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

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Abstract

Tumorigenic cells are similar to neural stem cells or embryonic neural cells in regulatory networks, tumorigenicity and pluripotent differentiation potential. By integrating the evidence from developmental biology, tumor biology and evolution, I will make a detailed discussion on the observations and propose that neural stemness underlies two coupled cell properties, tumorigenicity and pluripotent differentiation potential. Neural stemness property of tumorigenic cells can hopefully integrate different observations/concepts underlying tumorigenesis. Neural stem cells and tumorigenic cells share regulatory networks; both exhibit neural stemness, tumorigenicity and pluripotent differentiation potential; both depend on expression or activation of ancestral genes; both rely primarily on aerobic glycolytic metabolism; both can differentiate into various cells/tissues that are derived from three germ layers, leading to tumor formation resembling severely disorganized or more degenerated process of embryonic tissue differentiation; both are enriched in long genes with more splice variants that provide more plastic scaffolds for cell differentiation, etc. Neural regulatory networks, which include higher levels of basic machineries of cell physiological functions and developmental programs, work concertedly to define a basic state with fast cell cycle and proliferation. This is predestined by the evolutionary advantage of neural state, the ground or initial state for multicellularity with adaptation to an ancient environment. Tumorigenesis might represent a process of restoration of neural ground state, thereby restoring a state with fast proliferation and pluripotent differentiation potential in somatic cells. Tumorigenesis and pluripotent differentiation potential might be better understood from understanding neural stemness, and cancer therapy should benefit more from targeting neural stemness.

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References

  1. Hajdu, S. I. (2011). A note from history: landmarks in history of cancer, part 1. Cancer, 117, 1097–1102

    Article  PubMed  Google Scholar 

  2. Burrell, R. A., McGranahan, N., Bartek, J., & Swanton, C. (2013). The causes and consequences of genetic heterogeneity in cancer evolution. Nature, 501, 338–345

    Article  CAS  PubMed  Google Scholar 

  3. Meacham, C. E., & Morrison, S. J. (2013). Tumour heterogeneity and cancer cell plasticity. Nature, 501, 328–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Friedmann-Morvinski, D., & Verma, I. M. (2014). Dedifferentiation and reprogramming: origins of cancer stem cells. EMBO Reports, 15, 244–253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Prasetyanti, P. R., & Medema, J. P. (2017). Intra-tumor heterogeneity from a cancer stem cell perspective. Molecular Cancer, 16, 41

    Article  PubMed  PubMed Central  Google Scholar 

  6. Dagogo-Jack, I., & Shaw, A. T. (2018). Tumour heterogeneity and resistance to cancer therapies. Nature Reviews. Clinical Oncology, 15, 81–94

    Article  CAS  PubMed  Google Scholar 

  7. Paduch, R. (2015). Theories of cancer origin. European Journal of Cancer Prevention, 24, 57–67

    Article  PubMed  Google Scholar 

  8. Hanselmann, R. G., & Welter, C. (2016). Origin of cancer: an information, energy, and matter disease. Frontiers in Cell and Developmental Biology, 4, 121

    Article  PubMed  PubMed Central  Google Scholar 

  9. Gilbert, S. F., & Barresi, M. J. (2016). Early amphibian development. In Developmental Biology (11th Ed., pp. 333-364). Sinauer Associates, Inc

  10. Grunz, H., & Tacke, L. (1989). Neural differentiation of Xenopus laevis ectoderm takes place after disaggregation and delayed reaggregation without inducer. Cell Differentiation and Development, 28, 211–217

    Article  CAS  PubMed  Google Scholar 

  11. Godsave, S. F., & Slack, J. M. (1989). Clonal analysis of mesoderm induction in Xenopus laevis. Developmental Biology, 134, 486–490

    Article  CAS  PubMed  Google Scholar 

  12. Sato, S. M., & Sargent, T. D. (1989). Development of neural inducing capacity in dissociated Xenopus embryos. Developmental Biology, 134, 263–266

    Article  CAS  PubMed  Google Scholar 

  13. Harland, R. (2000). Neural induction. Current Opinion in Genetics & Development, 10, 357–362

    Article  CAS  Google Scholar 

  14. De Robertis, E. M., & Kuroda, H. (2004). Dorsal-ventral patterning and neural induction in Xenopus embryos. Annual Review of Cell and Developmental Biology, 20, 285–308

    Article  PubMed  PubMed Central  Google Scholar 

  15. De Robertis, E. M. (2006). Spemann’s organizer and self-regulation in amphibian embryos. Nature Reviews. Molecular Cell Biology, 7, 296–302

    Article  PubMed  PubMed Central  Google Scholar 

  16. Muñoz-Sanjuán, I., & Brivanlou, A. H. (2002). Neural induction, the default model and embryonic stem cells. Nature Reviews. Neuroscience, 3, 271–280

    Article  PubMed  Google Scholar 

  17. Tropepe, V., Hitoshi, S., Sirard, C., Mak, T. W., Rossant, J., & van der Kooy, D. (2001). Direct neural fate specification from embryonic stem cells: a primitive mammalian neural stem cell stage acquired through a default mechanism. Neuron, 30, 65–78

    Article  CAS  PubMed  Google Scholar 

  18. Ying, Q. L., Stavridis, M., Griffiths, D., Li, M., & Smith, A. (2003). Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture. Nature Biotechnology, 21, 183–186

    Article  CAS  PubMed  Google Scholar 

  19. Smukler, S. R., Runciman, S. B., Xu, S., & van der Kooy, D. (2006). Embryonic stem cells assume a primitive neural stem cell fate in the absence of extrinsic influences. The Journal of Cell Biology, 172, 79–90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ying, Q. L., Nichols, J., Chambers, I., & Smith, A. (2003). BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell, 115, 281–292

    Article  CAS  PubMed  Google Scholar 

  21. Malaguti, M., Nistor, P. A., Blin, G., Pegg, A., Zhou, X., & Lowell, S. (2013). Bone morphogenic protein signalling suppresses differentiation of pluripotent cells by maintaining expression of E-Cadherin. eLife, 2, e01197

  22. Ben-David, U., & Benvenisty, N. (2011). The tumorigenicity of human embryonic and induced pluripotent stem cells. Nature Reviews. Cancer, 11, 268–277

    Article  CAS  PubMed  Google Scholar 

  23. Zhang, Z., Lei, A., Xu, L., Chen, L., Chen, Y., Zhang, X., & Cao, Y. (2017). Similarity in gene-regulatory networks suggests that cancer cells share characteristics of embryonic neural cells. The Journal of Biological Chemistry, 292, 12842–12859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cao, Y. (2017). Tumorigenesis as a process of gradual loss of original cell identity and gain of properties of neural precursor/progenitor cells. Cell & Bioscience, 7, 61

    Article  Google Scholar 

  25. Lei, A., Chen, L., Zhang, M., Yang, X., Xu, L., Cao, N., & Cao, Y. (2019). EZH2 regulates protein stability via recruiting USP7 to mediate neuronal gene expression in cancer cells. Frontiers in Genetics, 10, 422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Neman, J., Termini, J., Wilczynski, S., Vaidehi, N., Choy, C., Kowolik, C. M., & Jandial, R. (2014). Human breast cancer metastases to the brain display GABAergic properties in the neural niche. Proceedings of the National Academy of Sciences of the United States of America, 111, 984–989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Boire, A., Brastianos, P. K., Garzia, L., & Valiente, M. (2020). Brain metastasis. Nature Reviews Cancer, 20, 4–11

