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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

Effect of doxorubicin on metabolic activity and apoptosis of neuroblastoma cell lines. MTT assay of the untreated and doxorubicin treated Neuro2a (A), SK-N-SH (B), and IMR-32 (C) cells of either AD or AI phenotype revealed slower metabolic activity of the AI cells. Doxorubicin lowered the metabolic activity of both the phenotypes of all cell lines. (D) Graphical representation of the apoptosis assay at 24, 48, and 72 h following doxorubicin (Dx; 0, 0.01, and 0.1 μg/ml) treatment shows that the AI cells are more resistant to doxorubicin than the AD cells. The change in viability between the treated and untreated groups of AI cells is less for all time points and drug doses. Data points expressed as mean ± S.D. (n = 3).
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Figure 3: Effect of doxorubicin on metabolic activity and apoptosis of neuroblastoma cell lines. MTT assay of the untreated and doxorubicin treated Neuro2a (A), SK-N-SH (B), and IMR-32 (C) cells of either AD or AI phenotype revealed slower metabolic activity of the AI cells. Doxorubicin lowered the metabolic activity of both the phenotypes of all cell lines. (D) Graphical representation of the apoptosis assay at 24, 48, and 72 h following doxorubicin (Dx; 0, 0.01, and 0.1 μg/ml) treatment shows that the AI cells are more resistant to doxorubicin than the AD cells. The change in viability between the treated and untreated groups of AI cells is less for all time points and drug doses. Data points expressed as mean ± S.D. (n = 3).

Mentions: Anchorage independent phenotypes grew slower than AD phenotypes in all cell lines as indicated by cell cycle analysis and MTT assay (Figures 2A,B and 3A–C). The AD cells were also found to be more sensitive to the chemotherapeutic agent doxorubicin than the AI cells (Figure 3D).


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

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

Effect of doxorubicin on metabolic activity and apoptosis of neuroblastoma cell lines. MTT assay of the untreated and doxorubicin treated Neuro2a (A), SK-N-SH (B), and IMR-32 (C) cells of either AD or AI phenotype revealed slower metabolic activity of the AI cells. Doxorubicin lowered the metabolic activity of both the phenotypes of all cell lines. (D) Graphical representation of the apoptosis assay at 24, 48, and 72 h following doxorubicin (Dx; 0, 0.01, and 0.1 μg/ml) treatment shows that the AI cells are more resistant to doxorubicin than the AD cells. The change in viability between the treated and untreated groups of AI cells is less for all time points and drug doses. Data points expressed as mean ± S.D. (n = 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Effect of doxorubicin on metabolic activity and apoptosis of neuroblastoma cell lines. MTT assay of the untreated and doxorubicin treated Neuro2a (A), SK-N-SH (B), and IMR-32 (C) cells of either AD or AI phenotype revealed slower metabolic activity of the AI cells. Doxorubicin lowered the metabolic activity of both the phenotypes of all cell lines. (D) Graphical representation of the apoptosis assay at 24, 48, and 72 h following doxorubicin (Dx; 0, 0.01, and 0.1 μg/ml) treatment shows that the AI cells are more resistant to doxorubicin than the AD cells. The change in viability between the treated and untreated groups of AI cells is less for all time points and drug doses. Data points expressed as mean ± S.D. (n = 3).
Mentions: Anchorage independent phenotypes grew slower than AD phenotypes in all cell lines as indicated by cell cycle analysis and MTT assay (Figures 2A,B and 3A–C). The AD cells were also found to be more sensitive to the chemotherapeutic agent doxorubicin than the AI cells (Figure 3D).

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