Skip to main content

Advertisement

SpringerLink
Log in

Therapeutic Effectiveness of Anticancer Agents Targeting Different Signaling Molecules Involved in Asymmetric Division of Cancer Stem Cell

  • Published:
Stem Cell Reviews and Reports Aims and scope Submit manuscript

Abstract

Intra-tumoral heterogeneity is maintained by cancer stem cells (CSCs) with dysregulated self-renewal and asymmetric cell division (ACD). According to the cancer stem cell theory, by ACD a CSC can generate two daughter progenies with different fates such as one cancer stem cell and one differentiated cell. Therefore, this type of mitotic division supports vital process of the maintenance of CSC population. But this CSC pool reservation by ACD complicates the treatment of cancer patients, as CSCs give rise to aggressive clones which are prone to metastasis and drug-insensitivity. Hence, identification of therapeutic modalities which can target ACD of cancer stem cell is an intriguing part of cancer research. In this review, other than the discussion about the extrinsic inducers of ACD role of different proteins, miRNAs and lncRNAs in this type of cell division is also mentioned. Other than these, mode of action of the proven and potential drugs targeting ACD of CSC is also discussed here.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data Availability

Not applicable.

References

  1. Buczacki, S., Davies, R. J., & Winton, D. J. (2011). Stem cells, quiescence and rectal carcinoma: An unexplored relationship and potential therapeutic target. British Journal of Cancer, 105(9), 1253–1259. https://doi.org/10.1038/bjc.2011.362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Aponte, P. M., & Caicedo, A. (2017). Stemness in cancer: Stem cells, cancer stem cells, and their microenvironment. Stem Cells International, 2017, e5619472. https://doi.org/10.1155/2017/5619472

    Article  CAS  Google Scholar 

  3. Knoblich, J. A. (2010). Asymmetric cell division: Recent developments and their implications for tumour biology. Nature Reviews. Molecular Cell Biology, 11(12), 849–860. https://doi.org/10.1038/nrm3010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rasin, M.-R., Gazula, V.-R., Breunig, J. J., Kwan, K. Y., Johnson, M. B., Liu-Chen, S., …, & Sestan, N. (2007). Numb and Numbl are required for maintenance of cadherin-based adhesion and polarity of neural progenitors. Nature Neuroscience, 10(7), 819–827. https://doi.org/10.1038/nn1924

  5. Lark, K. G., Consigli, R. A., & Minocha, H. C. (1966). Segregation of Sister Chromatids in Mammalian Cells. Science, 154(3753), 1202–1205. https://doi.org/10.1126/science.154.3753.1202

    Article  CAS  PubMed  Google Scholar 

  6. Cairns, J. (1975). Mutation selection and the natural history of cancer. Nature, 255(5505), 197–200. https://doi.org/10.1038/255197a0

    Article  CAS  PubMed  Google Scholar 

  7. Karpowicz, P., Morshead, C., Kam, A., Jervis, E., Ramunas, J., Cheng, V., & van der Kooy, D. (2005). Support for the immortal strand hypothesis: Neural stem cells partition DNA asymmetrically in vitro. Journal of Cell Biology, 170(5), 721–732. https://doi.org/10.1083/jcb.200502073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kusch, J., Liakopoulos, D., & Barral, Y. (2003). Spindle asymmetry: A compass for the cell. Trends in Cell Biology, 13(11), 562–569. https://doi.org/10.1016/j.tcb.2003.09.008

    Article  CAS  PubMed  Google Scholar 

  9. Higgins, C. D., & Goldstein, B. (2010). Asymmetric cell division: A new way to divide unequally. Current Biology, 20(23), R1029–R1031. https://doi.org/10.1016/j.cub.2010.10.051

    Article  CAS  PubMed  Google Scholar 

  10. Sugiarto, S., Persson, A. I., Munoz, E. G., Waldhuber, M., Lamagna, C., Andor, N., …, & Petritsch, C. (2011). Asymmetry-defective oligodendrocyte progenitors are glioma precursors. Cancer Cell, 20(3), 328–340. https://doi.org/10.1016/j.ccr.2011.08.011

  11. Cicalese, A., Bonizzi, G., Pasi, C. E., Faretta, M., Ronzoni, S., Giulini, B., …, & Pelicci, P. G. (2009). The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell, 138(6), 1083–1095. https://doi.org/10.1016/j.cell.2009.06.048

  12. Dey-Guha, I., Wolfer, A., Yeh, A. C., J. G. Albeck, Darp, R., Leon, E., …, & Ramaswamy, S. (2011). Asymmetric cancer cell division regulated by AKT. Proceedings of the National Academy of Sciences of the United States of America, 108(31), 12845–12850. https://doi.org/10.1073/pnas.1109632108

  13. Lathia, J. D., Hitomi, M., Gallagher, J., Gadani, S. P., Adkins, J., Vasanji, A., …, & Rich, J. N. (2011). Distribution of CD133 reveals glioma stem cells self-renew through symmetric and asymmetric cell divisions. Cell Death & Disease, 2, e200. https://doi.org/10.1038/cddis.2011.80

  14. O’Brien, C. A., Kreso, A., Ryan, P., Hermans, K. G., Gibson, L., Wang, Y., …, & Dick, J. E. (2012). ID1 and ID3 regulate the self-renewal capacity of human colon cancer-initiating cells through p21. Cancer Cell, 21(6), 777–792. https://doi.org/10.1016/j.ccr.2012.04.036

  15. Pece, S., Tosoni, D., Confalonieri, S., Mazzarol, G., Vecchi, M., Ronzoni, S., …, & Di Fiore, P. P. (2010). Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell, 140(1), 62–73. https://doi.org/10.1016/j.cell.2009.12.007

  16. Pine, S. R., Ryan, B. M., Varticovski, L., Robles, A. I., & Harris, C. C. (2010). Microenvironmental modulation of asymmetric cell division in human lung cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 107(5), 2195–2200. https://doi.org/10.1073/pnas.0909390107

    Article  PubMed  PubMed Central  Google Scholar 

  17. Bu, P., Chen, K.-Y., Chen, J. H., Wang, L., Walters, J., Shin, Y. J., …, & Shen, X. (2013). A microRNA miR-34a regulated bimodal switch targets notch in colon cancer stem cells. Cell Stem Cell, 12(5), 602–615. https://doi.org/10.1016/j.stem.2013.03.002

  18. Qu, Y., Gharbi, N., Yuan, X., Olsen, J. R., Blicher, P., Dalhus, B., …, & Ke, X. (2016). Axitinib blocks Wnt/β-catenin signaling and directs asymmetric cell division in cancer. Proceedings of the National Academy of Sciences, 113(33), 9339–9344. https://doi.org/10.1073/pnas.1604520113

  19. Goulas, S., Conder, R., & Knoblich, J. A. (2012). The par complex and integrins direct asymmetric cell division in adult intestinal stem cells. Cell Stem Cell, 11(4), 529–540. https://doi.org/10.1016/j.stem.2012.06.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mukherjee, S., Kong, J., & Brat, D. J. (2015). Cancer stem cell division: When the rules of asymmetry are broken. Stem Cells and Development, 24(4), 405–416. https://doi.org/10.1089/scd.2014.0442

    Article  PubMed  Google Scholar 

  21. Mohan, A., Raj R., R., Mohan, G., K. P., P., & Maliekal, T. T. (2021). Reporters of cancer stem cells as a tool for drug discovery. Frontiers in Oncology, 11. https://doi.org/10.3389/fonc.2021.669250

  22. Wang, Q.-Z., Lu, Y.-H., Jiang, N., Diao, Y., & Xu, R.-A. (2010). The asymmetric division and tumorigenesis of stem cells. Chinese Journal of Cancer, 29(3), 248–253. https://doi.org/10.5732/cjc.009.10668

    Article  PubMed  Google Scholar 

  23. Peitzsch, C., Tyutyunnykova, A., Pantel, K., & Dubrovska, A. (2017). Cancer stem cells: The root of tumor recurrence and metastases. Seminars in Cancer Biology, 44, 10–24. https://doi.org/10.1016/j.semcancer.2017.02.011

    Article  CAS  PubMed  Google Scholar 

  24. Phi, L. T. H., Sari, I. N., Yang, Y.-G., Lee, S.-H., Jun, N., Kim, K. S., …, & Kwon, H. Y. (2018). Cancer Stem Cells (CSCs) in drug resistance and their therapeutic implications in cancer treatment. Stem Cells International, 2018, 1–16. https://doi.org/10.1155/2018/5416923

  25. Hitomi, M., Chumakova, A. P., Silver, D. J., Knudsen, A. M., Pontius, W. D., Murphy, S., …, & Lathia, J. D. (2021). Asymmetric cell division promotes therapeutic resistance in glioblastoma stem cells. JCI Insight, 6(3). https://doi.org/10.1172/jci.insight.130510

  26. Chen, W., Dong, J., Haiech, J., Kilhoffer, M.-C., & Zeniou, M. (2016). Cancer stem cell quiescence and plasticity as major challenges in cancer therapy. Stem Cells International, 2016, 1–16. https://doi.org/10.1155/2016/1740936

    Article  CAS  Google Scholar 

  27. Tomasetti, C., & Levy, D. (2010). Role of symmetric and asymmetric division of stem cells in developing drug resistance. Proceedings of the National Academy of Sciences, 107(39), 16766–16771. https://doi.org/10.1073/pnas.1007726107

    Article  Google Scholar 

  28. Iwasa, Y., Nowak, M. A., & Michor, F. (2006). Evolution of resistance during clonal expansion. Genetics, 172(4), 2557–2566. https://doi.org/10.1534/genetics.105.049791

    Article  PubMed  PubMed Central  Google Scholar 

  29. Plaks, V., Kong, N., & Werb, Z. (2015). The cancer stem cell niche: How essential is the niche in regulating stemness of tumor cells? Cell Stem Cell, 16(3), 225–238. https://doi.org/10.1016/j.stem.2015.02.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zahan, T., Das, P. K., Akter, S. F., Habib, R., Rahman, Md. H., Karim, Md. R., & Islam, F. (2020). Therapy resistance in cancers: Phenotypic, metabolic, epigenetic and tumour microenvironmental perspectives. Anti-Cancer Agents in Medicinal Chemistry, 20(18), 2190–2206. https://doi.org/10.2174/1871520620999200730161829

    Article  CAS  PubMed  Google Scholar 

  31. Kunisaki, Y., Bruns, I., Scheiermann, C., Ahmed, J., Pinho, S., Zhang, D., …, & Frenette, P. S. (2013). Arteriolar niches maintain haematopoietic stem cell quiescence. Nature, 502(7473), 637–643. https://doi.org/10.1038/nature12612

  32. Kiel, M. J., Yilmaz, O. H., Iwashita, T., Yilmaz, O. H., Terhorst, C., & Morrison, S. J. (2005). SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell, 121(7), 1109–1121. https://doi.org/10.1016/j.cell.2005.05.026

    Article  CAS  PubMed  Google Scholar 

  33. Snippert, H. J., van der Flier, L. G., Sato, T., van Es, J. H., van den Born, M., Kroon-Veenboer, C., …, & Clevers, H. (2010). Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell, 143(1), 134–144. https://doi.org/10.1016/j.cell.2010.09.016

  34. Lopez-Garcia, C., Klein, A. M., Simons, B. D., & Winton, D. J. (2010). Intestinal stem cell replacement follows a pattern of neutral drift. Science (New York, N.Y.), 330(6005), 822–825. https://doi.org/10.1126/science.1196236

    Article  CAS  PubMed  Google Scholar 

  35. Albini, A., Bruno, A., Gallo, C., Pajardi, G., Noonan, D. M., & Dallaglio, K. (2015). Cancer stem cells and the tumor microenvironment: Interplay in tumor heterogeneity. Connective Tissue Research, 56(5), 414–425. https://doi.org/10.3109/03008207.2015.1066780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cancer Stem Cells and the Tumor Microenvironment: Soloists or Choral Singers | Bentham Science. (n.d.). Retrieved November 16, 2022, from https://www.eurekaselect.com/article/13659

  37. Albini, A., Cesana, E., & Noonan, D. M. (2011). Cancer stem cells and the tumor microenvironment: Soloists or choral singers. Current Pharmaceutical Biotechnology, 12(2), 171–181. https://doi.org/10.2174/138920111794295756

    Article  CAS  PubMed  Google Scholar 

  38. Siegrist, S. E., & Doe, C. Q. (2006). Extrinsic cues orient the cell division axis in Drosophila embryonic neuroblasts. Development (Cambridge, England), 133(3), 529–536. https://doi.org/10.1242/dev.02211

    Article  CAS  PubMed  Google Scholar 

  39. Barui, A., & Datta, P. (2019). Biophysical factors in the regulation of asymmetric division of stem cells. Biological Reviews, 94(3), 810–827. https://doi.org/10.1111/brv.12479

    Article  PubMed  Google Scholar 

  40. Lagadec, C., Vlashi, E., Alhiyari, Y., Phillips, T. M., Bochkur Dratver, M., & Pajonk, F. (2013). Radiation-induced notch signaling in breast cancer stem cells. International Journal of Radiation Oncology*Biology*Physics, 87(3), 609–618. https://doi.org/10.1016/j.ijrobp.2013.06.2064

    Article  CAS  PubMed  Google Scholar 

  41. Tomasetti, C., & Vogelstein, B. (2017). On the slope of the regression between stem cell divisions and cancer risk, and the lack of correlation between stem cell divisions and environmental factors-associated cancer risk. PLOS ONE, 12(5), e0175535. https://doi.org/10.1371/journal.pone.0175535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wu, S., Powers, S., Zhu, W., & Hannun, Y. A. (2016). Substantial contribution of extrinsic risk factors to cancer development. Nature, 529(7584), 43–47. https://doi.org/10.1038/nature16166

    Article  CAS  PubMed  Google Scholar 

  43. Analysing differences between scenarios - ScienceDirect. (n.d.). Retrieved November 16, 2022, from https://www.sciencedirect.com/science/article/pii/S0169207022000346?via%3Dihub

  44. Pajonk, F., Vlashi, E., & McBride, W. H. (2010). Radiation resistance of cancer stem cells: The 4 R’s of radiobiology revisited. Stem Cells, 28(4), 639–648. https://doi.org/10.1002/stem.318

    Article  CAS  PubMed  Google Scholar 

  45. Umar, S. (2010). Intestinal stem cells. Current Gastroenterology Reports, 12(5), 340–348. https://doi.org/10.1007/s11894-010-0130-3

    Article  PubMed  PubMed Central  Google Scholar 

  46. Grün, A., Kuhnt, T., Schlomm, T., Olze, H., Budach, V., & Stromberger, C. (2020). Repeat radiation for local recurrence of head and neck tumors and in prostate cancer. Deutsches Ärzteblatt International, 117(10), 167–174. https://doi.org/10.3238/arztebl.2020.0167

    Article  PubMed  PubMed Central  Google Scholar 

  47. Withers, H. R., Maciejewski, B., Taylor, J. M., & Hliniak, A. (1988). Accelerated repopulation in head and neck cancer. Frontiers of Radiation Therapy and Oncology, 22, 105–110. https://doi.org/10.1159/000415101

    Article  CAS  PubMed  Google Scholar 

  48. Campa, V. M., Gutiérrez-Lanza, R., Cerignoli, F., Díaz-Trelles, R., Nelson, B., Tsuji, T., …, & Mercola, M. (2008). Notch activates cell cycle reentry and progression in quiescent cardiomyocytes. The Journal of Cell Biology, 183(1), 129–141. https://doi.org/10.1083/jcb.200806104

  49. Phillips, T. M., McBride, W. H., & Pajonk, F. (2006). The Response of CD24 −/low /CD44 + Breast Cancer–Initiating Cells to Radiation. JNCI: Journal of the National Cancer Institute, 98(24), 1777–1785. https://doi.org/10.1093/jnci/djj495

  50. Srinivasan, T., Walters, J., Bu, P., Than, E. B., Tung, K.-L., Chen, K.-Y., …, & Shen, X. (2016). NOTCH signaling regulates asymmetric cell fate of fast- and slow-cycling colon cancer–initiating cells. Cancer Research, 76(11), 3411–3421. https://doi.org/10.1158/0008-5472.CAN-15-3198

  51. Ehrhart, E. J., Segarini, P., Tsang, M.L.-S., Carroll, A. G., & Barcellos-Hoff, M. H. (1997). Latent transforming growth factor β1 activation in situ: Quantitative and functional evidence after low-dose γ-irradiation 1. The FASEB Journal, 11(12), 991–1002. https://doi.org/10.1096/fasebj.11.12.9337152

    Article  CAS  PubMed  Google Scholar 

  52. Najafi, M., Farhood, B., Mortezaee, K., Kharazinejad, E., Majidpoor, J., & Ahadi, R. (2020). Hypoxia in solid tumors: A key promoter of cancer stem cell (CSC) resistance. Journal of Cancer Research and Clinical Oncology, 146(1), 19–31. https://doi.org/10.1007/s00432-019-03080-1

    Article  PubMed  Google Scholar 

  53. de Almeida Rainho, M., Mencalha, A. L., & Thole, A. A. (2021). Hypoxia effects on cancer stem cell phenotype in colorectal cancer: A mini-review. Molecular Biology Reports, 48(11), 7527–7535. https://doi.org/10.1007/s11033-021-06809-9

    Article  CAS  Google Scholar 

  54. Liu, W., Wen, Y., Bi, P., Lai, X., Liu, X. S., Liu, X., & Kuang, S. (2012). Hypoxia promotes satellite cell self-renewal and enhances the efficiency of myoblast transplantation. Development (Cambridge, England), 139(16), 2857–2865. https://doi.org/10.1242/dev.079665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Khan, W. S., Adesida, A. B., & Hardingham, T. E. (2007). Hypoxic conditions increase hypoxia-inducible transcription factor 2α and enhance chondrogenesis in stem cells from the infrapatellar fat pad of osteoarthritis patients. Arthritis Research & Therapy, 9(3), R55. https://doi.org/10.1186/ar2211

    Article  CAS  Google Scholar 

  56. Shang, J., Liu, H., Li, J., & Zhou, Y. (2014). Roles of hypoxia during the chondrogenic differentiation of mesenchymal stem cells. Current Stem Cell Research & Therapy, 9(2), 141–147. https://doi.org/10.2174/1574888x09666131230142459

    Article  CAS  Google Scholar 

  57. Hurt, E. M., Kawasaki, B. T., Klarmann, G. J., Thomas, S. B., & Farrar, W. L. (2008). CD44+CD24− prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis. British Journal of Cancer, 98(4), 756–765. https://doi.org/10.1038/sj.bjc.6604242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yao, L., Pandit, A., Yao, S., & McCaig, C. D. (2011). Electric field-guided neuron migration: A novel approach in neurogenesis. Tissue Engineering Part B: Reviews, 17(3), 143–153. https://doi.org/10.1089/ten.teb.2010.0561

    Article  PubMed  Google Scholar 

  59. Funk, R. H. W. (2015). Endogenous electric fields as guiding cue for cell migration. Frontiers in Physiology, 6. https://doi.org/10.3389/fphys.2015.00143

  60. McMurray, R. J., Gadegaard, N., Tsimbouri, P. M., Burgess, K. V., McNamara, L. E., Tare, R., …, & Dalby, M. J. (2011). Nanoscale surfaces for the long-term maintenance of mesenchymal stem cell phenotype and multipotency. Nature Materials, 10(8), 637–644. https://doi.org/10.1038/nmat3058

  61. Chen, Y.-A., Lu, C.-Y., Cheng, T.-Y., Pan, S.-H., Chen, H.-F., & Chang, N.-S. (2019). WW domain-containing proteins YAP and TAZ in the hippo pathway as key regulators in stemness maintenance, tissue homeostasis, and tumorigenesis. Frontiers in Oncology, 9, 60. https://doi.org/10.3389/fonc.2019.00060

    Article  PubMed  PubMed Central  Google Scholar 

  62. Elbediwy, A., Vincent-Mistiaen, Z. I., & Thompson, B. J. (2016). YAP and TAZ in epithelial stem cells: A sensor for cell polarity, mechanical forces and tissue damage. BioEssays, 38(7), 644–653. https://doi.org/10.1002/bies.201600037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Piccolo, S., Dupont, S., & Cordenonsi, M. (2014). The biology of YAP/TAZ: Hippo signaling and beyond. Physiological Reviews, 94(4), 1287–1312. https://doi.org/10.1152/physrev.00005.2014

    Article  CAS  PubMed  Google Scholar 

  64. Lam, A. K., & Phillips, B. T. (2017). Wnt Signaling Polarizes C. elegans Asymmetric Cell Divisions During Development. In J.-P. Tassan & J. Z. Kubiak (Eds.), Asymmetric Cell Division in Development, Differentiation and Cancer (vol. 61, pp. 83–114). Springer International Publishing. https://doi.org/10.1007/978-3-319-53150-2_4

  65. Egger, B., Gold, K. S., & Brand, A. H. (2011). Regulating the balance between symmetric and asymmetric stem cell division in the developing brain. Fly, 5(3), 237–241. https://doi.org/10.4161/fly.5.3.15640

    Article  CAS  PubMed  Google Scholar 

  66. Drug resistance mechanisms of cancer stem-like cells and their therapeutic potential as drug targets. (n.d.). Retrieved November 16, 2022, from https://cdrjournal.com/article/view/3153

