RRC ID 68626
Author Yang Z, Zhang L, Ma A, Liu L, Li J, Gu J, Liu Y.
Title Transient mTOR inhibition facilitates continuous growth of liver tumors by modulating the maintenance of CD133+ cell populations.
Journal PLoS One
Abstract The mammalian target of the rapamycin (mTOR) pathway, which drives cell proliferation, is frequently hyperactivated in a variety of malignancies. Therefore, the inhibition of the mTOR pathway has been considered as an appropriate approach for cancer therapy. In this study, we examined the roles of mTOR in the maintenance and differentiation of cancer stem-like cells (CSCs), the conversion of conventional cancer cells to CSCs and continuous tumor growth in vivo. In H-Ras-transformed mouse liver tumor cells, we found that pharmacological inhibition of mTOR with rapamycin greatly increased not only the CD133+ populations both in vitro and in vivo but also the expression of stem cell-like genes. Enhancing mTOR activity by over-expressing Rheb significantly decreased CD133 expression, whereas knockdown of the mTOR yielded an opposite effect. In addition, mTOR inhibition severely blocked the differentiation of CD133+ to CD133- liver tumor cells. Strikingly, single-cell culture experiments revealed that CD133- liver tumor cells were capable of converting to CD133+ cells and the inhibition of mTOR signaling substantially promoted this conversion. In serial implantation of tumor xenografts in nude BALB/c mice, the residual tumor cells that were exposed to rapamycin in vivo displayed higher CD133 expression and had increased secondary tumorigenicity compared with the control group. Moreover, rapamycin treatment also enhanced the level of stem cell-associated genes and CD133 expression in certain human liver tumor cell lines, such as Huh7, PLC/PRC/7 and Hep3B. The mTOR pathway is significantly involved in the generation and the differentiation of tumorigenic liver CSCs. These results may be valuable for the design of more rational strategies to control clinical malignant HCC using mTOR inhibitors.
Volume 6(12)
Pages e28405
Published 2011-1-1
DOI 10.1371/journal.pone.0028405
PII PONE-D-11-20249
PMID 22145042
PMC PMC3228748
MeSH AC133 Antigen Animals Antibiotics, Antineoplastic / pharmacology Antigens, CD / genetics Antigens, CD / metabolism* Apoptosis / drug effects Blotting, Western Carcinoma, Hepatocellular / genetics Carcinoma, Hepatocellular / metabolism Carcinoma, Hepatocellular / pathology* Cell Differentiation / drug effects Cell Line, Tumor Cell Proliferation* Glycoproteins / genetics Glycoproteins / metabolism* Humans Liver / cytology Liver / drug effects Liver / metabolism Liver Neoplasms / genetics Liver Neoplasms / metabolism Liver Neoplasms / pathology* Male Mice Mice, Inbred BALB C Mice, Knockout Mice, Nude Neoplastic Stem Cells / metabolism Neoplastic Stem Cells / pathology* Peptides / genetics Peptides / metabolism* RNA, Messenger / genetics Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Sirolimus / pharmacology TOR Serine-Threonine Kinases / antagonists & inhibitors* TOR Serine-Threonine Kinases / metabolism Tumor Suppressor Protein p53 / physiology
IF 2.74
Human and Animal Cells HuH-7(RCB1366)