PDAC患者的异种移植原代培养物中可检测到，而且在富含癌症干细胞的3D球体培养物中ANTXR1表达显著增加。重要的是，ANTXR1细胞还共同表达其他已知的PaCSC标志物，如CD44、CD133和自发荧光，并且与ANTXR1细胞相比，ANTXR1细胞表现出增强的癌症干细胞功能和分子特性，包括自我更新增加和多能性相关基因的表达。因此，本研究验证了ANTXR1作为一种新的PaCSC标志物，我们建议将其用于识别这种肿瘤类型中的癌症干细胞，并在开发针对PDAC的癌症干细胞靶向治疗中加以利用。