  67. Kopan, R. (2012). Notch signaling. Cold Spring Harbor Perspectives in Biology, 4(10), a011213–a011213. https://doi.org/10.1101/cshperspect.a011213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lobry, C., Oh, P., & Aifantis, I. (2011). Oncogenic and tumor suppressor functions of Notch in cancer: It’s NOTCH what you think. Journal of Experimental Medicine, 208(10), 1931–1935. https://doi.org/10.1084/jem.20111855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Katoh, M., & Katoh, M. (2007). Notch signaling in gastrointestinal tract (Review). International Journal of Oncology. https://doi.org/10.3892/ijo.30.1.247

    Article  PubMed  Google Scholar 

  70. Leong, K. G., & Karsan, A. (2006). Recent insights into the role of Notch signaling in tumorigenesis. Blood, 107(6), 2223–2233. https://doi.org/10.1182/blood-2005-08-3329

    Article  CAS  PubMed  Google Scholar 

  71. Liu, Z.-H., Dai, X.-M., & Du, B. (2015). Hes1: A key role in stemness, metastasis and multidrug resistance. Cancer Biology & Therapy, 16(3), 353–359. https://doi.org/10.1080/15384047.2015.1016662

    Article  CAS  Google Scholar 

  72. Flores, A. N., McDermott, N., Meunier, A., & Marignol, L. (2014). NUMB inhibition of NOTCH signalling as a therapeutic target in prostate cancer. Nature Reviews Urology, 11(9), 499–507. https://doi.org/10.1038/nrurol.2014.195

    Article  CAS  Google Scholar 

  73. Sang, L., Roberts, J. M., & Coller, H. A. (2010). Hijacking HES1: How tumors co-opt the anti-differentiation strategies of quiescent cells. Trends in Molecular Medicine, 16(1), 17–26. https://doi.org/10.1016/j.molmed.2009.11.001

    Article  CAS  PubMed  Google Scholar 

  74. Nakamura, Y., Sakakibara, S., Miyata, T., Ogawa, M., Shimazaki, T., Weiss, S., …, & Okano, H. (2000). The bHLH Gene Hes1 as a repressor of the neuronal commitment of CNS stem cells. The Journal of Neuroscience, 20(1), 283–293. https://doi.org/10.1523/JNEUROSCI.20-01-00283.2000

  75. Yang, L., Tang, H., Kong, Y., Xie, X., Chen, J., Song, C., …, & Xie, X. (2015). LGR5 promotes breast cancer progression and maintains stem-like cells through activation of Wnt/β-catenin signaling. Stem Cells, 33(10), 2913–2924. https://doi.org/10.1002/stem.2083

  76. Fan, C., He, L., Kapoor, A., Rybak, A. P., De Melo, J., Cutz, J.-C., & Tang, D. (2009). PTEN inhibits BMI1 function independently of its phosphatase activity. Molecular Cancer, 8(1), 98. https://doi.org/10.1186/1476-4598-8-98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Choi, H. Y., Seok, J., Kang, G.-H., Lim, K. M., & Cho, S.-G. (2021). The role of NUMB/NUMB isoforms in cancer stem cells. BMB Reports, 54(7), 335–343. https://doi.org/10.5483/BMBRep.2021.54.7.048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Habib, S. J., Chen, B.-C., Tsai, F.-C., Anastassiadis, K., Meyer, T., Betzig, E., & Nusse, R. (2013). A localized Wnt signal orients asymmetric stem cell division in vitro. Science, 339(6126), 1445–1448. https://doi.org/10.1126/science.1231077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Reya, T., & Clevers, H. (2005). Wnt signalling in stem cells and cancer. Nature, 434(7035), 843–850. https://doi.org/10.1038/nature03319

    Article  CAS  PubMed  Google Scholar 

  80. Sato, N., Meijer, L., Skaltsounis, L., Greengard, P., & Brivanlou, A. H. (2004). Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nature Medicine, 10(1), 55–63. https://doi.org/10.1038/nm979

    Article  CAS  PubMed  Google Scholar 

  81. Davidson, K. C., Adams, A. M., Goodson, J. M., McDonald, C. E., Potter, J. C., Berndt, J. D., …, & Moon, R. T. (2012). Wnt/β-catenin signaling promotes differentiation, not self-renewal, of human embryonic stem cells and is repressed by Oct4. Proceedings of the National Academy of Sciences, 109(12), 4485–4490. https://doi.org/10.1073/pnas.1118777109

  82. Zhang, K., Guo, Y., Wang, X., Zhao, H., Ji, Z., Cheng, C., …, & Gao, W.-Q. (2017). WNT/β-catenin directs self-renewal symmetric cell division of hTERThigh Prostate cancer stem cells. Cancer Research, 77(9), 2534–2547. https://doi.org/10.1158/0008-5472.CAN-16-1887

  83. Boyd, L., Guo, S., Levitan, D., Stinchcomb, D. T., & Kemphues, K. J. (1996). PAR-2 is asymmetrically distributed and promotes association of P granules and PAR-1 with the cortex in C. elegans embryos. Development, 122(10), 3075–3084. https://doi.org/10.1242/dev.122.10.3075

    Article  CAS  PubMed  Google Scholar 

  84. Guo, S., & Kemphues, K. J. (1995). par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed. Cell, 81(4), 611–620. https://doi.org/10.1016/0092-8674(95)90082-9

    Article  CAS  PubMed  Google Scholar 

  85. Sailer, A., Anneken, A., Li, Y., Lee, S., & Munro, E. (2015). Dynamic opposition of clustered proteins stabilizes cortical polarity in the C. elegans zygote. Developmental Cell, 35(1), 131–142. https://doi.org/10.1016/j.devcel.2015.09.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kumfer, K. T., Cook, S. J., Squirrell, J. M., Eliceiri, K. W., Peel, N., O’Connell, K. F., & White, J. G. (2010). CGEF-1 and CHIN-1 regulate CDC-42 activity during asymmetric division in the Caenorhabditis elegans embryo. Molecular Biology of the Cell, 21(2), 266–277. https://doi.org/10.1091/mbc.e09-01-0060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Neumüller, R. A., & Knoblich, J. A. (2009). Dividing cellular asymmetry: Asymmetric cell division and its implications for stem cells and cancer. Genes & Development, 23(23), 2675–2699. https://doi.org/10.1101/gad.1850809

    Article  CAS  Google Scholar 

  88. Lang, C. F., & Munro, E. (2017). The PAR proteins: From molecular circuits to dynamic self-stabilizing cell polarity. Development, 144(19), 3405–3416. https://doi.org/10.1242/dev.139063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Harris, T. J. C. (2017). Protein clustering for cell polarity: Par-3 as a paradigm. F1000Research. https://doi.org/10.12688/f1000research.11976.1

  90. Bultje, R. S., Castaneda-Castellanos, D. R., Jan, L. Y., Jan, Y.-N., Kriegstein, A. R., & Shi, S.-H. (2009). Mammalian Par3 regulates progenitor cell asymmetric division via Notch signaling in the developing neocortex. Neuron, 63(2), 189–202. https://doi.org/10.1016/j.neuron.2009.07.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Chen, S., Chen, J., Shi, H., Wei, M., Castaneda-Castellanos, D. R., Bultje, R. S., …, & Shi, S.-H. (2013). Regulation of microtubule stability and organization by Mammalian Par3 in specifying neuronal polarity. Developmental Cell, 24(1), 26–40. https://doi.org/10.1016/j.devcel.2012.11.014