    Article  CAS  PubMed  Google Scholar 

  28. Venkataramani, V., Tanev, D. I., Strahle, C., Studier-Fischer, A., Fankhauser, L., Kessler, T., & Kuner, T. (2019). Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature, 573(7775), 532–538

    Article  CAS  PubMed  Google Scholar 

  29. Venkatesh, H. S., Morishita, W., Geraghty, A. C., Silverbush, D., Gillespie, S. M., Arzt, M. … Monje, M. (2019). Electrical and synaptic integration of glioma into neural circuits. Nature, 573, 539–545

  30. Zeng, Q., Michael, I. P., Zhang, P., Saghafinia, S., Knott, G., Jiao, W. … Hanahan, D. (2019). Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature, 573, 526–531

  31. Reavis, H. D., Chen, H. I., & Drapkin, R. (2020). Tumor innervation: cancer has some nerve. Trends in Cancer, 6, 1059–1067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mauffrey, P., Tchitchek, N., Barroca, V., Bemelmans, A. P., Firlej, V., Allory, Y. … Magnon, C. (2019). Progenitors from the central nervous system drive neurogenesis in cancer. Nature, 569, 672–678

  33. Li, Z., Guo, X., Huang, H., Wang, C., Yang, F., Zhang, Y. … Xi, R. (2020). A switch in tissue stem cell identity causes neuroendocrine tumors in drosophila gut. Cell Reports, 30, 1724–17344

  34. Müller, F. J., Goldmann, J., Löser, P., & Loring, J. F. (2010). A call to standardize teratoma assays used to define human pluripotent cell lines. Cell Stem Cell, 6, 412–414

    Article  PubMed  Google Scholar 

  35. Yasuda, S., & Sato, Y. (2015). Tumorigenicity assessment of human cell-processed therapeutic products. Biologicals, 43, 416–421

    Article  CAS  PubMed  Google Scholar 

  36. Germain, N. D., Hartman, N. W., Cai, C., Becker, S., Naegele, J. R., & Grabel, L. B. (2012). Teratocarcinoma formation in embryonic stem cell-derived neural progenitor hippocampal transplants. Cell Transplantation, 21, 1603–1611

    Article  PubMed  Google Scholar 

  37. Deng, J., Zhang, Y., Xie, Y., Zhang, L., & Tang, P. (2018). Cell transplantation for spinal cord injury: tumorigenicity of induced pluripotent stem cell-derived neural stem/progenitor cells. Stem Cells International, 2018, 5653787

  38. Amariglio, N., Hirshberg, A., Scheithauer, B. W., Cohen, Y., Loewenthal, R., Trakhtenbrot, L. … Rechavi, G. (2009). Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Medicine, 6, e1000029

  39. Xu, L., Zhang, M., Shi, L., Yang, X., Chen, L., Cao, N. … Cao, Y. (2021). Neural stemness contributes to cell tumorigenicity. Cell & Bioscience, 11, 21

  40. Mullen, A. C., & Wrana, J. L. (2017). TGF-β family signaling in embryonic and somatic stem-cell renewal and differentiation. Cold Spring Harbor Perspectives in Biology, 9, a022186

    Article  PubMed  PubMed Central  Google Scholar 

  41. Massagué, J. (2008). TGFbeta in cancer. Cell, 134, 215–230

    Article  PubMed  PubMed Central  Google Scholar 

  42. Seoane, J., & Gomis, R. R. (2017). TGF-β family signaling in tumor suppression and cancer progression. Cold Spring Harbor Perspectives in Biology, 9, a022277

    Article  PubMed  PubMed Central  Google Scholar 

  43. Clarke, D. L., Johansson, C. B., Wilbertz, J., Veress, B., Nilsson, E., Karlström, H. … Frisén, J. (2000). Generalized potential of adult neural stem cells. Science, 288, 1660–1663

  44. Serakinci, N., Tulay, P., & Kalkan, R. (2018). Role of mesenchymal stem cells in cancer development and their use in cancer therapy. Advances in Experimental Medicine and Biology, 1083, 45–62

    Article  CAS  PubMed  Google Scholar 

  45. Ra, J. C., Shin, I. S., Kim, S. H., Kang, S. K., Kang, B. C., Lee, H. Y. … Kwon, E. (2011). Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem Cells and Development, 20, 1297–1308

  46. Sykova, E., & Forostyak, S. (2013). Stem cells in regenerative medicine. Laser Therapy, 22, 87–92

    Article  PubMed  PubMed Central  Google Scholar 

  47. Yong, K. W., Choi, J. R., Dolbashid, A. S., & Safwani, W. (2018). Biosafety and bioefficacy assessment of human mesenchymal stem cells: what do we know so far? Regenerative Medicine, 13, 219–232

    Article  CAS  PubMed  Google Scholar 

  48. Lauvrak, S. U., Munthe, E., Kresse, S. H., Stratford, E. W., Namløs, H. M., Meza-Zepeda, L. A., & Myklebost, O. (2013). Functional characterisation of osteosarcoma cell lines and identification of mRNAs and miRNAs associated with aggressive cancer phenotypes. British Journal of Cancer, 109, 2228–2236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Méndez-Ferrer, S., Michurina, T. V., Ferraro, F., Mazloom, A. R., Macarthur, B. D., Lira, S. A. … Frenette, P. S. (2010). Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature, 466, 829–834

  50. Ricci-Vitiani, L., Lombardi, D. G., Pilozzi, E., Biffoni, M., Todaro, M., Peschle, C., & De Maria, R. (2007). Identification and expansion of human colon-cancer-initiating cells. Nature, 445, 111–115

    Article  CAS  PubMed  Google Scholar 

  51. Fox, R. G., Lytle, N. K., Jaquish, D. V., Park, F. D., Ito, T., Bajaj, J. … Reya, T. (2016). Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma. Nature, 534, 407–411

  52. Boumahdi, S., Driessens, G., Lapouge, G., Rorive, S., Nassar, D., Le Mercier, M. … Blanpain, C. (2014). SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma. Nature, 511, 246–250

  53. Nakanishi, Y., Seno, H., Fukuoka, A., Ueo, T., Yamaga, Y., Maruno, T. … Chiba, T. (2013). Dclk1 distinguishes between tumor and normal stem cells in the intestine. Nature Genetics, 45, 98–103

  54. McGrail, M., Batz, L., Noack, K., Pandey, S., Huang, Y., Gu, X., & Essner, J. J. (2010). Expression of the zebrafish CD133/prominin1 genes in cellular proliferation zones in the embryonic central nervous system and sensory organs. Developmental Dynamics, 239, 1849–1857

    Article  CAS  PubMed  Google Scholar 

  55. Mizuguchi, M., Qin, J., Yamada, M., Ikeda, K., & Takashima, S. (1999). High expression of doublecortin and KIAA0369 protein in fetal brain suggests their specific role in neuronal migration. The American Journal of Pathology, 155, 1713–1721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Matsumoto, N., Pilz, D. T., & Ledbetter, D. H. (1999). Genomic structure, chromosomal mapping, and expression pattern of human DCAMKL1 (KIAA0369), a homologue of DCX (XLIS). Genomics, 56, 179–183

    Article  CAS  PubMed  Google Scholar 

  57. Thisse, B., Pflumio, S., Fürthauer, M., Loppin, B., Heyer, V., Degrave, A. … Thisse, C. (2001). Expression of the zebrafish genome during embryogenesis (NIH R01 RR15402). ZFIN Direct Data Submission (http://zfin.org)

