Neural is Fundamental: Neural Stemness as the Ground State of Cell Tumorigenicity and Differentiation Potential

Abstract

Tumorigenesis is a complex biological phenomenon that includes extensive genetic and phenotypic heterogeneities and complicated regulatory mechanisms. In the recent few years, our studies demonstrate that tumor-initiating cells are similar to neural stem/progenitor cells in regulatory networks, tumorigenicity and pluripotent differentiation potential. In the review, I will make further discussion on these observations and propose a rule of cell biology by integrating these findings with evidence from developmental biology, tumor biology and evolution, which suggests that neural stemness underlies two coupled cell properties, tumorigenicity and pluripotent differentiation potential. Tumorigenicity and phenotypic heterogeneity in tumor is a result of acquirement of neural stemness in cells. The neural stemness property of tumor-initiating cells can hopefully integrate different concepts/hypotheses underlying tumorigenesis. Neural stem cells/neural progenitors and tumor-initiating cells share regulatory networks; both exhibit neural stemness, tumorigenicity and differentiation potential; both are dependent on expression or activation of ancestral genes (the atavistic effect); both rely primarily on aerobic glycolytic metabolism; both can differentiate into various cells or tissues that are derived from three germ layers, resembling severely disorganized or more severely degenerated process of embryonic development; both are enriched in long genes with more splice variants that provide more plastic scaffolds for cell differentiation, etc. The property of neural stemness might be a key point to understand tumorigenesis and pluripotent differentiation potential, and possibly explain certain pathological observations in tumors that have been inexplicable. Therefore, behind the complexity of tumorigenesis might be a general rule of cell biology, i.e., neural stemness represents the ground state of cell tumorigenicity and pluripotent differentiation potential.

Suppression of Cell Tumorigenicity by Non-neural Pro-differentiation Factors via Inhibition of Neural Property in Tumorigenic Cells

“…Accordingly, in xenograft assays with immunodeficient nude mice, enforced Foxa3 ( Figures 2H–J ) or HHEX expression ( Figures 2K–M ) significantly inhibited tumorigenicity of NE-4C cells ( Supplementary Table 6 ). Expressions of the detected proteins or genes above are all enriched in neural stem cells or embryonic neural cells during embryogenesis ( Zhang et al, 2017 ; Cao, 2020 ; Xu et al, 2021 ). This result reinforces that neural stemness is required for cell tumorigenicity, and loss of neural stemness means the reduction or loss of cell tumorigenicity ( Xu et al, 2021 ).…”

“…This means that genes specify a tissue or an organ must in the meantime repress the genes specifying adjacent or other tissues or organs, thereby maintaining the integrity of the tissue or organ, and establishing the boundaries between different tissues or organs. As we have elucidated that tumorigenic cells have the property of neural stemness, which defines the tumorigenic and differentiation potentials in a cell because of the evolutionary advantage of neural stemness ( Zhang et al, 2017 ; Cao, 2020 ; Xu et al, 2021 ). In other words, all embryonic or somatic cell types are built on the ground of neural stemness.…”

“…Moreover, tumor cells capable of tumor formation also show the potential of differentiation of different cell types derived from three germ layers ( Xu et al, 2021 ). Together with the evolutionary advantage of neural state and other studies in developmental biology, tumor biology and evolution, in particular the neural default model of embryonic pluripotent cells, we proposed that neural stemness represents the ground state of tumorigenic and differentiation potential ( Cao, 2020 ). This means that tumorigenesis resembles a process of severely chaotic and degenerated embryonic tissue differentiation, which is driven by cells with the property of neural stemness ( Cao, 2017 , 2020 ; Xu et al, 2021 ).…”

“…Together with the evolutionary advantage of neural state and other studies in developmental biology, tumor biology and evolution, in particular the neural default model of embryonic pluripotent cells, we proposed that neural stemness represents the ground state of tumorigenic and differentiation potential ( Cao, 2020 ). This means that tumorigenesis resembles a process of severely chaotic and degenerated embryonic tissue differentiation, which is driven by cells with the property of neural stemness ( Cao, 2017 , 2020 ; Xu et al, 2021 ). There has been evidence that neural progenitor cells (NPCs) promote tumor growth and metastasis ( Mauffrey et al, 2019 ), and gain of neural stemness in intestinal stem cells drives tumorigenesis ( Li Z. et al, 2020 ).…”

“…Neural stemness as the ground state (the neural ground state) of tumorigenicity and differentiation potential is reflected by that many machineries required for basic physiological functions of cells and factors involved in developmental programs are enriched in embryonic neural cells or NSCs, such as those for cell cycle, ribosome biogenesis, proteasome assembly, protein translation, spliceosome, epigenetic modification, reprogramming, etc. ( Cao, 2020 ). These machineries or factors, most of which are upregulated in and promote tumorigenesis, work together to define a cell state of fast cell cycle and high proliferation with the potential of pluripotent differentiation.…”