  92. Zhou, P.-J., Wang, X., An, N., Wei, L., Zhang, L., Huang, X., …, & Gao, W.-Q. (2019). Loss of Par3 promotes prostatic tumorigenesis by enhancing cell growth and changing cell division modes. Oncogene, 38(12), 2192–2205. https://doi.org/10.1038/s41388-018-0580-x

  93. The Polarity Protein Par6 Induces Cell Proliferation and Is Overexpressed in Breast Cancer - PMC. (n.d.). Retrieved November 17, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948755/

  94. Lim, Y. W., Wen, F.-L., Shankar, P., Shibata, T., & Motegi, F. (2021). A balance between antagonizing PAR proteins specifies the pattern of asymmetric and symmetric divisions in C. elegans embryogenesis. Cell Reports, 36(1), 109326. https://doi.org/10.1016/j.celrep.2021.109326

    Article  CAS  PubMed  Google Scholar 

  95. Wirtz-Peitz, F., Nishimura, T., & Knoblich, J. A. (2008). Linking cell cycle to asymmetric division: Aurora-A phosphorylates the par complex to regulate Numb localization. Cell, 135(1), 161–173. https://doi.org/10.1016/j.cell.2008.07.049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. par-6, a gene involved in the establishment of asymmetry in early C. elegans embryos, mediates the asymmetric localization of PAR-3 | Development | The Company of Biologists. (n.d.). Retrieved November 17, 2022, from https://journals.biologists.com/dev/article/122/10/3133/38958/par-6-a-gene-involved-in-the-establishment-of

  97. Suzuki, A., & Ohno, S. (2006). The PAR-aPKC system: Lessons in polarity. Journal of Cell Science, 119(6), 979–987. https://doi.org/10.1242/jcs.02898

    Article  CAS  PubMed  Google Scholar 

  98. Suzuki, A., Yamanaka, T., Hirose, T., Manabe, N., Mizuno, K., Shimizu, M., …, & Ohno, S. (2001). Atypical protein kinase C is involved in the evolutionarily conserved par protein complex and plays a critical role in establishing epithelia-specific junctional structures. The Journal of Cell Biology, 152(6), 1183–1196. https://doi.org/10.1083/jcb.152.6.1183

  99. Macara, I. G. (2004). Parsing the polarity code. Nature Reviews Molecular Cell Biology, 5(3), 220–231. https://doi.org/10.1038/nrm1332

    Article  CAS  PubMed  Google Scholar 

  100. Atypical protein kinase C cooperates with PAR-3 to establish embryonic polarity in Caenorhabditis elegans - PubMed. (n.d.). Retrieved November 17, 2022, from https://pubmed.ncbi.nlm.nih.gov/9716526/

  101. Prehoda, K. E. (2009). Polarization of Drosophila neuroblasts during asymmetric division. Cold Spring Harbor Perspectives in Biology, 1(2), a001388–a001388. https://doi.org/10.1101/cshperspect.a001388

    Article  PubMed  PubMed Central  Google Scholar 

  102. Liu, J., Sato, C., Cerletti, M., & Wagers, A. (2010). Notch Signaling in the Regulation of Stem Cell Self-Renewal and Differentiation. In Current Topics in Developmental Biology (vol. 92, pp. 367–409). Elsevier. https://doi.org/10.1016/S0070-2153(10)92012-7

  103. Bilder, D., & Perrimon, N. (2000). Localization of apical epithelial determinants by the basolateral PDZ protein Scribble. Nature, 403(6770), 676–680. https://doi.org/10.1038/35001108

    Article  CAS  PubMed  Google Scholar 

  104. Powell, A. E., Shung, C.-Y., Saylor, K. W., Müllendorf, K. A., Weiss, J. B., & Wong, M. H. (2010). Lessons from development: A role for asymmetric stem cell division in cancer. Stem Cell Research, 4(1), 3–9. https://doi.org/10.1016/j.scr.2009.09.005

    Article  CAS  PubMed  Google Scholar 

  105. Paglia, S., Sollazzo, M., Di Giacomo, S., de Biase, D., Pession, A., & Grifoni, D. (2017). Failure of the PTEN/aPKC/Lgl axis primes formation of adult brain tumours in Drosophila. BioMed Research International, 2017, 1–14. https://doi.org/10.1155/2017/2690187

    Article  CAS  Google Scholar 

  106. Ohshiro, T., Yagami, T., Zhang, C., & Matsuzaki, F. (2000). Role of cortical tumour-suppressor proteins in asymmetric division of Drosophila neuroblast. Nature, 408(6812), 593–596. https://doi.org/10.1038/35046087

    Article  CAS  PubMed  Google Scholar 

  107. Khazaei, M. R., & Püschel, A. W. (2009). Phosphorylation of the par polarity complex protein Par3 at serine 962 Is mediated by Aurora A and regulates its function in neuronal polarity. Journal of Biological Chemistry, 284(48), 33571–33579. https://doi.org/10.1074/jbc.M109.055897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Rolls, M. M., Albertson, R., Shih, H.-P., Lee, C.-Y., & Doe, C. Q. (2003). Drosophila aPKC regulates cell polarity and cell proliferation in neuroblasts and epithelia. Journal of Cell Biology, 163(5), 1089–1098. https://doi.org/10.1083/jcb.200306079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kuphal, S., Wallner, S., Schimanski, C. C., Bataille, F., Hofer, P., Strand, S., …, & Bosserhoff, A. K. (2006). Expression of Hugl-1 is strongly reduced in malignant melanoma. Oncogene, 25(1), 103–110. https://doi.org/10.1038/sj.onc.1209008

  110. Yasumi, M., Sakisaka, T., Hoshino, T., Kimura, T., Sakamoto, Y., Yamanaka, T., …, & Takai, Y. (2005). Direct Binding of Lgl2 to LGN during Mitosis and Its Requirement for Normal Cell Division. Journal of Biological Chemistry, 280(8), 6761–6765. https://doi.org/10.1074/jbc.C400440200

  111. Liu, X., Lu, D., Ma, P., Liu, H., Cao, Y., Sang, B., …, & Zhou, X. (2015). Hugl-1 inhibits glioma cell growth in intracranial model. Journal of Neuro-Oncology, 125(1), 113–121. https://doi.org/10.1007/s11060-015-1901-3

  112. Barros, C. S., Phelps, C. B., & Brand, A. H. (2003). Drosophila nonmuscle myosin II promotes the asymmetric segregation of cell fate determinants by cortical exclusion rather than active transport. Developmental Cell, 5(6), 829–840. https://doi.org/10.1016/s1534-5807(03)00359-9

    Article  CAS  PubMed  Google Scholar 

  113. Katayama, H., Brinkley, W. R., & Sen, S. (2003). The Aurora kinases: Role in cell transformation and tumorigenesis. Cancer Metastasis Reviews, 22(4), 451–464. https://doi.org/10.1023/a:1023789416385

    Article  PubMed  Google Scholar 

  114. Nikonova, A. S., Astsaturov, I., Serebriiskii, I. G., Dunbrack, R. L., & Golemis, E. A. (2013). Aurora A kinase (AURKA) in normal and pathological cell division. Cellular and Molecular Life Sciences, 70(4), 661–687. https://doi.org/10.1007/s00018-012-1073-7

