title: Transient mTOR inhibition facilitates continuous growth of liver tumors by modulating the maintenance of CD133+ cell populations.
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.
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Renji Hospital, Shanghai Cancer Institute, Shanghai, China.
authors.forename: Zhaojuan
authors.initials: Z
authors.lastname: Yang
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Aihui
authors.initials: A
authors.lastname: Ma
authors.forename: Lanlan
authors.initials: L
authors.lastname: Liu
authors.forename: Jinjun
authors.initials: J
authors.lastname: Li
authors.forename: Jianren
authors.initials: J
authors.lastname: Gu
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D000071916:AC133 Antigen; D000903:Antibiotics, Antineoplastic; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus