J Cancer 2022; 13(9):2810-2843. doi:10.7150/jca.72628 This issue

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Mutation or not, what directly establishes a neoplastic state, namely cellular immortality and autonomy, still remains unknown and should be prioritized in our research

Shengming Zhu1#, Jiangang Wang2#, Lucas Zellmer3, Ningzhi Xu4, Mei Liu4, Yun Hu5, Hong Ma6✉, Fei Deng7✉, Wenxiu Yang8✉, Dezhong Joshua Liao8,9✉

1. Department of Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, P.R. China.
2. Department of Health Management Center, The Third Xiangya Hospital, Central South University, 138 Tong-Zi-Po Road, Changsha 410013, Hunan Province, P. R. China.
3. Department of Medicine, Hennepin County Medical Center, 730 South 8th St., Minneapolis, MN 55415, USA.
4. Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
5. Department of Pathology, School of Stomatology, Guizhou Medical University, 9 Beijing Road, Guiyang 550004, Guizhou Province, P.R. China.
6. Department of Oral and Maxillofacial Surgery, School of Stomatology, Guizhou Medical University, 9 Beijing Road, Guiyang 550004, Guizhou Province, P.R. China.
7. Department of Pathology, The Third Affiliated Hospital, Zunyi Medical University, Zunyi City 563000, Guizhou Province, P.R. China.
8. Department of Pathology, The Affiliated Hospital, Guizhou Medical University, Guiyang 550004, Guizhou Province, P.R. China.
9. Key Lab of Endemic and Ethnic Diseases of the Ministry of Education of China in Guizhou Medical University, Guiyang, Guizhou Province 550004, P. R. China.
#These authors contributed equally to this work.

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Citation:
Zhu S, Wang J, Zellmer L, Xu N, Liu M, Hu Y, Ma H, Deng F, Yang W, Liao DJ. Mutation or not, what directly establishes a neoplastic state, namely cellular immortality and autonomy, still remains unknown and should be prioritized in our research. J Cancer 2022; 13(9):2810-2843. doi:10.7150/jca.72628. Available from https://www.jcancer.org/v13p2810.htm

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Abstract

Graphic abstract

Although the concept that cancer is caused by mutations has been widely accepted, there still are ample data deprecating it. For example, embryonic cells displaced in non-embryonic environments may develop to cancer, whereas cancer cells placed in embryonic environments may be reverted to phenotypic normal. Although many intracellular or extracellular aberrations are known to be able to initiate a lengthy tumorigenesis, the molecular or cellular alterations that directly establish a neoplastic state, namely cellular immortality and autonomy, still remain unknown. Hereditary traits are encoded not only by gene sequences but also by karyotype and DNA or chromosomal structures that may be altered via non-mutational mechanisms, such as post-translational modifications of nuclear proteins, to initiate tumorigenesis. However, the immortal and autonomous nature of neoplasms makes them “new” organisms, meaning that neoplasms should have mutations to distinguish themselves from their host patients in the genome. Neoplasms are malignant if they bear epigenetic or genetic alterations in mutator genes, i.e. the genes whose alterations accelerate other genes to mutate, whereas neoplasms are benign if their epigenetic or genetic aberrations occur only in non-mutator genes. Future mechanistic research should be focused on identifying the alterations that directly establish cellular immortality and autonomy. Benign tumors may have many fewer alterations and thus be much better models than cancers for such research. Future translational research should be aimed at identifying the cellular factors that control cancer cells' phenotypes and at establishing approaches of directing cancer cells towards differentiation, which should be a promising therapeutic tactic.

Keywords: Epigenetic, Genetic, Neoplastic transformation, Stem cell, Tumor classification