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The epigenetic influence of tumor and embryonic microenvironments: how different are they?

Abbott DE, Bailey CM, Postovit LM, Seftor EA, Margaryan N, Seftor RE, Hendrix MJ - Cancer Microenviron (2008)

Bottom Line: The microenvironment is being increasingly recognized as a critical component in tumor progression and metastases.As such, the bi-directional signaling of extracellular mediators that promote tumor growth within the microenvironment is a focus of intense scrutiny.Moreover, we have a better appreciation of the convergence of embryonic and tumorigenic signaling pathways that might stimulate further consideration of targeting Nodal in aggressive tumor cells resulting in a down-regulation of tumorigenic potential and plasticity.

View Article: PubMed Central - PubMed

Affiliation: Children's Memorial Research Center, Department of Surgery, Northwestern University/Feinberg School of Medicine, Chicago, IL 60614, USA.

ABSTRACT
The microenvironment is being increasingly recognized as a critical component in tumor progression and metastases. As such, the bi-directional signaling of extracellular mediators that promote tumor growth within the microenvironment is a focus of intense scrutiny. Interestingly, there are striking similarities between the phenotypes of aggressive tumor and embryonic stem cells, particularly with respect to specific signaling pathways underlying their intriguing plasticity. Here, we demonstrate the epigenetic influence of the hESC microenvironment on the reprogramming of aggressive melanoma cells using an innovative 3-D model. Specifically, our laboratory has previously demonstrated the redifferentiation of these melanoma cells to a more melanocyte-like phenotype (Postovit et al., Stem Cells 24(3):501-505, 2006), and now we show the loss of VE-Cadherin expression (indicative of a plastic vasculogenic phenotype) and the loss of Nodal expression (a plasticity stem cell marker) in tumor cells exposed to the hESC microenvironment. Further studies with the 3-D culture model revealed the epigenetic influence of aggressive melanoma cells on hESCs resulting in the down-regulation of plasticity markers and the emergence of phenotype-specific genes. Additional studies with the aggressive melanoma conditioned matrix microenvironment demonstrated the transdifferentiation of normal melanocytes into melanoma-like cells exhibiting a vasculogenic phenotype. Collectively, these studies have advanced our understanding of the epigenetic influence associated with the microenvironments of hESCs and aggressive melanoma cells, and shed new light on their therapeutic implications. Moreover, we have a better appreciation of the convergence of embryonic and tumorigenic signaling pathways that might stimulate further consideration of targeting Nodal in aggressive tumor cells resulting in a down-regulation of tumorigenic potential and plasticity.

No MeSH data available.


Related in: MedlinePlus

The microenvironment of hESCs epigenetically inhibits the vasculogenic phenotype of aggressive melanoma cells. a Phase-contrast microscopy of C8161 metastatic melanoma cells grown on a control Matrigel matrix (upper panel) and induced to form spheroids (a marked morphological alteration resembling hESC colonies) following exposure to a 3-D hESC microenvironment (hESC CMTX; lower panel). b This induction of spheroid formation is reversible as C8161 melanoma cells exposed to control Matrigel matrix following exposure to hESC CMTX are able to resume their plastic phenotype and form vasculogenic-like networks following a 7-day recovery period. c Western blot analysis of VE-Cadherin protein in C8161 cells exposed for 3 days to either control (unconditioned) Matrigel or to Matrigel conditioned by hESCs (hESC CMTX). Some cancer cells exposed to the hESC CMTX were subsequently recovered on control (unconditioned) Matrigel for 2 to 14 days prior to Western blot analysis. Actin is used as a loading control
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Fig2: The microenvironment of hESCs epigenetically inhibits the vasculogenic phenotype of aggressive melanoma cells. a Phase-contrast microscopy of C8161 metastatic melanoma cells grown on a control Matrigel matrix (upper panel) and induced to form spheroids (a marked morphological alteration resembling hESC colonies) following exposure to a 3-D hESC microenvironment (hESC CMTX; lower panel). b This induction of spheroid formation is reversible as C8161 melanoma cells exposed to control Matrigel matrix following exposure to hESC CMTX are able to resume their plastic phenotype and form vasculogenic-like networks following a 7-day recovery period. c Western blot analysis of VE-Cadherin protein in C8161 cells exposed for 3 days to either control (unconditioned) Matrigel or to Matrigel conditioned by hESCs (hESC CMTX). Some cancer cells exposed to the hESC CMTX were subsequently recovered on control (unconditioned) Matrigel for 2 to 14 days prior to Western blot analysis. Actin is used as a loading control

Mentions: Both hESCs and certain aggressive cancer cells have the ability to affect/alter their respective microenvironments to induce epigenetic effects on subsequent cell populations when placed into these conditioned microenvironments. In particular, an extracellular matrix conditioned by hESCs results in dramatic changes in cells introduced into this environment. Figure 2a reveals the profound morphological changes that aggressive melanoma cells (C8161) display following culture on an hESC CMTX. Compared to controls (C8161 cells grown on an unconditioned control matrix; top panel), where melanoma cells grow primarily in an over-confluent monolayer, these same cells form spheroidal clusters in a manner similar to the morphology characteristic of stem cells cultured on an hESC CMTX (bottom panel).Fig. 2


The epigenetic influence of tumor and embryonic microenvironments: how different are they?

