Abstract
The ability of high-risk neuroblastoma to survive unfavorable growth conditions and multimodal therapy has produced an elusive childhood cancer with remarkably poor prognosis. A novel phenomenon enabling neuroblastoma to survive selection pressure is its capacity for reversible adaptive plasticity. This plasticity allows cells to transition between highly proliferative anchorage dependent (AD) and slow growing, anoikis-resistant anchorage independent (AI) phenotypes. Both phenotypes are present in established mouse and human tumors. The differential gene expression profile of the two cellular phenotypes in the mouse Neuro2a cell line delineated pathways of proliferation in AD cells or tyrosine kinase activation/ apoptosis inhibition in AI cells. A 20 fold overexpression of inhibitor of differentiation 2 (Id2) was identified in AD cells while up-regulation of genes involved in anoikis resistance like PI3K/Akt, Erk, Bcl2 and integrins was observed in AI cells. Similarly, differential expression of Id2 and other genes of interest were also observed in the AD and AI phenotypes of human neuroblastoma cell lines, SK-N-SH and IMR-32; as well as in primary human tumor specimens. Forced down-regulation of Id2 in AD cells or overexpression in AI cells induced the cells to gain characteristics of the other phenotype. Id2 binds both TGFβ and Smad2/3 and appears critical for maintaining the proliferative phenotype at least partially through negative regulation of the TGFβ/Smad pathway. Simultaneously targeting the differential molecular pathways governing reversible adaptive plasticity resulted in 50% cure of microscopic disease and delayed tumor growth in established mouse neuroblastoma tumors. We present a mechanism that accounts for reversible adaptive plasticity and a molecular basis for combined targeted therapies in neuroblastoma.
Highlights
Neuroblastoma is a pediatric solid tumor originating from neural crest progenitors
A wide array of genes involved in anoikis resistance including Bcl2, PI3K/Akt, EGFR, Ras, integrin a1, a3, a5, b1 and b3 were found to be overexpressed in the anchorage independent (AI) cells (Table S1)
To gain further insight into the mechanism driving this adaptation, we explored gene expression in the two heterogenous phenotypes of Neuro2a cells and examined potential target molecules involved in the phenotypic transition
Summary
Neuroblastoma is a pediatric solid tumor originating from neural crest progenitors. This disease displays considerable clinical variability, reflected in patient outcomes that range from spontaneous regression to lethal disease [1,2,3]. Since neuroblastoma tumor cells arise from embryonic neural crest cells, the AI cells are grown as spheroids in neural stem cell serum free culture conditions while the AD counterparts proliferate rapidly and attach to the plate in regular serum rich media [19]. The importance of this finding translates to tumor growth as both phenotypes are capable of reversible transition and specific molecular markers enabled us to observe both cell types in established mouse and human neuroblastoma tumors. We have identified this phenomenon in multiple other tumor types (unpublished observations) and other human cancers frequently display substantial intra-tumor heterogeneity in cellular morphology and gene expression [5]
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