  58. Han, R., Wang, R., Zhao, Q., Han, Y., Zong, S., Miao, S. … Wang, L. (2016). Trim69 regulates zebrafish brain development by ap-1 pathway. Scientific Reports, 6, 24034

  59. Chen, J., Niu, N., Zhang, J., Qi, L., Shen, W., Donkena, K. V. … Liu, J. (2019). Polyploid Giant Cancer Cells (PGCCs): the evil roots of cancer. Current Cancer Drug Targets, 19, 360–367

  60. Moein, S., Adibi, R., da Silva Meirelles, L., Nardi, N. B., & Gheisari, Y. (2020). Cancer regeneration: Polyploid cells are the key drivers of tumor progression. Biochimica et Biophysica Acta. Reviews on Cancer, 1874, 188408

    Article  CAS  PubMed  Google Scholar 

  61. Was, H., Borkowska, A., Olszewska, A., Klemba, A., Marciniak, M., Synowiec, A., & Kieda, C. (2021). Polyploidy formation in cancer cells: How a Trojan horse is born. Seminars in Cancer Biology, S1044-579X(21), 00053–00055 Advance online publication

    Google Scholar 

  62. Saleh, T., Carpenter, V. J., Bloukh, S., & Gewirtz, D. A. (2020). Targeting tumor cell senescence and polyploidy as potential therapeutic strategies. Seminars in Cancer Biology, S1044-579X(20), 30270–30274 Advance online publication

    Google Scholar 

  63. Saini, G., Joshi, S., Garlapati, C., Li, H., Kong, J., Krishnamurthy, J. … Aneja, R. (2021). Polyploid giant cancer cell characterization: New frontiers in predicting response to chemotherapy in breast cancer. Seminars in Cancer Biology, S1044-579 × (21)00067-5

  64. Niu, N., Mercado-Uribe, I., & Liu, J. (2017). Dedifferentiation into blastomere-like cancer stem cells via formation of polyploid giant cancer cells. Oncogene, 36, 4887–4900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Pruszak, J., Sonntag, K. C., Aung, M. H., Sanchez-Pernaute, R., & Isacson, O. (2007). Markers and methods for cell sorting of human embryonic stem cell-derived neural cell populations. Stem Cells, 25, 2257–2268

    Article  PubMed  PubMed Central  Google Scholar 

  66. Chen, K. A., Laywell, E. D., Marshall, G., Walton, N., Zheng, T., & Steindler, D. A. (2006). Fusion of neural stem cells in culture. Experimental Neurology, 198, 129–135

    Article  CAS  PubMed  Google Scholar 

  67. Marusyk, A., Almendro, V., & Polyak, K. (2012). Intra-tumour heterogeneity: a looking glass for cancer? Nature Reviews. Cancer, 12, 323–334

    Article  CAS  PubMed  Google Scholar 

  68. McGranahan, N., & Swanton, C. (2015). Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell, 27, 15–26

    Article  CAS  PubMed  Google Scholar 

  69. Quintanal-Villalonga, Ã., Chan, J. M., Yu, H. A., Pe’er, D., Sawyers, C. L., Sen, T., & Rudin, C. M. (2020). Lineage plasticity in cancer: a shared pathway of therapeutic resistance. Nature Reviews. Clinical Oncology, 17, 360–371

    Article  PubMed  PubMed Central  Google Scholar 

  70. Clevers, H. (2011). The cancer stem cell: premises, promises and challenges. Nature Medicine, 17, 313–319

    Article  CAS  PubMed  Google Scholar 

  71. Beck, B., & Blanpain, C. (2013). Unravelling cancer stem cell potential. Nature Reviews. Cancer, 13, 727–738

    Article  CAS  PubMed  Google Scholar 

  72. Shmelkov, S. V., Butler, J. M., Hooper, A. T., Hormigo, A., Kushner, J., Milde, T., … Rafii, S. (2008). CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors. The Journal of Clinical Investigation, 118, 2111–2120

  73. Beier, D., Hau, P., Proescholdt, M., Lohmeier, A., Wischhusen, J., Oefner, P. J. … Beier, C. P. (2007). CD133(+) and CD133(-) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Research, 67, 4010–4015

  74. Mintz, B., & Illmensee, K. (1975). Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proceedings of the National Academy of Sciences of the United States of America, 72, 3585–3589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Papaioannou, V. E., McBurney, M. W., Gardner, R. L., & Evans, M. J. (1975). Fate of teratocarcinoma cells injected into early mouse embryos. Nature, 258, 70–73

    Article  CAS  PubMed  Google Scholar 

  76. Scaffidi, P., & Misteli, T. (2011). In vitro generation of human cells with cancer stem cell properties. Nature Cell Biology, 13, 1051–1061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ricci-Vitiani, L., Pallini, R., Biffoni, M., Todaro, M., Invernici, G., Cenci, T. … De Maria, R. (2010). Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature, 468, 824–828

  78. Wang, R., Chadalavada, K., Wilshire, J., Kowalik, U., Hovinga, K. E., Geber, A. … Tabar, V. (2010). Glioblastoma stem-like cells give rise to tumour endothelium. Nature, 468, 829–833

  79. Cheng, L., Huang, Z., Zhou, W., Wu, Q., Donnola, S., Liu, J. K. … Bao, S. (2013). Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell, 153, 139–152

  80. Vermeulen, L., Todaro, M., de Sousa Mello, F., Sprick, M. R., Kemper, K., Perez Alea, M. … Medema, J. P. (2008). Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proceedings of the National Academy of Sciences of the United States of America, 105, 13427–13432

  81. Kim, K., Higashi, M., Fumino, S., & Tajiri, T. (2019). Derivation of neural stem cells from human teratomas. Stem Cell Research, 41, 101633

    Article  CAS  PubMed  Google Scholar 

  82. Yachida, S., Fukushima, N., Nakanishi, Y., Akasu, T., Kitamura, H., Sakamoto, M., & Shimoda, T. (2003). Alpha-fetoprotein-producing carcinoma of the colon: report of a case and review of the literature. Diseases of the Colon and Rectum, 46, 826–831

    Article  PubMed  Google Scholar 

  83. Anzai, H., Kazama, S., Kiyomatsu, T., Nishikawa, T., Tanaka, T., Tanaka, J. … Watanabe, T. (2015). Alpha-fetoprotein-producing early rectal carcinoma: a rare case report and review. World Journal of Surgical Oncology, 13, 180

  84. Gong, W., Su, Y., Liu, A., Liu, J., Sun, D., Jiang, T., … Sun, P. (2018). Clinical characteristics and treatments of patients with alpha-fetoprotein producing gastric carcinoma. Neoplasma, 65, 326–330

  85. Abid, H., & Gnanajothy, R. (2019). Osteoclast giant cell tumor of pancreas: a case report and literature review. Cureus, 11, e4710

    PubMed  PubMed Central  Google Scholar 

  86. Njoumi, N., Elalami, F. H., Attolou, G., Saoud, O., Elabsi, M., Echarrab, M. … Chkoff, M. R. (2014). Undifferentiated pancreatic carcinoma with osteoclast-like giant cells: a case report. Journal of Gastrointestinal Cancer, 45(Suppl 1), 96–98

  87. Sah, S. K., Li, Y., & Li, Y. (2015). Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells: a rare case report and review of the literature. International Journal of Clinical and Experimental Pathology, 8, 11785–11791

    PubMed  PubMed Central  Google Scholar 

  88. Togawa, Y., Tonouchi, A., Chiku, T., Sano, W., Doki, T., Yano, K. … Toyoda, A. (2010). A case report of undifferentiated carcinoma with osteoclast-like giant cells of the pancreas and literature review. Clinical Journal of Gastroenterology, 3, 195–203