Abbott DE, Bailey CM, Postovit LM, Seftor EA, Margaryan N, Seftor RE, Hendrix MJ - Cancer Microenviron (2008)

The microenvironment of hESCs epigenetically inhibits the vasculogenic phenotype of aggressive melanoma cells. a Phase-contrast microscopy of C8161 metastatic melanoma cells grown on a control Matrigel matrix (upper panel) and induced to form spheroids (a marked morphological alteration resembling hESC colonies) following exposure to a 3-D hESC microenvironment (hESC CMTX; lower panel). b This induction of spheroid formation is reversible as C8161 melanoma cells exposed to control Matrigel matrix following exposure to hESC CMTX are able to resume their plastic phenotype and form vasculogenic-like networks following a 7-day recovery period. c Western blot analysis of VE-Cadherin protein in C8161 cells exposed for 3 days to either control (unconditioned) Matrigel or to Matrigel conditioned by hESCs (hESC CMTX). Some cancer cells exposed to the hESC CMTX were subsequently recovered on control (unconditioned) Matrigel for 2 to 14 days prior to Western blot analysis. Actin is used as a loading control
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Related In: Results  -  Collection

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Fig2: The microenvironment of hESCs epigenetically inhibits the vasculogenic phenotype of aggressive melanoma cells. a Phase-contrast microscopy of C8161 metastatic melanoma cells grown on a control Matrigel matrix (upper panel) and induced to form spheroids (a marked morphological alteration resembling hESC colonies) following exposure to a 3-D hESC microenvironment (hESC CMTX; lower panel). b This induction of spheroid formation is reversible as C8161 melanoma cells exposed to control Matrigel matrix following exposure to hESC CMTX are able to resume their plastic phenotype and form vasculogenic-like networks following a 7-day recovery period. c Western blot analysis of VE-Cadherin protein in C8161 cells exposed for 3 days to either control (unconditioned) Matrigel or to Matrigel conditioned by hESCs (hESC CMTX). Some cancer cells exposed to the hESC CMTX were subsequently recovered on control (unconditioned) Matrigel for 2 to 14 days prior to Western blot analysis. Actin is used as a loading control
Mentions: Both hESCs and certain aggressive cancer cells have the ability to affect/alter their respective microenvironments to induce epigenetic effects on subsequent cell populations when placed into these conditioned microenvironments. In particular, an extracellular matrix conditioned by hESCs results in dramatic changes in cells introduced into this environment. Figure 2a reveals the profound morphological changes that aggressive melanoma cells (C8161) display following culture on an hESC CMTX. Compared to controls (C8161 cells grown on an unconditioned control matrix; top panel), where melanoma cells grow primarily in an over-confluent monolayer, these same cells form spheroidal clusters in a manner similar to the morphology characteristic of stem cells cultured on an hESC CMTX (bottom panel).Fig. 2

Bottom Line: The microenvironment is being increasingly recognized as a critical component in tumor progression and metastases.As such, the bi-directional signaling of extracellular mediators that promote tumor growth within the microenvironment is a focus of intense scrutiny.Moreover, we have a better appreciation of the convergence of embryonic and tumorigenic signaling pathways that might stimulate further consideration of targeting Nodal in aggressive tumor cells resulting in a down-regulation of tumorigenic potential and plasticity.

View Article: PubMed Central - PubMed

Affiliation: Children's Memorial Research Center, Department of Surgery, Northwestern University/Feinberg School of Medicine, Chicago, IL 60614, USA.

ABSTRACT
The microenvironment is being increasingly recognized as a critical component in tumor progression and metastases. As such, the bi-directional signaling of extracellular mediators that promote tumor growth within the microenvironment is a focus of intense scrutiny. Interestingly, there are striking similarities between the phenotypes of aggressive tumor and embryonic stem cells, particularly with respect to specific signaling pathways underlying their intriguing plasticity. Here, we demonstrate the epigenetic influence of the hESC microenvironment on the reprogramming of aggressive melanoma cells using an innovative 3-D model. Specifically, our laboratory has previously demonstrated the redifferentiation of these melanoma cells to a more melanocyte-like phenotype (Postovit et al., Stem Cells 24(3):501-505, 2006), and now we show the loss of VE-Cadherin expression (indicative of a plastic vasculogenic phenotype) and the loss of Nodal expression (a plasticity stem cell marker) in tumor cells exposed to the hESC microenvironment. Further studies with the 3-D culture model revealed the epigenetic influence of aggressive melanoma cells on hESCs resulting in the down-regulation of plasticity markers and the emergence of phenotype-specific genes. Additional studies with the aggressive melanoma conditioned matrix microenvironment demonstrated the transdifferentiation of normal melanocytes into melanoma-like cells exhibiting a vasculogenic phenotype. Collectively, these studies have advanced our understanding of the epigenetic influence associated with the microenvironments of hESCs and aggressive melanoma cells, and shed new light on their therapeutic implications. Moreover, we have a better appreciation of the convergence of embryonic and tumorigenic signaling pathways that might stimulate further consideration of targeting Nodal in aggressive tumor cells resulting in a down-regulation of tumorigenic potential and plasticity.

No MeSH data available.


Related in: MedlinePlus