L1 Cell Adhesion Molecule Confers Radioresistance to Ovarian Cancer and Defines a New Cancer Stem Cell Population

被引:28
作者
Terraneo, Nastassja [1 ]
Jacob, Francis [2 ,3 ]
Peitzsch, Claudia [4 ,5 ,6 ,7 ]
Dubrovska, Anna [6 ,7 ,8 ,9 ]
Krudewig, Christiane [10 ]
Huang, Yen-Lin [2 ,3 ]
Heinzelmann-Schwarz, Viola [2 ,3 ,11 ]
Schibli, Roger [1 ,12 ]
Behe, Martin [1 ]
Gruenberg, Juergen [1 ]
机构
[1] ETH, Paul Scherrer Inst, USZ, Ctr Radiopharmaceut Sci, CH-5232 Villigen, Switzerland
[2] Univ Hosp Basel, Dept Biomed, Ovarian Canc Res, CH-4031 Basel, Switzerland
[3] Univ Basel, CH-4031 Basel, Switzerland
[4] Natl Ctr Tumor Dis NCT, Partner Site Dresden, D-01307 Dresden, Germany
[5] German Canc Res Ctr, D-69120 Heidelberg, Germany
[6] Tech Univ Dresden, Fac Med, OncoRay Natl Ctr Radiat Res Oncol, D-01307 Dresden, Germany
[7] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, D-01307 Dresden, Germany
[8] German Canc Consortium DKTK, Partner Site Dresden, D-01307 Dresden, Germany
[9] Helmholtz Zentrum Dresden Rossendorf, Inst Radiooncol OncoRay, D-01307 Dresden, Germany
[10] Univ Zurich, Vetsuisse Fac, Inst Vet Pathol, LAMP, CH-8057 Zurich, Switzerland
[11] Univ Hosp Basel, Hosp Women, CH-4031 Basel, Switzerland
[12] Swiss Fed Inst Technol, Dept Chem & Appl Biosci, CH-8093 Zurich, Switzerland
关键词
L1 cell adhesion molecule; ovarian cancer; stem cells; radioresistance; CRISPR-Cas9; epithelial-to-mesenchymal transition; EPITHELIAL-MESENCHYMAL TRANSITION; ANTIBODY THERAPY; TGF-BETA; EMT; L1CAM; EXPRESSION; PLASTICITY; SURVIVAL; GROWTH; RADIOIMMUNOTHERAPY;
D O I
10.3390/cancers12010217
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Many solid tumors, including ovarian cancer, contain small populations of cancer stem cells (CSCs). These cells are usually resistant against conventional cancer therapies and play a role in disease recurrence. We demonstrated that the L1 cell adhesion molecule (L1CAM) is a new CSC target in ovarian cancer, triggering radioresistance. Using fluorescence-activated cell sorting, specific cell populations expressing L1CAM alone or in combination with the established CSC marker CD133 were isolated from three ovarian cancer cell lines. Double-positive L1CAM+/CD133+ cells displayed higher spherogenic and clonogenic properties in comparison to L1CAM-/CD133- cells. Furthermore, L1CAM+/CD133+ cells retained highest clonogenic capacity after irradiation and exhibited up-regulation of some CSC-specific genes, enhanced tumor-initiating capacity, self-renewal and higher tumor take rate in nude mice when compared with other cell populations. Superior radioresistance by L1CAM expression was confirmed by deletion of L1CAM using CRISPR-Cas9 technology. Moreover, we found expression signatures associated with epithelial-to-mesenchymal transition phenotype in L1CAM deleted cells. These results indicate that L1CAM in combination with CD133 defines a new cancer cell population of ovarian tumor-initiating cells with the implication of targeting L1CAM as a novel therapeutic approach for ovarian CSCs.
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页数:17
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