Epithelial Cells Derived from Human Embryonic Stem Cells Display P16INK4A Senescence, Hypermotility, and Differentiation Properties Shared by Many P63+ Somatic Cell Types

Dabelsteen, Sally; Hercule, Paula; Barron, Patricia; Rice, Meghan A.; Dorsainville, Gregory; Rheinwald, James G.

doi:10.1002/stem.64

Cited by 47 publications

(65 citation statements)

References 57 publications

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“…In this study, the tumor-suppressor gene P16(INK4A), which acts against the self-renewal of ES cells (10,12), was repressed in iPC cells. Our analysis indicated that P16(INK4A) expression increased in PostiPC cells, which may relate to the notion that P16(INK4A) up-regulation is involved in the suppression of transformed phenotypes and their sensitization to therapeutic agents (24).…”

Section: Discussionmentioning

confidence: 81%

“…The repression of tumor-suppressor genes extends the lifespan of embryonic stem (ES) cells or increases the induction efficiency of iPS cells and maintains their immortalized state (10)(11)(12). The results indicated that introduction of transcription factor genes into gastrointestinal cancer cells resulted in reprogramming of cells to a pluripotent state and sensitized them to differentiation induction.…”

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confidence: 99%

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Defined factors induce reprogramming of gastrointestinal cancer cells

Miyoshi

Ishii

Nagai

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

256

266

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Although cancer is a disease with genetic and epigenetic origins, the possible effects of reprogramming by defined factors remain to be fully understood. We studied the effects of the induction or inhibition of cancer-related genes and immature status-related genes whose alterations have been reported in gastrointestinal cancer cells. Retroviral-mediated introduction of induced pluripotent stem (iPS) cell genes was necessary for inducing the expression of immature status-related proteins, including Nanog, Ssea4, Tra-1-60, and Tra-1-80 in esophageal, stomach, colorectal, liver, pancreatic, and cholangiocellular cancer cells. Induced cells, but not parental cells, possessed the potential to express morphological patterns of ectoderm, mesoderm, and endoderm, which was supported by epigenetic studies, indicating methylation of DNA strands and the histone H3 protein at lysine 4 in promoter regions of pluripotency-associated genes such as NANOG . In in vitro analysis induced cells showed slow proliferation and were sensitized to differentiation-inducing treatment, and in vivo tumorigenesis was reduced in NOD/SCID mice. This study demonstrated that pluripotency was manifested in induced cells, and that the induced pluripotent cancer (iPC) cells were distinct from natural cancer cells with regard to their sensitivity to differentiation-inducing treatment. Retroviral-mediated introduction of iPC cells confers higher sensitivity to chemotherapeutic agents and differentiation-inducing treatment.

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Section: Discussionmentioning

confidence: 81%

mentioning

confidence: 99%

Defined factors induce reprogramming of gastrointestinal cancer cells

Miyoshi

Ishii

Nagai

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

256

266

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“…The ability of hESC differentiation to epithelial lineages has also been studied in recent decades. Dabelsteen and Iuchi et al found that hESCs can differentiate into keratinocyte-like cells expressing p63, K14, and involucrin [216,217]. However, hESC-derived keratinocytes are different from postnatal keratinocytes due to their much lower proliferative potential in culture.…”