  89. Bauditz, J., Rudolph, B., & Wermke, W. (2006). Osteoclast-like giant cell tumors of the pancreas and liver. World Journal of Gastroenterology, 12, 7878–7883

    Article  PubMed  PubMed Central  Google Scholar 

  90. Dioscoridi, L., Bisogni, D., & Freschi, G. (2015). Hepatocellular carcinoma with osteoclast-like giant cells: report of the seventh case in the literature. Case Reports in Surgery, 2015, 836105

  91. Ikeda, T., Seki, S., Maki, M., Noguchi, N., Kawamura, T., Arii, S. … Hirokawa, K. (2003). Hepatocellular carcinoma with osteoclast-like giant cells: possibility of osteoclastogenesis by hepatocyte-derived cells. Pathology International, 53, 450–456

  92. Kuwano, H., Sonoda, T., Hashimoto, H., & Enjoji, M. (1984). Hepatocellular carcinoma with osteoclast-like giant cells. Cancer, 54, 837–842

    Article  CAS  PubMed  Google Scholar 

  93. Rosai, J. (1990). Liver cell carcinoma with osteoclast-like giant cells: nonepitheliogenic giant cells in diverse malignancies. Hepatology, 12, 782–783

    Article  CAS  PubMed  Google Scholar 

  94. Goel, G., Rao, S., & Khurana, N. (2011). Malignant melanoma with osteoclast-like giant cells: A report of two cases. Journal of Cancer Research and Therapeutics, 7, 336–338

    Article  PubMed  Google Scholar 

  95. Al-Brahim, N., & Salama, S. (2005). Malignant melanoma with osteoclast-like giant cells: an unusual host response: immunohistochemical and ultrastructural study of three cases and literature review. The American Journal of Dermatopathology, 27, 126–129

    Article  PubMed  Google Scholar 

  96. Jiménez-Heffernan, J. A., Adrados, M., Muñoz-Hernández, P., Fernández-Rico, P., Ballesteros-García, A. I., & Fraga, J. (2018). Cytologic Features of Malignant Melanoma with Osteoclast-Like Giant Cells. Acta Cytologica, 62, 151–154

    Article  PubMed  Google Scholar 

  97. Houang, M., Castillo, C., La Marca, S., Combemale, P., Wang, Q., Paindavoine, S. … de la Fouchardiere A. (2015). An unusual case of desmoplastic melanoma containing an osteoclast-like giant cell-rich nodule. The American Journal of Dermatopathology, 37, 299–304

  98. Nakahashi, H., Tsuneyoshi, M., Ishida, T., Minagawa, S., Owaki, Y., Momii, S., & Eimoto, T. (1987). Undifferentiated carcinoma of the lung with osteoclast-like giant cells. The Japanese Journal of Surgery, 17, 199–203

    Article  CAS  PubMed  Google Scholar 

  99. Matsukuma, S., Takeo, H., Kato, K., & Sato, K. (2014). Numerous osteoclast-like giant cells in metastases from lung adenocarcinoma, but absent from primary tumor. Thoracic Cancer, 5, 354–357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Lindholm, K. E., Kalhor, N., & Moran, C. A. (2019). Osteoclast-like giant cell-rich carcinomas of the lung: a clinicopathological, immunohistochemical, and molecular study of 3 cases. Human Pathology, 85, 168–173

    Article  CAS  PubMed  Google Scholar 

  101. Kong, L., Peng, W., Liu, J., Wang, W., Gong, P., Yu, G., & Li, J. (2015). Squamous cell carcinoma of lung associated with osteoclast-like giant cells: report of a case. International Journal of Clinical and Experimental Pathology, 8, 11823–11825

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Dahm, H. H. (2017). Non-small cell carcinoma of the lung with osteoclast-like giant cells. International Journal of Surgical Pathology, 25, 258–261

    Article  PubMed  Google Scholar 

  103. Stewart, C. J., & Mutch, A. F. (1991). Breast carcinoma with osteoclast-like giant cells. Cytopathology, 2, 215–219

    Article  CAS  PubMed  Google Scholar 

  104. Agnantis, N. T., & Rosen, P. P. (1979). Mammary carcinoma with osteoclast-like giant cells. A study of eight cases with follow-up data. American Journal of Clinical Pathology, 72, 383–389

    Article  CAS  PubMed  Google Scholar 

  105. Fadare, O., & Gill, S. A. (2009). Solid neuroendocrine carcinoma of the breast with osteoclast-like giant cells. The Breast Journal, 15, 205–206

    Article  PubMed  Google Scholar 

  106. Ginter, P. S., Petrova, K., & Hoda, S. A. (2015). The grossly “rusty” tumor of breast: invasive ductal carcinoma with osteoclast-like giant cells. International Journal of Surgical Pathology, 23, 32–33

    Article  PubMed  Google Scholar 

  107. Ohashi, R., Hayama, A., Matsubara, M., Watarai, Y., Sakatani, T., Naito, Z., & Shimizu, A. (2018). Breast carcinoma with osteoclast-like giant cells: A cytological-pathological correlation with a literature review. Annals of Diagnostic Pathology, 33, 1–5

    Article  PubMed  Google Scholar 

  108. Hoorweg, J. J., Loftus, B. M., & Hilgers, F. J. (1997). Osteoid and bone formation in a nasal mucosal melanoma and its metastasis. Histopathology, 31, 465–468

    Article  CAS  PubMed  Google Scholar 

  109. Dekkers, I. A., Cleven, A., Lamb, H. J., & Kroon, H. M. (2019). Primary Osteosarcoma of the Breast. Radiographics, 39, 626–629

    Article  PubMed  Google Scholar 

  110. Drummond, C. J., Hanna, J. A., Garcia, M. R., Devine, D. J., Heyrana, A. J., Finkelstein, D. … Hatley, M. E. (2018). Hedgehog Pathway Drives Fusion-Negative Rhabdomyosarcoma Initiated From Non-myogenic Endothelial Progenitors. Cancer Cell, 33, 108–1245

  111. Rubin, H. (1985). Cancer as a dynamic developmental disorder. Cancer Research, 45, 2935–2942

    CAS  PubMed  Google Scholar 

  112. Solter, D. (2006). From teratocarcinomas to embryonic stem cells and beyond: a history of embryonic stem cell research. Nature Reviews. Genetics, 7, 319–327

    Article  CAS  PubMed  Google Scholar 

  113. Knoepfler, P. S. (2009). Deconstructing stem cell tumorigenicity: a roadmap to safe regenerative medicine. Stem Cells, 27, 1050–1056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Riggs, J. W., Barrilleaux, B. L., Varlakhanova, N., Bush, K. M., Chan, V., & Knoepfler, P. S. (2013). Induced pluripotency and oncogenic transformation are related processes. Stem Cells and Development, 22, 37–50

    Article  CAS  PubMed  Google Scholar 

  115. Cheng, L., Hu, W., Qiu, B., Zhao, J., Yu, Y., Guan, W. … Pei, G. (2014). Generation of neural progenitor cells by chemical cocktails and hypoxia. Cell Research, 24, 665–679

  116. Domazet-Loso, T., Brajković, J., & Tautz, D. (2007). A phylostratigraphy approach to uncover the genomic history of major adaptations in metazoan lineages. Trends in Genetics, 23, 533–539

