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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

Down-regulation of Nodal expression by exposure to the hESC microenvironment or by knock down with Nodal morpholino leads to abrogation metastatic melanoma tumorigenicity. a The ratio of tumor cell proliferation to apoptosis in tumors derived from human metastatic melanoma cells (C8161), determined by immunohistochemical staining for Ki-67 and terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling (TUNEL). Prior to injection into a mouse, C8161 cells were cultured for 3 days on control or hESC conditioned matrices (hESC CMTX), or treated with MO Nodal to knock down Nodal expression. Bars represent mean normalized values±standard deviation, and values indicated by an asterisk are significantly different from control values (p < 0.05). b In vivo tumor formation in mice injected with Nodal morpholino-transfected C8161 cells (MO Nodal) vs. melanoma cells transfected with control morpholino (MO Control), introduced orthotopically subcutaneously. Values represent the median tumor volume (mm3)±interquartile range (n = 5/group, p < 0.05)
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Fig6: Down-regulation of Nodal expression by exposure to the hESC microenvironment or by knock down with Nodal morpholino leads to abrogation metastatic melanoma tumorigenicity. a The ratio of tumor cell proliferation to apoptosis in tumors derived from human metastatic melanoma cells (C8161), determined by immunohistochemical staining for Ki-67 and terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling (TUNEL). Prior to injection into a mouse, C8161 cells were cultured for 3 days on control or hESC conditioned matrices (hESC CMTX), or treated with MO Nodal to knock down Nodal expression. Bars represent mean normalized values±standard deviation, and values indicated by an asterisk are significantly different from control values (p < 0.05). b In vivo tumor formation in mice injected with Nodal morpholino-transfected C8161 cells (MO Nodal) vs. melanoma cells transfected with control morpholino (MO Control), introduced orthotopically subcutaneously. Values represent the median tumor volume (mm3)±interquartile range (n = 5/group, p < 0.05)

Mentions: Since Nodal is expressed and secreted in a dysregulated fashion by aggressive melanoma cells which do not express Lefty (an endogenous Nodal inhibitor, as shown in Table 1), a direct assumption would be that targeted disruption of Nodal could have significant effects on tumor cell growth. This was shown to be the case when Nodal morpholino treatment (morpholine ring-based anti-sense nucleotides) of C8161 cells was found to decrease the proliferation/apoptosis ratio of the cells by nearly 80% compared to controls (Fig. 6a). A similar effect was seen when the C8161 cells were cultured on an hESC CMTX, and might be attributed to the deposition of inhibitors of Nodal, such as Lefty, into the hESC CMTX. These in vitro data are supported by in vivo experiments which demonstrate and confirm the effects of Nodal inhibition on tumor growth [5]. C8161 melanoma cells treated with Nodal morpholino and harvested for xenograft transplantation in the subcutaneous tissue of nude mice exhibit significantly less tumor formation and growth than cells treated with control morpholinos (Fig. 6b). More than 2 weeks following implantation, tumor volume in treated C8161 xenografts remained less than 20% of controls. After 2 weeks, Nodal is re-expressed in the melanoma xenografts and tumorigenicity resumes. This intriguing finding suggests that targeted and sustained therapy against a key developmental factor, such as Nodal, may represent a new therapeutic approach to treating cancer.Fig. 6


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)

Down-regulation of Nodal expression by exposure to the hESC microenvironment or by knock down with Nodal morpholino leads to abrogation metastatic melanoma tumorigenicity. a The ratio of tumor cell proliferation to apoptosis in tumors derived from human metastatic melanoma cells (C8161), determined by immunohistochemical staining for Ki-67 and terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling (TUNEL). Prior to injection into a mouse, C8161 cells were cultured for 3 days on control or hESC conditioned matrices (hESC CMTX), or treated with MO Nodal to knock down Nodal expression. Bars represent mean normalized values±standard deviation, and values indicated by an asterisk are significantly different from control values (p < 0.05). b In vivo tumor formation in mice injected with Nodal morpholino-transfected C8161 cells (MO Nodal) vs. melanoma cells transfected with control morpholino (MO Control), introduced orthotopically subcutaneously. Values represent the median tumor volume (mm3)±interquartile range (n = 5/group, p < 0.05)
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Fig6: Down-regulation of Nodal expression by exposure to the hESC microenvironment or by knock down with Nodal morpholino leads to abrogation metastatic melanoma tumorigenicity. a The ratio of tumor cell proliferation to apoptosis in tumors derived from human metastatic melanoma cells (C8161), determined by immunohistochemical staining for Ki-67 and terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling (TUNEL). Prior to injection into a mouse, C8161 cells were cultured for 3 days on control or hESC conditioned matrices (hESC CMTX), or treated with MO Nodal to knock down Nodal expression. Bars represent mean normalized values±standard deviation, and values indicated by an asterisk are significantly different from control values (p < 0.05). b In vivo tumor formation in mice injected with Nodal morpholino-transfected C8161 cells (MO Nodal) vs. melanoma cells transfected with control morpholino (MO Control), introduced orthotopically subcutaneously. Values represent the median tumor volume (mm3)±interquartile range (n = 5/group, p < 0.05)
Mentions: Since Nodal is expressed and secreted in a dysregulated fashion by aggressive melanoma cells which do not express Lefty (an endogenous Nodal inhibitor, as shown in Table 1), a direct assumption would be that targeted disruption of Nodal could have significant effects on tumor cell growth. This was shown to be the case when Nodal morpholino treatment (morpholine ring-based anti-sense nucleotides) of C8161 cells was found to decrease the proliferation/apoptosis ratio of the cells by nearly 80% compared to controls (Fig. 6a). A similar effect was seen when the C8161 cells were cultured on an hESC CMTX, and might be attributed to the deposition of inhibitors of Nodal, such as Lefty, into the hESC CMTX. These in vitro data are supported by in vivo experiments which demonstrate and confirm the effects of Nodal inhibition on tumor growth [5]. C8161 melanoma cells treated with Nodal morpholino and harvested for xenograft transplantation in the subcutaneous tissue of nude mice exhibit significantly less tumor formation and growth than cells treated with control morpholinos (Fig. 6b). More than 2 weeks following implantation, tumor volume in treated C8161 xenografts remained less than 20% of controls. After 2 weeks, Nodal is re-expressed in the melanoma xenografts and tumorigenicity resumes. This intriguing finding suggests that targeted and sustained therapy against a key developmental factor, such as Nodal, may represent a new therapeutic approach to treating cancer.Fig. 6

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