Elite Model for the Generation of Induced Pluripotent Cancer Cells (iPCs)

Lai, Jason; Kong, Chunyang; Mahalingam, Dashayini; Xie, Xiaojin

doi:10.1371/journal.pone.0056702

Cited by 8 publications

(12 citation statements)

References 32 publications

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“…In previous studies, distinct types of cancer cells, including melanoma cells, lung cancer cells and gastrointestinal cancer cells, have been reprogrammed into stem cell-like pluripotent cells by the nuclear transfer technique or by delivery of OSKM factors (Oct4, Sox2, Klf4 and c-Myc). [24][25][26] Our present study has shown that forced expression of HNF1A, HNF4A and FOXA3 not only induces cell cycle arrest and apoptosis (data not shown) but also converted HCC cells into rHeps, which lost malignant characteristics. In addition, we analyzed the cancer-related genes in our microarray data, and found some oncogenic genes were suppressed and a few tumor suppressor genes were upregulated in rHeps compared with control cells, findings that warrant further investigation (Supplementary information, Table S1).…”

Section: Discussionmentioning

confidence: 57%

Conversion of hepatoma cells to hepatocyte-like cells by defined hepatocyte nuclear factors

Cheng

Cai

et al. 2018

Cell Res

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Normal cells become cancer cells after a malignant transformation, but whether cancer cells can be reversed to normal status remains elusive. Here, we report that the combination of hepatocyte nuclear factor 1A (HNF1A), HNF4A and forkhead box protein A3 (FOXA3) synergistically reprograms hepatocellular carcinoma (HCC) cells to hepatocyte-like cells (reprogrammed hepatocytes, rHeps). Our results show that rHeps lose the malignant phenotypes of cancer cells and retrieve hepatocyte-specific characteristics including hepatocyte-like morphology; global expression pattern of genes and specific biomarkers of hepatocytes; and the unique hepatic functions of albumin (ALB) secretion, glycogen synthesis, low-density lipoprotein (LDL) uptake, urea production, cytochrome P450 enzymes induction and drug metabolism. Intratumoral injection of these three factors efficiently shrank patientderived tumor xenografts and reprogrammed HCC cells in vivo. Most importantly, transplantation of rHeps in the liver of fumarylacetoacetate hydrolase-deficient (Fah −/− ) mice led to the reconstruction of hepatic lobules and the restoration of hepatic function. Mechanistically, exogenous expression of HNF1A, HNF4A and FOXA3 in HCC cells initiated the endogenous expression of numerous hepatocyte nuclear factors, which promoted the conversion of HCC cells to hepatocyte-like cells. Collectively, our results indicate the successful conversion of hepatoma cells to hepatocyte-like cells, not only extending our current knowledge of cell reprogramming but also providing a route towards a novel therapeutic strategy for cancer.

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Section: Discussionmentioning

confidence: 57%

Conversion of hepatoma cells to hepatocyte-like cells by defined hepatocyte nuclear factors

Cheng

Cai

et al. 2018

Cell Res

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“…Hence, reprogramming of normal somatic cells follows a continuous stochastic model, where all transduced cells have equal probability to be transformed into a pluripotent state [ 57 , 58 ]. In contrast, evidences have been presented to support the elite model for cancer-cell reprogramming in which only a selected subset of cells in the heterogeneous cancer cell population may be fully reprogrammed into iPCs [ 59 ]. Our work here highlights challenges and in fully reprogramming cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Incomplete cellular reprogramming of colorectal cancer cells elicits an epithelial/mesenchymal hybrid phenotype