    Article  CAS  PubMed  Google Scholar 

  117. Sebé-Pedrós, A., Degnan, B. M., & Ruiz-Trillo, I. (2017). The origin of Metazoa: a unicellular perspective. Nature Reviews. Genetics, 18, 498–512

    Article  PubMed  Google Scholar 

  118. Clarke, L., & van der Kooy, D. (2009). Low oxygen enhances primitive and definitive neural stem cell colony formation by inhibiting distinct cell death pathways. Stem Cells, 27, 1879–1886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Vernon, A. E., & Philpott, A. (2003). The developmental expression of cell cycle regulators in Xenopus laevis. Gene Expression Patterns, 3, 179–192

    Article  CAS  PubMed  Google Scholar 

  120. Hatch, V. L., Marin-Barba, M., Moxon, S., Ford, C. T., Ward, N. J., Tomlinson, M. L. … Wheeler, G. N. (2016). The positive transcriptional elongation factor (P-TEFb) is required for neural crest specification. Developmental Biology, 416, 361–372

  121. Baserga, R. (2007). Is cell size important? Cell Cycle, 6, 814–816

    Article  CAS  PubMed  Google Scholar 

  122. Turi, Z., Lacey, M., Mistrik, M., & Moudry, P. (2019). Impaired ribosome biogenesis: mechanisms and relevance to cancer and aging. Aging, 11, 2512–2540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Robson, A., Owens, N. D., Baserga, S. J., Khokha, M. K., & Griffin, J. N. (2016). Expression of ribosomopathy genes during Xenopus tropicalis embryogenesis. BMC Developmental Biology, 16, 38

    Article  PubMed  PubMed Central  Google Scholar 

  124. Altmann, C. R., Bell, E., Sczyrba, A., Pun, J., Bekiranov, S., Gaasterland, T., & Brivanlou, A. H. (2001). Microarray-based analysis of early development in Xenopus laevis. Developmental Biology, 236, 64–75

    Article  CAS  PubMed  Google Scholar 

  125. Weinstein, D. C., Honoré, E., & Hemmati-Brivanlou, A. (1997). Epidermal induction and inhibition of neural fate by translation initiation factor 4AIII. Development, 124, 4235–4242

    Article  CAS  PubMed  Google Scholar 

  126. Yan, B., Neilson, K. M., & Moody, S. A. (2010). Microarray identification of novel downstream targets of FoxD4L1/D5, a critical component of the neural ectodermal transcriptional network. Developmental Dynamics, 239, 3467–3480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Chau, K. F., Shannon, M. L., Fame, R. M., Fonseca, E., Mullan, H., Johnson, M. B. … Lehtinen, M. K. (2018). Downregulation of ribosome biogenesis during early forebrain development. eLife, 7, e36998

  128. Hasegawa, K., Shiraishi, T., & Kinoshita, T. (1999). Xoom: a novel oocyte membrane protein maternally expressed and involved in the gastrulation movement of Xenopus embryos. The International Journal of Developmental Biology, 43, 479–485

    CAS  PubMed  Google Scholar 

  129. Parain, K., Mazurier, N., Bronchain, O., Borday, C., Cabochette, P., Chesneau, A. … Perron, M. (2012). A large scale screen for neural stem cell markers in Xenopus retina. Developmental Neurobiology, 72, 491–506

  130. Hu, R., Huang, W., Liu, J., Jin, M., Wu, Y., Li, J. … Cao, Y. (2019). Mutagenesis of putative ciliary genes with the CRISPR/Cas9 system in zebrafish identifies genes required for retinal development. FASEB Journal, 33, 5248–5256

  131. Bush, S. J., Chen, L., Tovar-Corona, J. M., & Urrutia, A. O. (2017). Alternative splicing and the evolution of phenotypic novelty. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 372, 20150474

    Article  PubMed  PubMed Central  Google Scholar 

  132. Baralle, F. E., & Giudice, J. (2017). Alternative splicing as a regulator of development and tissue identity. Nature Reviews. Molecular Cell Biology, 18, 437–451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Dichmann, D. S., Fletcher, R. B., & Harland, R. M. (2008). Expression cloning in Xenopus identifies RNA-binding proteins as regulators of embryogenesis and Rbmx as necessary for neural and muscle development. Developmental Dynamics, 237, 1755–1766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Voigt, J., Chen, J. A., Gilchrist, M., Amaya, E., & Papalopulu, N. (2005). Expression cloning screening of a unique and full-length set of cDNA clones is an efficient method for identifying genes involved in Xenopus neurogenesis. Mechanisms of Development, 122, 289–306

    Article  CAS  PubMed  Google Scholar 

  135. Liu, K. J., & Harland, R. M. (2005). Inhibition of neurogenesis by SRp38, a neuroD-regulated RNA-binding protein. Development, 132, 1511–1523

    Article  CAS  PubMed  Google Scholar 

  136. Li, C., Hu, R., Hou, N., Wang, Y., Wang, Z., Yang, T. … Li, T. (2018). Alteration of the Retinoid Acid-CBP Signaling Pathway in Neural Crest Induction Contributes to Enteric Nervous System Disorder. Frontiers in Pediatrics, 6, 382

  137. Schwenty-Lara, J., Nürnberger, A., & Borchers, A. (2019). Loss of function of Kmt2d, a gene mutated in Kabuki syndrome, affects heart development in Xenopus laevis. Developmental Dynamics, 248, 465–476

    Article  CAS  PubMed  Google Scholar 

  138. Nicetto, D., Hahn, M., Jung, J., Schneider, T. D., Straub, T., David, R. … Rupp, R. A. (2013). Suv4-20 h histone methyltransferases promote neuroectodermal differentiation by silencing the pluripotency-associated Oct-25 gene. PLoS Genetics, 9, e1003188

  139. Saritas-Yildirim, B., Childers, C. P., Elsik, C. G., & Silva, E. M. (2015). Identification of REST targets in the Xenopus tropicalis genome. BMC Genomics, 16, 380

    Article  PubMed  PubMed Central  Google Scholar 

  140. Kawaguchi, A., Ochi, H., Sudou, N., & Ogino, H. (2012). Comparative expression analysis of the H3K27 demethylases, JMJD3 and UTX, with the H3K27 methylase, EZH2, in Xenopus. The International Journal of Developmental Biology, 56, 295–300

    Article  CAS  PubMed  Google Scholar 

  141. Wang, C. D., Guo, X. F., Wong, T., Wang, H., Qi, X. F., Cai, D. Q. … Zhao, H. (2019). Developmental expression of three prmt genes in Xenopus. Zoological Research, 40, 102–107

  142. Zhang, X., Gao, Y., Lu, L., Zhang, Z., Gan, S., Xu, L. … Cao, Y. (2015). JmjC domain-containing protein 6 (Jmjd6) derepresses the transcriptional repressor transcription factor 7-like 1 (Tcf7l1) and is required for body axis patterning during Xenopus embryogenesis. The Journal of Biological Chemistry, 290, 20273–20283

  143. Xu, Y., Zhang, M., Li, W., Zhu, X., Bao, X., Qin, B. … Esteban, M. A. (2016). Transcriptional control of somatic cell reprogramming. Trends in Cell Biology, 26, 272–288

  144. Buitrago-Delgado, E., Nordin, K., Rao, A., Geary, L., & LaBonne, C. (2015). NEURODEVELOPMENT. Shared regulatory programs suggest retention of blastula-stage potential in neural crest cells. Science, 348, 1332–1335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Bellmeyer, A., Krase, J., Lindgren, J., & LaBonne, C. (2003). The protooncogene c-myc is an essential regulator of neural crest formation in xenopus. Developmental Cell, 4, 827–839

