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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

3-D model to study the epigenetic influence of the microenvironment on cell phenotype. Compact colonies of human embryonic stem cells (hESCs) or cancer cells are seeded onto a 3-D matrix (composed of Matrigel or type I collagen) for 3 to 4 days, then removed, resulting in a conditioned 3-D matrix (CMTX) onto which other cell types (such as hESCs, cancer cells, or normal melanocytes) are seeded and incubated for 3–4 days. Subsequently, changes in cell morphology, gene and protein expression as well as behavioral function(s) of the cells can be examined
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Fig1: 3-D model to study the epigenetic influence of the microenvironment on cell phenotype. Compact colonies of human embryonic stem cells (hESCs) or cancer cells are seeded onto a 3-D matrix (composed of Matrigel or type I collagen) for 3 to 4 days, then removed, resulting in a conditioned 3-D matrix (CMTX) onto which other cell types (such as hESCs, cancer cells, or normal melanocytes) are seeded and incubated for 3–4 days. Subsequently, changes in cell morphology, gene and protein expression as well as behavioral function(s) of the cells can be examined

Mentions: Based on the concept that the hESC microenvironment provides a dynamic regulatory niche for stem cell function, we explored the possibility that this embryonic microenvironment could reprogram the plastic tumor cell phenotype. To address the need for a novel experimental design that expands on standard cellular gene and protein expression analysis, our laboratory has developed an in vitro model that employs a 3-D matrix (Fig. 1) to assess microenvironmental properties and influences when conditioned by specific cells types, primarily hESCs (aggressive cancer cells may also be used—to be discussed in more detail later). Briefly, cells are plated on a 3-D matrix for 3–4 days followed by lysis and removal using a dilute concentration of ammonium hydroxide. Cells of interest are subsequently re-plated on this conditioned matrix (CMTX). Following 3–4 days of growth on the conditioned matrix, cells are removed for morphological, proliferative, functional, RNA or protein analysis. This approach permits a comprehensive analysis of the myriad influences a conditioned microenvironment may exert on neighboring cells, and provides a foundation from which further work may be designed and undertaken.Fig. 1


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)

3-D model to study the epigenetic influence of the microenvironment on cell phenotype. Compact colonies of human embryonic stem cells (hESCs) or cancer cells are seeded onto a 3-D matrix (composed of Matrigel or type I collagen) for 3 to 4 days, then removed, resulting in a conditioned 3-D matrix (CMTX) onto which other cell types (such as hESCs, cancer cells, or normal melanocytes) are seeded and incubated for 3–4 days. Subsequently, changes in cell morphology, gene and protein expression as well as behavioral function(s) of the cells can be examined
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654360&req=5

Fig1: 3-D model to study the epigenetic influence of the microenvironment on cell phenotype. Compact colonies of human embryonic stem cells (hESCs) or cancer cells are seeded onto a 3-D matrix (composed of Matrigel or type I collagen) for 3 to 4 days, then removed, resulting in a conditioned 3-D matrix (CMTX) onto which other cell types (such as hESCs, cancer cells, or normal melanocytes) are seeded and incubated for 3–4 days. Subsequently, changes in cell morphology, gene and protein expression as well as behavioral function(s) of the cells can be examined
Mentions: Based on the concept that the hESC microenvironment provides a dynamic regulatory niche for stem cell function, we explored the possibility that this embryonic microenvironment could reprogram the plastic tumor cell phenotype. To address the need for a novel experimental design that expands on standard cellular gene and protein expression analysis, our laboratory has developed an in vitro model that employs a 3-D matrix (Fig. 1) to assess microenvironmental properties and influences when conditioned by specific cells types, primarily hESCs (aggressive cancer cells may also be used—to be discussed in more detail later). Briefly, cells are plated on a 3-D matrix for 3–4 days followed by lysis and removal using a dilute concentration of ammonium hydroxide. Cells of interest are subsequently re-plated on this conditioned matrix (CMTX). Following 3–4 days of growth on the conditioned matrix, cells are removed for morphological, proliferative, functional, RNA or protein analysis. This approach permits a comprehensive analysis of the myriad influences a conditioned microenvironment may exert on neighboring cells, and provides a foundation from which further work may be designed and undertaken.Fig. 1

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