    Article  CAS  PubMed  Google Scholar 

  115. Lee, C.-Y., Andersen, R. O., Cabernard, C., Manning, L., Tran, K. D., Lanskey, M. J., …, & Doe, C. Q. (2006). Drosophila Aurora-A kinase inhibits neuroblast self-renewal by regulating aPKC/Numb cortical polarity and spindle orientation. Genes & Development, 20(24), 3464–3474. https://doi.org/10.1101/gad.1489406

  116. Wang, H., Somers, G. W., Bashirullah, A., Heberlein, U., Yu, F., & Chia, W. (2006). Aurora-A acts as a tumor suppressor and regulates self-renewal of Drosophila neuroblasts. Genes & Development, 20(24), 3453–3463. https://doi.org/10.1101/gad.1487506

    Article  CAS  Google Scholar 

  117. Kim, A. J., & Griffin, E. E. (2021). PLK-1 Regulation of Asymmetric Cell Division in the Early C. elegans Embryo. Frontiers in Cell and Developmental Biology, 8. https://doi.org/10.3389/fcell.2020.632253

  118. Takaki, T., Trenz, K., Costanzo, V., & Petronczki, M. (2008). Polo-like kinase 1 reaches beyond mitosis—cytokinesis, DNA damage response, and development. Current Opinion in Cell Biology, 20(6), 650–660. https://doi.org/10.1016/j.ceb.2008.10.005

    Article  CAS  PubMed  Google Scholar 

  119. Budirahardja, Y., & Gönczy, P. (2008). PLK-1 asymmetry contributes to asynchronous cell division of C. elegans embryos. Development, 135(7), 1303–1313. https://doi.org/10.1242/dev.019075

    Article  CAS  PubMed  Google Scholar 

  120. Polo inhibits progenitor self-renewal and regulates Numb asymmetry by phosphorylating Pon | Nature. (n.d.). Retrieved November 17, 2022, from https://www.nature.com/articles/nature06056

  121. Rivers, D. M., Moreno, S., Abraham, M., & Ahringer, J. (2008). PAR proteins direct asymmetry of the cell cycle regulators Polo-like kinase and Cdc25. Journal of Cell Biology, 180(5), 877–885. https://doi.org/10.1083/jcb.200710018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. van Vugt, M. A. T. M., van de Weerdt, B. C. M., Vader, G., Janssen, H., Calafat, J., Klompmaker, R., …, & Medema, R. H. (2004). Polo-like Kinase-1 Is Required for Bipolar Spindle Formation but Is Dispensable for Anaphase Promoting Complex/Cdc20 Activation and Initiation of Cytokinesis. Journal of Biological Chemistry, 279(35), 36841–36854. https://doi.org/10.1074/jbc.M313681200

  123. Kulukian, A., & Fuchs, E. (2013). Spindle orientation and epidermal morphogenesis. Philosophical Transactions of the Royal Society B: Biological Sciences, 368(1629), 20130016. https://doi.org/10.1098/rstb.2013.0016

    Article  CAS  Google Scholar 

  124. Wodarz, A., Ramrath, A., Kuchinke, U., & Knust, E. (1999). Bazooka provides an apical cue for Inscuteable localization in Drosophila neuroblasts. Nature, 402(6761), 544–547. https://doi.org/10.1038/990128

    Article  CAS  PubMed  Google Scholar 

  125. Knoblich, J. A. (2010). Asymmetric cell division: Recent developments and their implications for tumour biology. Nature Reviews Molecular Cell Biology, 11(12), 849–860. https://doi.org/10.1038/nrm3010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Willard, F. S., Kimple, R. J., & Siderovski, D. P. (2004). Return of the GDI: The GoLoco motif in cell division. Annual Review of Biochemistry, 73(1), 925–951. https://doi.org/10.1146/annurev.biochem.73.011303.073756

    Article  CAS  PubMed  Google Scholar 

  127. Wodarz, A., & Näthke, I. (2007). Cell polarity in development and cancer. Nature Cell Biology, 9(9), 1016–1024. https://doi.org/10.1038/ncb433

    Article  CAS  PubMed  Google Scholar 

  128. Chia, W., Somers, W. G., & Wang, H. (2008). Drosophila neuroblast asymmetric divisions: Cell cycle regulators, asymmetric protein localization, and tumorigenesis. Journal of Cell Biology, 180(2), 267–272. https://doi.org/10.1083/jcb.200708159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Uemura, T., Shepherd, S., Ackerman, L., Jan, L. Y., & Jan, Y. N. (1989). Numb, a gene required in determination of cell fate during sensory organ formation in Drosophila embryos. Cell, 58(2), 349–360. https://doi.org/10.1016/0092-8674(89)90849-0

    Article  CAS  PubMed  Google Scholar 

  130. Gulino, A., Di Marcotullio, L., & Screpanti, I. (2010). The multiple functions of Numb. Experimental Cell Research, 316(6), 900–906. https://doi.org/10.1016/j.yexcr.2009.11.017

    Article  CAS  PubMed  Google Scholar 

  131. Zhong, W., Feder, J. N., Jiang, M.-M., Jan, L. Y., & Jan, Y. N. (1996). Asymmetric localization of a mammalian Numb homolog during mouse cortical neurogenesis. Neuron, 17(1), 43–53. https://doi.org/10.1016/S0896-6273(00)80279-2

    Article  CAS  PubMed  Google Scholar 

  132. Petersen, P. H., Zou, K., Hwang, J. K., Jan, Y. N., & Zhong, W. (2002). Progenitor cell maintenance requires Numb and numblike during mouse neurogenesis. Nature, 419(6910), 929–934. https://doi.org/10.1038/nature01124

    Article  CAS  PubMed  Google Scholar 

  133. Berdnik, D., Török, T., González-Gaitán, M., & Knoblich, J. A. (2002). The endocytic protein α-Adaptin is required for Numb-mediated asymmetric cell division in Drosophila. Developmental Cell, 3(2), 221–231. https://doi.org/10.1016/S1534-5807(02)00215-0

    Article  CAS  PubMed  Google Scholar 

  134. Yamamoto, S., Charng, W.-L., & Bellen, H. J. (2010). Endocytosis and Intracellular Trafficking of Notch and Its Ligands. In Current Topics in Developmental Biology (vol. 92, pp. 165–200). Elsevier. https://doi.org/10.1016/S0070-2153(10)92005-X

  135. Shao, X., Ding, Z., Zhao, M., Liu, K., Sun, H., Chen, J., …, & Li, H. (2017). Mammalian Numb protein antagonizes Notch by controlling postendocytic trafficking of the Notch ligand Delta-like 4. Journal of Biological Chemistry, 292(50), 20628–20643. https://doi.org/10.1074/jbc.M117.800946

  136. Guo, M., Jan, L. Y., & Jan, Y. N. (1996). Control of daughter cell fates during asymmetric division: Interaction of Numb and Notch. Neuron, 17(1), 27–41. https://doi.org/10.1016/S0896-6273(00)80278-0

    Article  PubMed  Google Scholar 

  137. O’Connor-Giles, K. M., & Skeath, J. B. (2003). Numb inhibits membrane localization of Sanpodo, a Four-pass transmembrane protein, to promote asymmetric divisions in Drosophila. Developmental Cell, 5(2), 231–243. https://doi.org/10.1016/S1534-5807(03)00226-0