    Article  CAS  PubMed  Google Scholar 

  146. Janesick, A., Abbey, R., Chung, C., Liu, S., Taketani, M., & Blumberg, B. (2013). ERF and ETV3L are retinoic acid-inducible repressors required for primary neurogenesis. Development, 140, 3095–3106

    Article  CAS  PubMed  Google Scholar 

  147. Thisse, B., & Thisse, C. (2004). Fast release clones: a high throughput expression analysis. ZFIN Direct Data Submission (http://zfin.org)

  148. Light, W., Vernon, A. E., Lasorella, A., Iavarone, A., & LaBonne, C. (2005). Xenopus Id3 is required downstream of Myc for the formation of multipotent neural crest progenitor cells. Development, 132, 1831–1841

    Article  CAS  PubMed  Google Scholar 

  149. Neff, A. W., King, M. W., Harty, M. W., Nguyen, T., Calley, J., Smith, R. C., & Mescher, A. L. (2005). Expression of Xenopus XlSALL4 during limb development and regeneration. Developmental Dynamics, 233, 356–367

    Article  CAS  PubMed  Google Scholar 

  150. Reijnen, M. J., Hamer, K. M., den Blaauwen, J. L., Lambrechts, C., Schoneveld, I., van Driel, R., & Otte, A. P. (1995). Polycomb and bmi-1 homologs are expressed in overlapping patterns in Xenopus embryos and are able to interact with each other. Mechanisms of Development, 53, 35–46

    Article  CAS  PubMed  Google Scholar 

  151. Li, I. C., Chan, C. T., Lu, Y. F., Wu, Y. T., Chen, Y. C., Li, G. B. … Hwang, S. P. (2011). Zebrafish krüppel-like factor 4a represses intestinal cell proliferation and promotes differentiation of intestinal cell lineages. PloS One, 6, e20974

  152. Bertrand, S., Thisse, B., Tavares, R., Sachs, L., Chaumot, A., Bardet, P. L. … Laudet, V. (2007). Unexpected novel relational links uncovered by extensive developmental profiling of nuclear receptor expression. PLoS Genetics, 3, e188

  153. Seo, S., Richardson, G. A., & Kroll, K. L. (2005). The SWI/SNF chromatin remodeling protein Brg1 is required for vertebrate neurogenesis and mediates transactivation of Ngn and NeuroD. Development, 132, 105–115

    Article  CAS  PubMed  Google Scholar 

  154. Tessmar, K., Loosli, F., & Wittbrodt, J. (2002). A screen for co-factors of Six3. Mechanisms of Development, 117, 103–113

    Article  CAS  PubMed  Google Scholar 

  155. Iwano, H., Nakamura, M., & Tajima, S. (2004). Xenopus MBD3 plays a crucial role in an early stage of development. Developmental Biology, 268, 416–428

    Article  CAS  PubMed  Google Scholar 

  156. Aldiri, I., & Vetter, M. L. (2009). Characterization of the expression pattern of the PRC2 core subunit Suz12 during embryonic development of Xenopus laevis. Developmental Dynamics, 238, 3185–3192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Bibonne, A., Néant, I., Batut, J., Leclerc, C., Moreau, M., & Gilbert, T. (2013). Three calcium-sensitive genes, fus, brd3 and wdr5, are highly expressed in neural and renal territories during amphibian development. Biochimica et Biophysica Acta, 1833, 1665–1671

    Article  CAS  PubMed  Google Scholar 

  158. Sen, R., Pezoa, S. A., Carpio Shull, L., Hernandez-Lagunas, L., Niswander, L. A., & Artinger, K. B. (2018). Kat2a and Kat2b Acetyltransferase Activity Regulates Craniofacial Cartilage and Bone Differentiation in Zebrafish and Mice. Journal of Developmental Biology, 6, 27

    Article  CAS  PubMed Central  Google Scholar 

  159. Wang, Y., Shupenko, C. C., Melo, L. F., & Strauss, P. R. (2006). DNA repair protein involved in heart and blood development. Molecular and Cellular Biology, 26, 9083–9093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Pan, Y., Kelly, L. E., & El-Hodiri, H. M. (2018). Identification of retinal homeobox (rax) gene-dependent genes by a microarray approach: The DNA endoglycosylase neil3 is a major downstream component of the rax genetic pathway. Developmental Dynamics, 247, 1199–1210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Gu, A., Ji, G., Yan, L., & Zhou, Y. (2013). The 8-oxoguanine DNA glycosylase 1 (ogg1) decreases the vulnerability of the developing brain to DNA damage. DNA Repair, 12, 1094–1104

    Article  CAS  PubMed  Google Scholar 

  162. Bustelo, X. R., & Dosil, M. (2018). Ribosome biogenesis and cancer: basic and translational challenges. Current Opinion in Genetics & Development, 48, 22–29

    Article  CAS  Google Scholar 

  163. Catez, F., Dalla Venezia, N., Marcel, V., Zorbas, C., Lafontaine, D., & Diaz, J. J. (2019). Ribosome biogenesis: An emerging druggable pathway for cancer therapeutics. Biochemical Pharmacology, 159, 74–81

    Article  CAS  PubMed  Google Scholar 

  164. Pelletier, J., Thomas, G., & Volarević, S. (2018). Ribosome biogenesis in cancer: new players and therapeutic avenues. Nature Reviews. Cancer, 18, 51–63

    Article  CAS  PubMed  Google Scholar 

  165. Bhat, M., Robichaud, N., Hulea, L., Sonenberg, N., Pelletier, J., & Topisirovic, I. (2015). Targeting the translation machinery in cancer. Nature Reviews. Drug Discovery, 14, 261–278

    Article  CAS  PubMed  Google Scholar 

  166. Chen, Y., Zhang, Y., & Guo, X. (2017). Proteasome dysregulation in human cancer: implications for clinical therapies. Cancer Metastasis Reviews, 36, 703–716

    Article  CAS  PubMed  Google Scholar 

  167. Soave, C. L., Guerin, T., Liu, J., & Dou, Q. P. (2017). Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing. Cancer Metastasis Reviews, 36, 717–736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Rousseau, A., & Bertolotti, A. (2018). Regulation of proteasome assembly and activity in health and disease. Nature Reviews. Molecular Cell Biology, 19, 697–712

    Article  CAS  PubMed  Google Scholar 

  169. Dvinge, H., Kim, E., Abdel-Wahab, O., & Bradley, R. K. (2016). RNA splicing factors as oncoproteins and tumour suppressors. Nature Reviews. Cancer, 16, 413–430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Wang, B. D., & Lee, N. H. (2018). Aberrant RNA splicing in cancer and drug resistance. Cancers, 10, 458

    Article  CAS  PubMed Central  Google Scholar 

  171. Bennett, R. L., & Licht, J. D. (2018). Targeting epigenetics in cancer. Annual Review of Pharmacology and Toxicology, 58, 187–207

    Article  CAS  PubMed  Google Scholar 

  172. Mohammad, H. P., Barbash, O., & Creasy, C. L. (2019). Targeting epigenetic modifications in cancer therapy: erasing the roadmap to cancer. Nature Medicine, 25, 403–418

    Article  CAS  PubMed  Google Scholar 

  173. Brown, J. S., O’Carrigan, B., Jackson, S. P., & Yap, T. A. (2017). Targeting DNA repair in cancer: beyond PARP inhibitors. Cancer Discovery, 7, 20–37

