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Reversible adaptive plasticity: a mechanism for neuroblastoma cell heterogeneity and chemo-resistance.

Chakrabarti L, Abou-Antoun T, Vukmanovic S, Sandler AD - Front Oncol (2012)

Bottom Line: The AI tumorspheres were found to be more resistant to chemotherapy and proliferated slower in vitro compared to the AD cells.Our results demonstrate that neuroblastoma cells are plastic, dynamic, and may optimize their ability to survive by changing their phenotype.Phenotypic switching appears to be an adaptive mechanism to unfavorable selection pressure and could explain the phenotypic and functional heterogeneity of neuroblastoma.

View Article: PubMed Central - PubMed

Affiliation: The Joseph E. Robert Center for Surgical Care, Children's National Medical Center Washington, DC, USA.

ABSTRACT
We describe a novel form of tumor cell plasticity characterized by reversible adaptive plasticity in murine and human neuroblastoma. Two cellular phenotypes were defined by their ability to exhibit adhered, anchorage dependent (AD) or sphere forming, anchorage independent (AI) growth. The tumor cells could transition back and forth between the two phenotypes and the transition was dependent on the culture conditions. Both cell phenotypes exhibited stem-like features such as expression of nestin, self-renewal capacity, and mesenchymal differentiation potential. The AI tumorspheres were found to be more resistant to chemotherapy and proliferated slower in vitro compared to the AD cells. Identification of specific molecular markers like MAP2, β-catenin, and PDGFRβ enabled us to characterize and observe both phenotypes in established mouse tumors. Irrespective of the phenotype originally implanted in mice, tumors grown in vivo show phenotypic heterogeneity in molecular marker signatures and are indistinguishable in growth or histologic appearance. Similar molecular marker heterogeneity was demonstrated in primary human tumor specimens. Chemotherapy or growth factor receptor inhibition slowed tumor growth in mice and promoted initial loss of AD or AI heterogeneity, respectively. Simultaneous targeting of both phenotypes led to further tumor growth delay with emergence of new unique phenotypes. Our results demonstrate that neuroblastoma cells are plastic, dynamic, and may optimize their ability to survive by changing their phenotype. Phenotypic switching appears to be an adaptive mechanism to unfavorable selection pressure and could explain the phenotypic and functional heterogeneity of neuroblastoma.

No MeSH data available.


Related in: MedlinePlus

Cell heterogeneity in human primary neuroblastoma tumors. Immunofluorescence staining with MAP2, β-catenin, and PDGFRβ on frozen sections of three human primary neuroblastoma specimens revealed scattered areas with differential MAP2, PDGFRβ, and β-catenin staining indicating similar heterogeneity of cells as seen in mouse tumors. Scale bar, 50 μm.
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Figure 8: Cell heterogeneity in human primary neuroblastoma tumors. Immunofluorescence staining with MAP2, β-catenin, and PDGFRβ on frozen sections of three human primary neuroblastoma specimens revealed scattered areas with differential MAP2, PDGFRβ, and β-catenin staining indicating similar heterogeneity of cells as seen in mouse tumors. Scale bar, 50 μm.

Mentions: The coexistence of AI and AD phenotypes in vivo could be unique to Neuro2a cells or cell lines in general, and may not be a reflection of events that occur in primary neuroblastoma tumors. To address this issue, frozen sections of three human neuroblastoma specimens were co-stained with nestin and MAP2 and separately with PDGFRβ and β-catenin specific antibodies. This analysis revealed similar heterogeneity of cells as seen in mouse tumors indicating that phenotypic heterogeneity exists in primary human neuroblastomas (Figure 8).


Reversible adaptive plasticity: a mechanism for neuroblastoma cell heterogeneity and chemo-resistance.

Chakrabarti L, Abou-Antoun T, Vukmanovic S, Sandler AD - Front Oncol (2012)

Cell heterogeneity in human primary neuroblastoma tumors. Immunofluorescence staining with MAP2, β-catenin, and PDGFRβ on frozen sections of three human primary neuroblastoma specimens revealed scattered areas with differential MAP2, PDGFRβ, and β-catenin staining indicating similar heterogeneity of cells as seen in mouse tumors. Scale bar, 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3412992&req=5

Figure 8: Cell heterogeneity in human primary neuroblastoma tumors. Immunofluorescence staining with MAP2, β-catenin, and PDGFRβ on frozen sections of three human primary neuroblastoma specimens revealed scattered areas with differential MAP2, PDGFRβ, and β-catenin staining indicating similar heterogeneity of cells as seen in mouse tumors. Scale bar, 50 μm.
Mentions: The coexistence of AI and AD phenotypes in vivo could be unique to Neuro2a cells or cell lines in general, and may not be a reflection of events that occur in primary neuroblastoma tumors. To address this issue, frozen sections of three human neuroblastoma specimens were co-stained with nestin and MAP2 and separately with PDGFRβ and β-catenin specific antibodies. This analysis revealed similar heterogeneity of cells as seen in mouse tumors indicating that phenotypic heterogeneity exists in primary human neuroblastomas (Figure 8).

Bottom Line: The AI tumorspheres were found to be more resistant to chemotherapy and proliferated slower in vitro compared to the AD cells.Our results demonstrate that neuroblastoma cells are plastic, dynamic, and may optimize their ability to survive by changing their phenotype.Phenotypic switching appears to be an adaptive mechanism to unfavorable selection pressure and could explain the phenotypic and functional heterogeneity of neuroblastoma.

View Article: PubMed Central - PubMed

Affiliation: The Joseph E. Robert Center for Surgical Care, Children's National Medical Center Washington, DC, USA.

ABSTRACT
We describe a novel form of tumor cell plasticity characterized by reversible adaptive plasticity in murine and human neuroblastoma. Two cellular phenotypes were defined by their ability to exhibit adhered, anchorage dependent (AD) or sphere forming, anchorage independent (AI) growth. The tumor cells could transition back and forth between the two phenotypes and the transition was dependent on the culture conditions. Both cell phenotypes exhibited stem-like features such as expression of nestin, self-renewal capacity, and mesenchymal differentiation potential. The AI tumorspheres were found to be more resistant to chemotherapy and proliferated slower in vitro compared to the AD cells. Identification of specific molecular markers like MAP2, β-catenin, and PDGFRβ enabled us to characterize and observe both phenotypes in established mouse tumors. Irrespective of the phenotype originally implanted in mice, tumors grown in vivo show phenotypic heterogeneity in molecular marker signatures and are indistinguishable in growth or histologic appearance. Similar molecular marker heterogeneity was demonstrated in primary human tumor specimens. Chemotherapy or growth factor receptor inhibition slowed tumor growth in mice and promoted initial loss of AD or AI heterogeneity, respectively. Simultaneous targeting of both phenotypes led to further tumor growth delay with emergence of new unique phenotypes. Our results demonstrate that neuroblastoma cells are plastic, dynamic, and may optimize their ability to survive by changing their phenotype. Phenotypic switching appears to be an adaptive mechanism to unfavorable selection pressure and could explain the phenotypic and functional heterogeneity of neuroblastoma.

No MeSH data available.


Related in: MedlinePlus