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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

Normal melanocytes acquire a vasculogenic-like dedifferentiated phenotype following exposure to the microenvironment of metastatic melanoma cells. Phase-contrast microscopy of human melanocytes and C8161 melanoma cells grown in 3-D matrices of type I collagen. Human epidermal melanocytes (HEMn) form dense monolayers when cultured on a 3-D collagen-I matrix (top). In contrast, metastatic melanoma cells (C8161) form vasculogenic-like networks (arrowheads). HEMn cells cultured on a matrix conditioned by C8161 cells (C8161 CMTX) are also able to form vasculogenic-like networks. Micron bar equals 200 μm for all micrographs
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Fig3: Normal melanocytes acquire a vasculogenic-like dedifferentiated phenotype following exposure to the microenvironment of metastatic melanoma cells. Phase-contrast microscopy of human melanocytes and C8161 melanoma cells grown in 3-D matrices of type I collagen. Human epidermal melanocytes (HEMn) form dense monolayers when cultured on a 3-D collagen-I matrix (top). In contrast, metastatic melanoma cells (C8161) form vasculogenic-like networks (arrowheads). HEMn cells cultured on a matrix conditioned by C8161 cells (C8161 CMTX) are also able to form vasculogenic-like networks. Micron bar equals 200 μm for all micrographs

Mentions: An example of how aggressive cancer cells (with an embryonic-like phenotype) may also affect their microenvironment to induce phenotypic changes in other cells is illustrated by culturing normal human melanocytes (which exhibit a homogeneously benign phenotype) on a matrix conditioned by aggressive melanoma cells (C8161). Figure 3 shows that C8161 cells cultured on a 3-D type I collagen matrix produce visible networks (delineated by arrows; left panel) as part of their vasculogenic mimicry phenotype. After the aggressive cancer cells were removed, human melanocytes were placed on the conditioned matrix, inducing these normal cells to form vasculogenic mimicry-like networks. Coincident with the initiation of the more aggressive phenotype was an induction of VE-Cadherin expression, suggesting an epigenetic modification consistent with a vascular cell-like molecular profile, similar to that of the aggressive melanoma phenotype [40]. This result highlights the powerful influence that certain cell types have on their microenvironment and in this instance, the bi-directional communication between normal melanocytes and a cancerous microenvironment led to the acquisition of tumor cell-like characteristics.Fig. 3


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)

Normal melanocytes acquire a vasculogenic-like dedifferentiated phenotype following exposure to the microenvironment of metastatic melanoma cells. Phase-contrast microscopy of human melanocytes and C8161 melanoma cells grown in 3-D matrices of type I collagen. Human epidermal melanocytes (HEMn) form dense monolayers when cultured on a 3-D collagen-I matrix (top). In contrast, metastatic melanoma cells (C8161) form vasculogenic-like networks (arrowheads). HEMn cells cultured on a matrix conditioned by C8161 cells (C8161 CMTX) are also able to form vasculogenic-like networks. Micron bar equals 200 μm for all micrographs
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2654360&req=5

Fig3: Normal melanocytes acquire a vasculogenic-like dedifferentiated phenotype following exposure to the microenvironment of metastatic melanoma cells. Phase-contrast microscopy of human melanocytes and C8161 melanoma cells grown in 3-D matrices of type I collagen. Human epidermal melanocytes (HEMn) form dense monolayers when cultured on a 3-D collagen-I matrix (top). In contrast, metastatic melanoma cells (C8161) form vasculogenic-like networks (arrowheads). HEMn cells cultured on a matrix conditioned by C8161 cells (C8161 CMTX) are also able to form vasculogenic-like networks. Micron bar equals 200 μm for all micrographs
Mentions: An example of how aggressive cancer cells (with an embryonic-like phenotype) may also affect their microenvironment to induce phenotypic changes in other cells is illustrated by culturing normal human melanocytes (which exhibit a homogeneously benign phenotype) on a matrix conditioned by aggressive melanoma cells (C8161). Figure 3 shows that C8161 cells cultured on a 3-D type I collagen matrix produce visible networks (delineated by arrows; left panel) as part of their vasculogenic mimicry phenotype. After the aggressive cancer cells were removed, human melanocytes were placed on the conditioned matrix, inducing these normal cells to form vasculogenic mimicry-like networks. Coincident with the initiation of the more aggressive phenotype was an induction of VE-Cadherin expression, suggesting an epigenetic modification consistent with a vascular cell-like molecular profile, similar to that of the aggressive melanoma phenotype [40]. This result highlights the powerful influence that certain cell types have on their microenvironment and in this instance, the bi-directional communication between normal melanocytes and a cancerous microenvironment led to the acquisition of tumor cell-like characteristics.Fig. 3

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