    Article  CAS  PubMed  Google Scholar 

  174. Klinakis, A., Karagiannis, D., & Rampias, T. (2020). Targeting DNA repair in cancer: current state and novel approaches. Cellular and Molecular Life Sciences, 77, 677–703

    Article  CAS  PubMed  Google Scholar 

  175. Gabel, H. W., Kinde, B., Stroud, H., Gilbert, C. S., Harmin, D. A., Kastan, N. R. … Greenberg, M. E. (2015). Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. Nature, 522, 89–93

  176. Zylka, M. J., Simon, J. M., & Philpot, B. D. (2015). Gene length matters in neurons. Neuron, 86, 353–355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Domazet-Loso, T., & Tautz, D. (2010). Phylostratigraphic tracking of cancer genes suggests a link to the emergence of multicellularity in metazoa. BMC Biology, 8, 66

    Article  PubMed  PubMed Central  Google Scholar 

  178. Bussey, K. J., Cisneros, L. H., Lineweaver, C. H., & Davies, P. (2017). Ancestral gene regulatory networks drive cancer. Proceedings of the National Academy of Sciences of the United States of America, 114, 6160–6162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Trigos, A. S., Pearson, R. B., Papenfuss, A. T., & Goode, D. L. (2017). Altered interactions between unicellular and multicellular genes drive hallmarks of transformation in a diverse range of solid tumors. Proceedings of the National Academy of Sciences of the United States of America, 114, 6406–6411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Trigos, A. S., Pearson, R. B., Papenfuss, A. T., & Goode, D. L. (2018). How the evolution of multicellularity set the stage for cancer. British Journal of Cancer, 118, 145–152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Anatskaya, O. V., Vinogradov, A. E., Vainshelbaum, N. M., Giuliani, A., & Erenpreisa, J. (2020). Phylostratic Shift of Whole-Genome Duplications in Normal Mammalian Tissues towards Unicellularity Is Driven by Developmental Bivalent Genes and Reveals a Link to Cancer. International Journal of Molecular Sciences, 21, 8759

    Article  CAS  PubMed Central  Google Scholar 

  182. Alfarouk, K. O., Shayoub, M. E., Muddathir, A. K., Elhassan, G. O., & Bashir, A. H. (2011). Evolution of Tumor Metabolism might Reflect Carcinogenesis as a Reverse Evolution process (Dismantling of Multicellularity). Cancers, 3, 3002–3017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Chen, H., Lin, F., Xing, K., & He, X. (2015). The reverse evolution from multicellularity to unicellularity during carcinogenesis. Nature Communications, 6, 6367

    Article  CAS  PubMed  Google Scholar 

  184. Kim, D. Y., Rhee, I., & Paik, J. (2014). Metabolic circuits in neural stem cells. Cellular and Molecular Life Sciences, 71, 4221–4241

    Article  CAS  PubMed  Google Scholar 

  185. Zheng, X., Boyer, L., Jin, M., Mertens, J., Kim, Y., Ma, L. … Hunter, T. (2016). Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation. eLife, 5, e13374

  186. Intlekofer, A. M., & Finley, L. (2019). Metabolic signatures of cancer cells and stem cells. Nature Metabolism, 1, 177–188

    Article  PubMed  PubMed Central  Google Scholar 

  187. Nishimura, K., Fukuda, A., & Hisatake, K. (2019). Mechanisms of the Metabolic Shift during Somatic Cell Reprogramming. International Journal of Molecular Sciences, 20, 2254

    Article  CAS  PubMed Central  Google Scholar 

  188. Rabelo, I., Arnaud-Sampaio, V. F., Adinolfi, E., Ulrich, H., & Lameu, C. (2021). Cancer metabostemness and metabolic reprogramming via P2 × 7 receptor. Cells, 10, 1782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Ribeiro, D. E., Glaser, T., Oliveira-Giacomelli, Ã., & Ulrich, H. (2019). Purinergic receptors in neurogenic processes. Brain Research Bulletin, 151, 3–11

    Article  CAS  PubMed  Google Scholar 

  190. Oliveira, Ã., Illes, P., & Ulrich, H. (2016). Purinergic receptors in embryonic and adult neurogenesis. Neuropharmacology, 104, 272–281

    Article  CAS  PubMed  Google Scholar 

  191. Yona, A. H., Manor, Y. S., Herbst, R. H., Romano, G. H., Mitchell, A., Kupiec, M. … Dahan, O. (2012). Chromosomal duplication is a transient evolutionary solution to stress. Proceedings of the National Academy of Sciences of the United States of America, 109, 21010–21015

  192. Cisneros, L., Bussey, K. J., Orr, A. J., Miočević, M., Lineweaver, C. H., & Davies, P. (2017). Ancient genes establish stress-induced mutation as a hallmark of cancer. PloS One, 12, e0176258

    Article  PubMed  PubMed Central  Google Scholar 

  193. Varela, C., Denis, J. A., Polentes, J., Feyeux, M., Aubert, S., Champon, B. … Lefort, N. (2012). Recurrent genomic instability of chromosome 1q in neural derivatives of human embryonic stem cells. The Journal of Clinical Investigation, 122, 569–574

  194. Peterson, S. E., & Loring, J. F. (2014). Genomic instability in pluripotent stem cells: implications for clinical applications. The Journal of Biological Chemistry, 289, 4578–4584

    Article  CAS  PubMed  Google Scholar 

  195. Sahakyan, A. B., & Balasubramanian, S. (2016). Long genes and genes with multiple splice variants are enriched in pathways linked to cancer and other multigenic diseases. BMC Genomics, 17, 225

    Article  PubMed  PubMed Central  Google Scholar 

  196. Sogabe, S., Hatleberg, W. L., Kocot, K. M., Say, T. E., Stoupin, D., Roper, K. E. … Degnan, B. M. (2019). Pluripotency and the origin of animal multicellularity. Nature, 570, 519–522

  197. Cao, Y., Siegel, D., & Knöchel, W. (2006). Xenopus POU factors of subclass V inhibit activin/nodal signaling during gastrulation. Mechanisms of Development, 123, 614–625

    Article  CAS  PubMed  Google Scholar 

  198. Snir, M., Ofir, R., Elias, S., & Frank, D. (2006). Xenopus laevis POU91 protein, an Oct3/4 homologue, regulates competence transitions from mesoderm to neural cell fates. The EMBO Journal, 25, 3664–3674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Lujan, E., & Wernig, M. (2012). The many roads to Rome: induction of neural precursor cells from fibroblasts. Current Opinion in Genetics & Development, 22, 517–522

    Article  CAS  Google Scholar 

  200. Shyamala, K., Yanduri, S., Girish, H. C., & Murgod, S. (2015). Neural crest: The fourth germ layer. Journal of Oral and Maxillofacial Pathology: JOMFP, 19, 221–229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Ozair, M. Z., Kintner, C., & Brivanlou, A. H. (2013). Neural induction and early patterning in vertebrates. Wiley Interdisciplinary Reviews. Developmental Biology, 2, 479–498

    Article  CAS  PubMed  Google Scholar 

  202. Itoh, F., Watabe, T., & Miyazono, K. (2014). Roles of TGF-β family signals in the fate determination of pluripotent stem cells. Seminars in Cell & Developmental Biology, 32, 98–106

    Article  CAS  Google Scholar 

  203. Meyers, E. A., & Kessler, J. A. (2017). TGF-β family signaling in neural and neuronal differentiation, development, and function. Cold Spring Harbor Perspectives in Biology, 9, a022244