Section: Embryonic Stem Cells For Skin Regenerationmentioning

confidence: 94%

Stem Cells and Nanostructures for Advanced Tissue Regeneration

Prabhakaran

Venugopal

Ghasemi‐Mobarakeh

et al. 2011

Biomedical Applications of Polymeric Nanofibers

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Stem cells are a promising alternative for cell therapy applications because of their self-renewing capability and potential to differentiate into a wide range of specialized cell lineages, including osteoblasts, chondrocytes, cardiomyocytes, and neuronal cells. Different kinds of stem cells are considered for cell-based tissue engineering approaches, of which bone-marrow-derived mesenchymal stem cells (BM-MSCs), adipose-derived stem cells (ADSCs) and embryonic stem cells (ESCs) are frequently utilized for advancement of new tissue engineering strategies. Nanostructures created by natural, synthetic, or composite polymeric biomaterials provide artificial templates of the extracellular matrix (ECM). They possess a high surface area to volume ratio, are porous with good mechanical properties, are sufficient to serve as a biomimetic platform to attract stem cells, cause differentiation, and provide functioning of the tissues. Nanoscale features such as fibers, pits, and grooves modulate cell behavior and might even stimulate the differentiation of stem cells to specific lineages; for example, the nanotopographical cues combined with chemical cues influence the neuronal induction of MSCs, resulting in high microtubule-associated protein expressions. Scaffolds can also be impregnated with several ligands for adhesion of receptors to the cells, or with other regulatory molecules and growth M.P. Prabhakaran (*) and J. Venugopal E3-05-12, Health Care and Energy Materials Laboratory, Nanoscience and Nanotechnology Initiative, Faculty of Engineering, National University of Singapore, 2 Engineering Drive 3, Singapore 117576, Singapore e-mail: nnimpp@nus.edu.sg L. Ghasemi-Mobarakeh Islamic Azad University, Najafabad Branch, Isfahan, Iran D. Kai NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 2 Engineering Drive 3, Singapore 117576, Singapore G. Jin and S. Ramakrishna Department of Mechanical Engineering, National University of Singapore, 2 Engineering Drive 3, Singapore 117576, Singapore factors for designed cell behavior or controlled cell differentiations. Different polymeric blends or fibers incorporated with nanoparticles (such as hydroxyapatite) in aligned or custom-made patterns can induce specific differentiation of stem cells for bone, cartilage, cardiac, nerve, and skin tissue regeneration. In this review, we will discuss the current state of the art and future perspectives on stem cells and their differentiation on nanoengineered substrates for advanced tissue regeneration.

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“…Human cell lines used in this study were the premalignant dysplastic oral keratinocyte line POE9n [27], [28]; the epidermal SCC cell line SCC-13 [29] and the oral SCC cell line SCC-68 [21]; the normal epidermal keratinocyte primary line Strain N [29], [30]; and N/E6(JH26) [21], a derivative of strain N engineered by retroviral transduction to express the JH26 mutant form of the E6 oncoprotein of HPV16 [31], [32]. All of these cell lines were derived in the Rheinwald lab and cultures for experiments were initiated from archival frozen stocks in the Rheinwald lab's collection.…”

Section: Methodsmentioning

confidence: 99%

RSK Activation of Translation Factor eIF4B Drives Abnormal Increases of Laminin γ2 and MYC Protein during Neoplastic Progression to Squamous Cell Carcinoma

et al. 2013

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Overexpression of the basement membrane protein Laminin γ2 (Lamγ2) is a feature of many epidermal and oral dysplasias and all invasive squamous cell carcinomas (SCCs). This abnormality has potential value as an immunohistochemical biomarker of premalignancy but its mechanism has remained unknown. We recently reported that Lamγ2 overexpression in culture is the result of deregulated translation controls and depends on the MAPK-RSK signaling cascade. Here we identify eIF4B as the RSK downstream effector responsible for elevated Lamγ2 as well as MYC protein in neoplastic epithelial cells. Premalignant dysplastic keratinocytes, SCC cells, and keratinocytes expressing the E6 oncoprotein of human papillomavirus (HPV) type 16 displayed MAPK-RSK and mTOR-S6K1 activation and overexpressed Lamγ2 and MYC in culture. Immunohistochemical staining of oral dysplasias and SCCs for distinct, RSK- and S6K1-specific S6 phosphorylation events revealed that their respective upstream pathways become hyperactive at the same time during neoplastic progression. However, pharmacologic kinase inhibitor studies in culture revealed that Lamγ2 and MYC overexpression depends on MAPK-RSK activity, independent of PI3K-mTOR-S6K1. eIF4B knockdown reduced Lamγ2 and MYC protein expression, consistent with the known requirement for eIF4B to translate mRNAs with long, complex 5′ untranslated regions (5′-UTRs). Accordingly, expression of a luciferase reporter construct preceded by the Lamγ2 5′-UTR proved to be RSK-dependent and mTOR-independent. These results demonstrate that RSK activation of eIF4B is causally linked to elevated Lamγ2 and MYC protein levels during neoplastic progression to invasive SCC. These findings have potential clinical significance for identifying premalignant lesions and for developing targeted drugs to treat SCC.

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Epithelial Cells Derived from Human Embryonic Stem Cells Display P16INK4A Senescence, Hypermotility, and Differentiation Properties Shared by Many P63+ Somatic Cell Types

Cited by 47 publications

References 57 publications

Defined factors induce reprogramming of gastrointestinal cancer cells

Defined factors induce reprogramming of gastrointestinal cancer cells

Stem Cells and Nanostructures for Advanced Tissue Regeneration

RSK Activation of Translation Factor eIF4B Drives Abnormal Increases of Laminin γ2 and MYC Protein during Neoplastic Progression to Squamous Cell Carcinoma

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