Neural stemness contributes to cell tumorigenicity

Abstract

Background Previous studies demonstrated the dependence of cancer on nerve. Recently, a growing number of studies reveal that cancer cells share the property and regulatory network with neural stem/progenitor cells. However, relationship between the property of neural stemness and cell tumorigenicity is unknown. Results We show that neural stem/progenitor cells, but not non-neural embryonic or somatic stem/progenitor cell types, exhibit tumorigenicity and the potential for differentiation into tissue types of all germ layers when they are placed in non-native environment by transplantation into immunodeficient nude mice. Likewise, cancer cells capable of tumor initiation have the property of neural stemness because of their abilities in neurosphere formation in neural stem cell-specific serum-free medium and in differentiation potential, in addition to their neuronal differentiation potential that was characterized previously. Moreover, loss of a pro-differentiation factor in myoblasts, which have no tumorigenicity, lead to the loss of myoblast identity, and gain of the property of neural stemness, tumorigenicity and potential for re-differentiation. These suggest that the property of neural stemness contributes to cell tumorigenicity, and tumor phenotypic heterogeneity might be an effect of differentiation potential of neural stemness. Bioinformatic analysis reveals that neural genes in general are correlated with embryonic development and cancer, in addition to their role in neural development; whereas non-neural genes are not. Most of neural specific genes emerged in typical species representing transition from unicellularity to multicellularity during evolution. Genes in Monosiga brevicollis, a unicellular species that is a closest known relative of metazoans, are biased toward neural cells. Conclusions We suggest that the property of neural stemness is the source of cell tumorigenicity. This is due to that neural biased unicellular state is the ground state for multicellularity and hence cell type diversification or differentiation during evolution, and tumorigenesis is a process of restoration of neural ground state in somatic cells along a default route that is pre-determined by an evolutionary advantage of neural state.

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

“…Hematopoietic stem cell transplantation has been widely used as a treatment for hematological cancers and other diseases. In our study, we also observed that embryonic fibroblasts and myoblasts are not tumorigenic (Xu et al, 2020). When either the muscle differentiation factor Myod1 was lost in myoblasts or a transcriptional repressor was lost in intestinal stem cells, the resulting cells gained neural stemness and tumorigenicity (Li et al, 2020;Xu et al, 2020).…”

“…If we consider the neural default state and tumorigenicity of ESCs, tumorigenicity of NSCs is not irrational. As a matter of fact, tumorigenicity is an intrinsic property of NSCs/NPCs (Xu et al, 2020). First, tumorigenicity was demonstrated for primNSCs that were derived from ESCs.…”

“…It is rather logical that tumorigenic cells are stronger in tumorigenicity in the absence of TGFbeta signaling. PrimNSC-derived tumors are composed of tissues of all germ layers, including immature neuroectodermal cells, differentiated neuronal cells, or keratinized structures from ectoderm, and full spectrum of tissues from mesoderm and endoderm (Xu et al, 2020). These tumors are very similar to teratoma formed by ESCs, suggesting that primNSCs, representing initial neuroectodermal cells, are pluripotent in differentiation potential.…”

“…These tumors are very similar to teratoma formed by ESCs, suggesting that primNSCs, representing initial neuroectodermal cells, are pluripotent in differentiation potential. Second, tumorigenicity was demonstrated for a NSC cell line derived from E9 mouse embryos (Xu et al, 2020). Subcutaneous transplantation of the cells caused formation of tumors, and tail vein injection of the cells led to formation of tumors in various tissues or regions of mouse body.…”

“…They exhibit seemingly both a promoting and an inhibitory effect on tumor progression (Serakinci et al, 2018). However, the cells themselves exhibit no tumorigenicity (Ra et al, 2011;Sykova and Forostyak, 2013;Yong et al, 2018;Xu et al, 2020).…”