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Tumor progression of culture‐adapted human embryonic stem cells during long‐term culture
Author(s) -
Yang Sheng,
Lin Ge,
Tan YueQiu,
Zhou Di,
Deng LeiYu,
Cheng DeHua,
Luo ShuWei,
Liu TianCheng,
Zhou XiaoYing,
Sun Zheng,
Xiang Yang,
Chen TianJi,
Wen JiFang,
Lu GuangXiu
Publication year - 2008
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.20574
Subject(s) - biology , embryonic stem cell , carcinogenesis , cell cycle , wnt signaling pathway , stem cell , cell culture , microarray analysis techniques , microbiology and biotechnology , cellular differentiation , teratoma , malignant transformation , cancer research , cell , gene , pathology , genetics , gene expression , medicine
Abstract Human embryonic stem cells (hESCs) during long‐term culture acquire chromosomal changes similar to those occurring in tumorigenesis. This was raised concerns about the progression from hESCs to malignant cells. This study aimed to investigate the changes in chromosomes, cell phenotype, and genes in culture‐adapted hESCs to ascertain whether tumorigenic transformation occurred. By cytogenetic analysis we found progressive karyotypic changes from simple to complex in ch HES‐3, one of the hESC lines established in our laboratory, during a long‐term suboptimal culture. We further compared ch HES‐3 cells at different karyotypic stages in cell surface markers, in vivo differentiation, cell cycle, apoptosis, and gene expression profiles. We found that the karyotypically aberrant ch HES‐3 had higher S‐phase fraction in cell cycle distributions and antiapoptosis ability. In vivo differentiation of karyotypically normal ch HES‐3 resulted in relatively mature teratoma, whereas karyotypically aberrant ch HES‐3 formed immature teratoma (grade III), in which more primary neural epithelium was revealed by pathological analysis. The microarray analysis and real‐time PCR results showed that some oncogenes were upregulated in karyotypically aberrant ch HES‐3 cells, whereas the genes related to differentiation were downregulated, and that Wnt signal pathway was activated. In conclusion, ch HES‐3 cells underwent deregulation of self‐renewal and dysfunction of related genes in long‐term culture adaptation, leading to malignant transformation. © 2008 Wiley‐Liss, Inc.