    Article  PubMed  Google Scholar 

  138. Frise, E., Knoblich, J. A., Younger-Shepherd, S., Jan, L. Y., & Jan, Y. N. (1996). The Drosophila Numb protein inhibits signaling of the Notch receptor during cell-cell interaction in sensory organ lineage. Proceedings of the National Academy of Sciences of the United States of America, 93(21), 11925–11932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. McGill, M. A., & McGlade, C. J. (2003). Mammalian Numb proteins promote Notch1 receptor ubiquitination and degradation of the Notch1 intracellular domain. Journal of Biological Chemistry, 278(25), 23196–23203. https://doi.org/10.1074/jbc.M302827200

    Article  CAS  PubMed  Google Scholar 

  140. Di Marcotullio, L., Greco, A., Mazzà, D., Canettieri, G., Pietrosanti, L., Infante, P., …, & Gulino, A. (2011). Numb activates the E3 ligase Itch to control Gli1 function through a novel degradation signal. Oncogene, 30(1), 65–76. https://doi.org/10.1038/onc.2010.394

  141. Tokumitsu, H., Hatano, N., Yokokura, S., Sueyoshi, Y., Nozaki, N., & Kobayashi, R. (2006). Phosphorylation of Numb regulates its interaction with the clathrin-associated adaptor AP-2. FEBS Letters, 580(24), 5797–5801. https://doi.org/10.1016/j.febslet.2006.09.043

    Article  CAS  PubMed  Google Scholar 

  142. Smith, C. A., Lau, K. M., Rahmani, Z., Dho, S. E., Brothers, G., She, Y. M., …, & McGlade, C. J. (2007). aPKC-mediated phosphorylation regulates asymmetric membrane localization of the cell fate determinant Numb. The EMBO Journal, 26(2), 468–480. https://doi.org/10.1038/sj.emboj.7601495

  143. Lu, B., Rothenberg, M., Jan, L. Y., & Jan, Y. N. (1998). Partner of Numb colocalizes with Numb during mitosis and directs Numb asymmetric localization in Drosophila neural and muscle progenitors. Cell, 95(2), 225–235. https://doi.org/10.1016/S0092-8674(00)81753-5

    Article  CAS  PubMed  Google Scholar 

  144. Giuffrida, D., & Rogers, I. M. (2010). Targeting cancer stem cell lines as a new treatment of human cancer. Recent Patents on Anti-Cancer Drug Discovery, 5(3), 205–218. https://doi.org/10.2174/157489210791760535

    Article  CAS  PubMed  Google Scholar 

  145. Zhu, K., Shan, Z., Zhang, L., & Wen, W. (2016). Phospho-pon binding-mediated fine-tuning of Plk1 activity. Structure, 24(7), 1110–1119. https://doi.org/10.1016/j.str.2016.04.012

    Article  CAS  PubMed  Google Scholar 

  146. Wang, H., Ouyang, Y., Somers, W. G., Chia, W., & Lu, B. (2007). Polo inhibits progenitor self-renewal and regulates Numb asymmetry by phosphorylating Pon. Nature, 449(7158), 96–100. https://doi.org/10.1038/nature06056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Knoblich, J. A., Jan, & Jan, Y. N. (1995). Asymmetric segregation of Numb and Prospero during cell division. Nature, 377(6550), 624–627. https://doi.org/10.1038/377624a0

    Article  CAS  PubMed  Google Scholar 

  148. Vessey, J. P., Amadei, G., Burns, S. E., Kiebler, M. A., Kaplan, D. R., & Miller, F. D. (2012). An asymmetrically localized Staufen2-dependent RNA complex regulates maintenance of mammalian neural stem cells. Cell Stem Cell, 11(4), 517–528. https://doi.org/10.1016/j.stem.2012.06.010

    Article  CAS  PubMed  Google Scholar 

  149. Wiener, Z., Högström, J., Hyvönen, V., Band, A. M., Kallio, P., Holopainen, T., …, & Alitalo, K. (2014). Prox1 promotes expansion of the colorectal cancer stem cell population to fuel tumor growth and ischemia resistance. Cell Reports, 8(6), 1943–1956. https://doi.org/10.1016/j.celrep.2014.08.034

  150. Wu, P.-S., Egger, B., & Brand, A. H. (2008). Asymmetric stem cell division: Lessons from Drosophila. Seminars in Cell & Developmental Biology, 19(3), 283–293. https://doi.org/10.1016/j.semcdb.2008.01.007

    Article  CAS  Google Scholar 

  151. Bajaj, J., Hamilton, M., Shima, Y., Chambers, K., Spinler, K., Van Nostrand, E. L., …, & Reya, T. (2020). An in vivo genome-wide CRISPR screen identifies the RNA-binding protein Staufen2 as a key regulator of myeloid leukemia. Nature Cancer, 1(4), 410–422. https://doi.org/10.1038/s43018-020-0054-2

  152. Li, P., Yang, X., Wasser, M., Cai, Y., & Chia, W. (1997). Inscuteable and staufen mediate asymmetric localization and segregation of prospero RNA during Drosophila neuroblast cell divisions. Cell, 90(3), 437–447. https://doi.org/10.1016/S0092-8674(00)80504-8

    Article  CAS  PubMed  Google Scholar 

  153. Broadus, J., Fuerstenberg, S., & Doe, C. Q. (1998). Staufen-dependent localization of prospero mRNA contributes to neuroblast daughter-cell fate. Nature, 391(6669), 792–795. https://doi.org/10.1038/35861

    Article  CAS  PubMed  Google Scholar 

  154. Gómez-López, S., Lerner, R. G., & Petritsch, C. (2014). Asymmetric cell division of stem and progenitor cells during homeostasis and cancer. Cellular and Molecular Life Sciences: CMLS, 71(4), 575–597. https://doi.org/10.1007/s00018-013-1386-1

    Article  CAS  PubMed  Google Scholar 

  155. Shen, C.-P., Jan, L. Y., & Jan, Y. N. (1997). Miranda is required for the asymmetric localization of prospero during mitosis in Drosophila. Cell, 90(3), 449–458. https://doi.org/10.1016/S0092-8674(00)80505-X

    Article  CAS  PubMed  Google Scholar 

  156. Shen, C.-P., Knoblich, J. A., Chan, Y.-M., Jiang, M.-M., Jan, L. Y., & Jan, Y. N. (1998). Miranda as a multidomain adapter linking apically localized Inscuteable and basally localized Staufen and Prospero during asymmetric cell division in Drosophila. Genes & Development, 12(12), 1837–1846.