et al. 2018

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BackgroundInduced pluripotency in cancer cells by ectopic expression of pluripotency-regulating factors may be used for disease modeling of cancers. MicroRNAs (miRNAs) are negative regulators of gene expression that play important role in reprogramming somatic cells. However, studies on the miRNA expression profile and the expression patterns of the mesenchymal-epithelial transition (MET)/epithelial-mesenchymal transition (EMT) genes in induced pluripotent cancer (iPC) cells are lacking.MethodsiPC clones were generated from two colorectal cancer (CRC) cell lines by retroviral transduction of the Yamanaka factors. The iPC clones obtained were characterized by morphology, expression of pluripotency markers and the ability to undergo in vitro tri-lineage differentiation. Genome-wide miRNA profiles of the iPC cells were obtained by microarray analysis and bioinformatics interrogation. Gene expression was done by real-time RT-PCR and immuno-staining; MET/EMT protein levels were determined by western blot analysis.ResultsThe CRC-iPC cells showed embryonic stem cell-like features and tri-lineage differentiation abilities. The spontaneously-differentiated post-iPC cells obtained were highly similar to the parental CRC cells. However, down-regulated pluripotency gene expression and failure to form teratoma indicated that the CRC-iPC cells had only attained partial pluripotency. The CRC-iPC cells shared similarities in the genome-wide miRNA expression profiles of both cancer and pluripotent embryonic stem cells. One hundred and two differentially-expressed miRNAs were identified in the CRC-iPC cells, which were predicted by bioinformatics analysis be closely involved in regulating cellular pluripotency and the expression of the MET/EMT genes, possibly via the phosphatidylinositol-3 kinases-protein kinase B (PI3K-Akt) and transforming growth factor beta (TGF-β) signaling pathways. Irregular and inconsistent expression patterns of the EMT vimentin and Snai1 and MET E-cadherin and occludin proteins were observed in the four CRC-iPC clones analyzed, which suggested an epithelial/mesenchymal hybrid phenotype in the partially reprogrammed CRC cells. MET/EMT gene expression was also generally reversed on re-differentiation, also suggesting epigenetic regulation.ConclusionsOur data support the elite model for cancer cell-reprogramming in which only a selected subset of cancer may be fully reprogrammed; partial cancer cell reprogramming may also elicit an epithelial-mesenchymal mixed phenotype, and highlight opportunities and challenges in cancer cell-reprogramming.Electronic supplementary materialThe online version of this article (10.1186/s12929-018-0461-1) contains supplementary material, which is available to authorized users.

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“…Alternately, the “stochastic model” states that most cells may undergo the process of reprogramming but just a minority completes it [ 106 ]. Lai and colleagues (2013) assessed this issue in reprogrammed cancer cells and concluded that the reprogramming process of these cells may follow the “elite model” [ 107 ]. According to the published results, only a small subpopulation of cells was selected for reprogramming as all obtained iPCs were free of mutations, unlike the parental cells.…”

Section: Cell-based Models Of Cscsmentioning

confidence: 99%

In vitro models of cancer stem cells and clinical applications

et al. 2016

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Cancer cells, stem cells and cancer stem cells have for a long time played a significant role in the biomedical sciences. Though cancer therapy is more effective than it was a few years ago, the truth is that still none of the current non-surgical treatments can cure cancer effectively. The reason could be due to the subpopulation called “cancer stem cells” (CSCs), being defined as those cells within a tumour that have properties of stem cells: self-renewal and the ability for differentiation into multiple cell types that occur in tumours.The phenomenon of CSCs is based on their resistance to many of the current cancer therapies, which results in tumour relapse. Although further investigation regarding CSCs is still needed, there is already evidence that these cells may play an important role in the prognosis of cancer, progression and therapeutic strategy. Therefore, long-term patient survival may depend on the elimination of CSCs. Consequently, isolation of pure CSC populations or reprogramming of cancer cells into CSCs, from cancer cell lines or primary tumours, would be a useful tool to gain an in-depth knowledge about heterogeneity and plasticity of CSC phenotypes and therefore carcinogenesis. Herein, we will discuss current CSC models, methods used to characterize CSCs, candidate markers, characteristic signalling pathways and clinical applications of CSCs. Some examples of CSC-specific treatments that are currently in early clinical phases will also be presented in this review.

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Elite Model for the Generation of Induced Pluripotent Cancer Cells (iPCs)

Cited by 8 publications

References 32 publications

Conversion of hepatoma cells to hepatocyte-like cells by defined hepatocyte nuclear factors

Conversion of hepatoma cells to hepatocyte-like cells by defined hepatocyte nuclear factors

Incomplete cellular reprogramming of colorectal cancer cells elicits an epithelial/mesenchymal hybrid phenotype

In vitro models of cancer stem cells and clinical applications

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