PO-277 Postmitotic neuron-like differentiation of cancer cells suggests that cancer cells have the properties of neural precursor/progenitor cells

Abstract

IntroductionCancer cells are dedifferentiated cells, and re-differentiation is expected to reduce malignancy. It is unclear, however, whether cancer cells can undergo terminal differentiation.Material and methodsCandidate regulators mediating cancer cell terminal differentiation were identified by applying a few rules to epigenetic factors. Cell lines of eight cancer types were tested for differentiation effect, validated with marker expression and gene expression profiling assays. Cell invasion/migration, MTT, colony formation, xenograft and a mouse tumour model assays were used for in vitro and in vivo detection of the effect of inhibition of these factors on malignant features of cancer cells and on tumour growth/development. Correlation between the function/expression of >3000 cancer-related genes/factors in cancer and in specific embryonic tissues were analysed using literature research and whole mount in situ hybridization with Xenopus embryos.Results and discussionsWe identified HDAC1/3, LSD1, EZH2 and DNMT1 as candidate factors. Upon inhibition of these factors, cancer cell lines underwent postmitotic neuron-like differentiation, accompanied with a loss of malignant properties. In agreement, these factors, together with a majority of pan-cancer promoting genes/factors or those being upregulated during tumorigenesis, including mesenchymal markers, show specific expression or play specific roles in embryonic neural precursor/progenitor tissues. This suggests that cancer cells and embryonic neural cells share a set of regulatory networks, conferring cancer cells with properties of neural precursor/progenitor cells. However, many pan-cancer suppressor genes/factors or those being downregulated during tumorigenesis, including epithelial marker CDH1, are non-neural. Thus, tumorigenesis might be a process of gradual loss of original cell identity and gain of properties of neural precursor/progenitor cells, in contrast to the notion of cancer EMT. Many other studies provide solid supports for our model.ConclusionCancer cells share regulatory networks with and have properties of neural precursor/progenitor cells.