Epigenetic Inheritance From Normal Origin Cells Can Determine the Aggressive Biology of Tumor-Initiating Cells and Tumor Heterogeneity.

The acquisition of genetic- and epigenetic-abnormalities during transformation has been recognized as the two fundamental factors that lead to tumorigenesis and determine the aggressive biology of tumor cells. However, there is a regularity that tumors derived from less-differentiated normal origin cells (NOCs) usually have a higher risk of vascular involvement, lymphatic and distant metastasis, which can be observed in both lymphohematopoietic malignancies and somatic cancers. Obviously, the hypothesis of genetic- and epigenetic-abnormalities is not sufficient to explain how the linear relationship between the cellular origin and the biological behavior of tumors is formed, because the cell origin of tumor is an independent factor related to tumor biology. In a given system, tumors can originate from multiple cell types, and tumor-initiating cells (TICs) can be mapped to different differentiation hierarchies of normal stem cells, suggesting that the heterogeneity of the origin of TICs is not completely chaotic. TIC's epigenome includes not only genetic- and epigenetic-abnormalities, but also established epigenetic status of genes inherited from NOCs. In reviewing previous studies, we found much evidence supporting that the status of many tumor-related "epigenetic abnormalities" in TICs is consistent with that of the corresponding NOC of the same differentiation hierarchy, suggesting that they may not be true epigenetic abnormalities. So, we speculate that the established statuses of genes that control NOC's migration, adhesion and colonization capabilities, cell-cycle quiescence, expression of drug transporters, induction of mesenchymal formation, overexpression of telomerase, and preference for glycolysis can be inherited to TICs through epigenetic memory and be manifested as their aggressive biology. TICs of different origins can maintain different degrees of innate stemness from NOC, which may explain why malignancies with stem cell phenotypes are usually more aggressive.