Abstract
BackgroundWe have been investigating how interruption of differentiation contributes to the oncogenic process and the possibility to reverse the transformed phenotype by restoring differentiation. In a previous report, we correlated the capacity of intracellular Notch (ICN) to suppress v-Src-mediated transformation of quail neuroretina (QNR/v-srcts) cells with the acquisition by these undifferentiated cells of glial differentiation markers.Methodology/Principal FindingsIn this work, we have identified autocrine TGF-β3 signaling activation as a major effector of Notch-induced phenotypic changes, sufficient to induce transition in differentiation markers expression, suppress morphological transformation and significantly inhibit anchorage-independent growth. We also show that this signaling is constitutive of and contributes to ex-vivo autonomous QNR cell differentiation and that its down-regulation is essential to achieve v-Src-induced transformation.Conclusions/SignificanceThese results support the possibility that Notch signaling induces differentiation and suppresses transformation by a novel mechanism, involving secreted proteins. They also underline the importance of extracellular signals in controlling the balance between normal and transformed phenotypes.
Highlights
Differentiation is a multi-step process resulting from a cascade of alternate activation and extinction of tissue-specific signaling pathways
We previously reported that stable expression of Notch intra cellular domain (ICN) suppresses transformation of embryonic quail neuroretina (QNR) cells induced by a temperature sensitive v-Src (QNR/v-srcts), without altering oncoprotein expression nor its downstream signaling activity
To understand the mechanisms by which Notch signaling activation suppressed cell transformation, we compared the transcription profile of QNR cells transformed by a v-src mutant encoding a temperature sensitive oncoprotein (QNR/v-srcts), with that of cells stably expressing intracellular Notch (ICN) (QNR/v-srcts/ICN). mRNA were prepared from cells maintained at permissive (37uC) or restrictive (41uC) temperature
Summary
Differentiation is a multi-step process resulting from a cascade of alternate activation and extinction of tissue-specific signaling pathways. The rationale for a differentiation therapy is based on the assumption that cancer cells have retained the potential to respond to appropriate differentiation signals, which in turn would be sufficient to restore a normal phenotype. This could be achieved either because the transformed cells undergo growth arrest or because they no longer respond to oncogenic stimuli. Developing models for the latter would be useful to identify pathways essential for transformation and possibly result in new therapeutic approaches. We correlated the capacity of intracellular Notch (ICN) to suppress v-Src-mediated transformation of quail neuroretina (QNR/v-srcts) cells with the acquisition by these undifferentiated cells of glial differentiation markers
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