    Article  PubMed  PubMed Central  Google Scholar 

  204. Sancho, M., & Rodríguez, T. A. (2013). Ready, set, differentiate!. eLife, 2, e01839

  205. Gomes Fernandes, M., Dries, R., Roost, M. S., Semrau, S., de Melo Bernardo, A., Davis, R. P. … de Lopes, S., A., &, S. M. (2016). BMP-SMAD Signaling Regulates Lineage Priming, but Is Dispensable for Self-Renewal in Mouse Embryonic Stem Cells. Stem Cell Reports, 6, 85–94

  206. Nichols, S. A., Dirks, W., Pearse, J. S., & King, N. (2006). Early evolution of animal cell signaling and adhesion genes. Proceedings of the National Academy of Sciences of the United States of America, 103, 12451–12456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. King, N., Westbrook, M. J., Young, S. L., Kuo, A., Abedin, M., Chapman, J. … Rokhsar, D. (2008). The genome of the choanoflagellate Monosiga brevicollis and the origin of metazoans. Nature, 451(7180), 783–788

  208. Srivastava, M., Simakov, O., Chapman, J., Fahey, B., Gauthier, M. E., Mitros, T. … Rokhsar, D. S. (2010). The Amphimedon queenslandica genome and the evolution of animal complexity. Nature, 466(7307), 720–726

  209. Adamska, M., Degnan, S. M., Green, K. M., Adamski, M., Craigie, A., Larroux, C., & Degnan, B. M. (2007). Wnt and TGF-beta expression in the sponge Amphimedon queenslandica and the origin of metazoan embryonic patterning. PloS One, 2, e1031

    Article  PubMed  PubMed Central  Google Scholar 

  210. Barker, N. (2014). Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nature Reviews. Molecular Cell Biology, 15, 19–33

    Article  CAS  PubMed  Google Scholar 

  211. Li, L., Mignone, J., Yang, M., Matic, M., Penman, S., Enikolopov, G., & Hoffman, R. M. (2003). Nestin expression in hair follicle sheath progenitor cells. Proceedings of the National Academy of Sciences of the United States of America, 100, 9958–9961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Jiang, M. H., Cai, B., Tuo, Y., Wang, J., Zang, Z. J., Tu, X. … Xiang, A. P. (2014). Characterization of Nestin-positive stem Leydig cells as a potential source for the treatment of testicular Leydig cell dysfunction. Cell Research, 24, 1466–1485

  213. Mokrý, J., Cízková, D., Filip, S., Ehrmann, J., Osterreicher, J., Kolár, Z., & English, D. (2004). Nestin expression by newly formed human blood vessels. Stem Cells and Development, 13, 658–664

    Article  PubMed  Google Scholar 

  214. Hagey, D. W., Klum, S., Kurtsdotter, I., Zaouter, C., Topcic, D., Andersson, O. … Muhr, J. (2018). SOX2 regulates common and specific stem cell features in the CNS and endoderm derived organs. PLoS Genetics, 14, e1007224

  215. Casanova, J. (2012). Stemness as a cell default state. EMBO Reports, 13, 396–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Pesaresi, M., Sebastian-Perez, R., & Cosma, M. P. (2019). Dedifferentiation, transdifferentiation and cell fusion: in vivo reprogramming strategies for regenerative medicine. The FEBS Journal, 286, 1074–1093

    Article  CAS  PubMed  Google Scholar 

  217. Kienle, G., & Kiene, H. (2012). From Reductionism to Holism: Systems-oriented Approaches in Cancer Research. Global Advances in Health and Medicine, 1, 68–77

    Article  PubMed  PubMed Central  Google Scholar 

  218. Jopling, C., Boue, S., & Izpisua Belmonte, J. C. (2011). Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration. Nature Reviews. Molecular Cell Biology, 12, 79–89

    Article  CAS  PubMed  Google Scholar 

  219. Jumabay, M., & Boström, K. I. (2015). Dedifferentiated fat cells: A cell source for regenerative medicine. World Journal of Stem Cells, 7, 1202–1214

    Article  PubMed  PubMed Central  Google Scholar 

  220. Lim, B., Lin, Y., & Navin, N. (2020). Advancing cancer research and medicine with single-cell genomics. Cancer Cell, 37, 456–470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Weinberg, R. A. (2014). Coming full circle-from endless complexity to simplicity and back again. Cell, 157, 267–271

    Article  CAS  PubMed  Google Scholar 

  222. Holohan, C., Van Schaeybroeck, S., Longley, D. B., & Johnston, P. G. (2013). Cancer drug resistance: an evolving paradigm. Nature Reviews. Cancer, 13, 714–726

    Article  CAS  PubMed  Google Scholar 

  223. Ramos, P., & Bentires-Alj, M. (2015). Mechanism-based cancer therapy: resistance to therapy, therapy for resistance. Oncogene, 34, 3617–3626

    Article  CAS  PubMed  Google Scholar 

  224. Lytle, N. K., Barber, A. G., & Reya, T. (2018). Stem cell fate in cancer growth, progression and therapy resistance. Nature Reviews. Cancer, 18, 669–680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Sharma, P., Hu-Lieskovan, S., Wargo, J. A., & Ribas, A. (2017). Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell, 168, 707–723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Syn, N. L., Teng, M., Mok, T., & Soo, R. A. (2017). De-novo and acquired resistance to immune checkpoint targeting. The Lancet Oncology, 18, e731–e741

    Article  PubMed  Google Scholar 

  227. de Miguel, M., & Calvo, E. (2020). Clinical challenges of immune checkpoint inhibitors. Cancer Cell, 38, 326–333

    Article  PubMed  Google Scholar 

  228. Frelaut, M., Le Tourneau, C., & Borcoman, E. (2019). Hyperprogression under Immunotherapy. International Journal of Molecular Sciences, 20, 2674

    Article  CAS  PubMed Central  Google Scholar 

  229. Adashek, J. J., Subbiah, I. M., Matos, I., Garralda, E., Menta, A. K., Ganeshan, D. M., & Subbiah, V. (2020). Hyperprogression and immunotherapy: fact, fiction, or alternative fact? Trends in Cancer, 6, 181–191

    Article  CAS  PubMed  Google Scholar 

  230. Krah, N. M., Narayanan, S. M., Yugawa, D. E., Straley, J. A., Wright, C., MacDonald, R. J., & Murtaugh, L. C. (2019). Prevention and reversion of pancreatic tumorigenesis through a differentiation-based mechanism. Developmental Cell, 50, 744–7544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Ishay-Ronen, D., Diepenbruck, M., Kalathur, R., Sugiyama, N., Tiede, S., Ivanek, R., ... Christofori, G. (2019). Gain fat-lose metastasis: converting invasive breast cancer cells into adipocytes inhibits cancer metastasis. Cancer Cell, 35, 17–326

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Funding

This work was supported by Shenzhen Science and Technology Program (Grant No.: JCYJ20210324120205015), and National Science Foundation of China (Grant No.: 31671499).

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  1. Shenzhen Research Institute of Nanjing University, Shenzhen, 518057, China

    Ying Cao

  2. Model Animal Research Center of Medical School, Nanjing University, 12 Xuefu Road, Pukou High-Tech Zone, 210061, Nanjing, China

    Ying Cao

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Ying Cao conceived and wrote the review.

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Correspondence to Ying Cao.

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Cao, Y. Neural is Fundamental: Neural Stemness as the Ground State of Cell Tumorigenicity and Differentiation Potential. Stem Cell Rev and Rep 18, 37–55 (2022). https://doi.org/10.1007/s12015-021-10275-y

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