    Article  CAS  Google Scholar 

  157. Ikeshima-Kataoka, H., Skeath, J. B., Nabeshima, Y., Doe, C. Q., & Matsuzaki, F. (1997). Miranda directs Prospero to a daughter cell during Drosophila asymmetric divisions. Nature, 390(6660), 625–629. https://doi.org/10.1038/37641

    Article  CAS  PubMed  Google Scholar 

  158. Matsuzaki, F., Ohshiro, T., Ikeshima-Kataoka, H., & Izumi, H. (1998). miranda localizes staufen and prospero asymmetrically in mitotic neuroblasts and epithelial cells in early Drosophila embryogenesis. Development (Cambridge, England), 125(20), 4089–4098. https://doi.org/10.1242/dev.125.20.4089

    Article  CAS  PubMed  Google Scholar 

  159. Betschinger, J., Mechtler, K., & Knoblich, J. A. (2006). Asymmetric segregation of the tumor suppressor brat regulates self-renewal in Drosophila neural stem cells. Cell, 124(6), 1241–1253. https://doi.org/10.1016/j.cell.2006.01.038

    Article  CAS  PubMed  Google Scholar 

  160. Lee, C.-Y., Wilkinson, B. D., Siegrist, S. E., Wharton, R. P., & Doe, C. Q. (2006). Brat is a Miranda cargo protein that promotes neuronal differentiation and inhibits neuroblast self-renewal. Developmental Cell, 10(4), 441–449. https://doi.org/10.1016/j.devcel.2006.01.017

    Article  CAS  PubMed  Google Scholar 

  161. Czerwińska, P., Mazurek, S., & Wiznerowicz, M. (2017). The complexity of TRIM28 contribution to cancer. Journal of Biomedical Science, 24(1), 63. https://doi.org/10.1186/s12929-017-0374-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Hadjimichael, C., Chanoumidou, K., Nikolaou, C., Klonizakis, A., Theodosi, G.-I., Makatounakis, T., …, & Kretsovali, A. (2017). Promyelocytic leukemia protein is an essential regulator of stem cell pluripotency and somatic cell reprogramming. Stem Cell Reports, 8(5), 1366–1378. https://doi.org/10.1016/j.stemcr.2017.03.006

  163. Cheng, B., Ren, X., & Kerppola, T. K. (2014). KAP1 represses differentiation-inducible genes in embryonic stem cells through cooperative binding with PRC1 and derepresses pluripotency-associated genes. Molecular and Cellular Biology, 34(11), 2075–2091. https://doi.org/10.1128/MCB.01729-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Oleksiewicz, U., Gładych, M., Raman, A. T., Heyn, H., Mereu, E., Chlebanowska, P., …, & Wiznerowicz, M. (2017). TRIM28 and interacting KRAB-ZNFs control self-renewal of human pluripotent stem cells through epigenetic repression of pro-differentiation genes. Stem Cell Reports, 9(6), 2065–2080. https://doi.org/10.1016/j.stemcr.2017.10.031

  165. Hatakeyama, S. (2017). TRIM family proteins: Roles in autophagy, immunity, and carcinogenesis. Trends in Biochemical Sciences, 42(4), 297–311. https://doi.org/10.1016/j.tibs.2017.01.002

    Article  CAS  PubMed  Google Scholar 

  166. Sonoda, J., & Wharton, R. P. (2001). Drosophila brain tumor is a translational repressor. Genes & Development, 15(6), 762–773. https://doi.org/10.1101/gad.870801

    Article  CAS  Google Scholar 

  167. Boulay, J.-L., Stiefel, U., Taylor, E., Dolder, B., Merlo, A., & Hirth, F. (2009). Loss of heterozygosity of TRIM3 in malignant gliomas. BMC Cancer, 9(1), 1–9. https://doi.org/10.1186/1471-2407-9-71

    Article  CAS  Google Scholar 

  168. Chen, G., Kong, J., Tucker-Burden, C., Anand, M., Rong, Y., Rahman, F., …, & Brat, D. J. (2014). Human Brat ortholog TRIM3 is a tumor suppressor that regulates asymmetric cell division in glioblastoma. Cancer Research, 74(16), 4536–4548. https://doi.org/10.1158/0008-5472.CAN-13-3703

  169. Izumi, H., & Kaneko, Y. (2014). Trim32 facilitates degradation of MYCN on spindle poles and induces asymmetric cell division in human neuroblastoma cells. Cancer Research, 74(19), 5620–5630. https://doi.org/10.1158/0008-5472.CAN-14-0169

    Article  CAS  PubMed  Google Scholar 

  170. Wang, L., Bu, P., Ai, Y., Srinivasan, T., Chen, H. J., Xiang, K., …, & Shen, X. (2016). A long non-coding RNA targets microRNA miR-34a to regulate colon cancer stem cell asymmetric division. eLife, 5, e14620. https://doi.org/10.7554/eLife.14620

  171. Zhang, Q., Wang, J., Li, N., Liu, Z., Chen, Z., Li, Z., …, & Gao, J. (2018). miR-34a increases the sensitivity of colorectal cancer cells to 5-fluorouracil in vitro and in vivo. American Journal of Cancer Research, 8(2), 280–290.

  172. Hwang, W.-L., Jiang, J.-K., Yang, S.-H., Huang, T.-S., Lan, H.-Y., Teng, H.-W., …, & Yang, M.-H. (2014). MicroRNA-146a directs the symmetric division of Snail-dominant colorectal cancer stem cells. Nature Cell Biology, 16(3), 268–280. https://doi.org/10.1038/ncb2910

  173. Yoshida, K., Yamamoto, Y., & Ochiya, T. (2021). miRNA signaling networks in cancer stem cells. Regenerative Therapy, 17, 1–7. https://doi.org/10.1016/j.reth.2021.01.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Nwaeburu, C. C., Abukiwan, A., Zhao, Z., & Herr, I. (2017). Quercetin-induced miR-200b-3p regulates the mode of self-renewing divisions in pancreatic cancer. Molecular Cancer, 16(1), 23. https://doi.org/10.1186/s12943-017-0589-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Huang, G., Wang, M., Li, X., Wu, J., Chen, S., Du, N., …, & Sun, X. (2019). TUSC7 suppression of Notch activation through sponging MiR-146 recapitulated the asymmetric cell division in lung adenocarcinoma stem cells. Life Sciences, 232, 116630. https://doi.org/10.1016/j.lfs.2019.116630

  176. Ghanbari-Movahed, M., Ghanbari-Movahed, Z., Momtaz, S., Kilpatrick, K. L., Farzaei, M. H., & Bishayee, A. (2021). Unlocking the secrets of cancer stem cells with γ-secretase inhibitors: A novel anticancer strategy. Molecules, 26(4), 972. https://doi.org/10.3390/molecules26040972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Qiao, L., & Wong, B. C. Y. (2009). Role of Notch signaling in colorectal cancer. Carcinogenesis, 30(12), 1979–1986. https://doi.org/10.1093/carcin/bgp236

    Article  CAS  PubMed  Google Scholar 

  178. Stallings-Mann, M., Jamieson, L., Regala, R. P., Weems, C., Murray, N. R., & Fields, A. P. (2006). A novel small-molecule inhibitor of protein kinase Ciota blocks transformed growth of non-small-cell lung cancer cells. Cancer Research, 66(3), 1767–1774. https://doi.org/10.1158/0008-5472.CAN-05-3405

    Article  CAS  PubMed  Google Scholar 

  179. Chen, S., Zhao, Y., Peng, H., Liang, L., Li, Y., Hu, X., …, & Xu, Y. (2021). Polarity Protein Par3 Sensitizes Breast Cancer to Paclitaxel by Promoting Cell Cycle Arrest. (preprint). In Review. https://doi.org/10.21203/rs.3.rs-819518/v1

  180. Schmoranzer, J., Fawcett, J. P., Segura, M., Tan, S., Vallee, R. B., Pawson, T., & Gundersen, G. G. (2009). Par3 and dynein associate to regulate local microtubule dynamics and centrosome orientation during migration. Current Biology, 19(13), 1065–1074. https://doi.org/10.1016/j.cub.2009.05.065

    Article  CAS  PubMed  Google Scholar 

  181. Tagal, V., & Roth, M. G. (2021). Loss of aurora kinase signaling allows lung cancer cells to adopt endoreplication and form polyploid giant cancer cells that resist antimitotic drugs. Cancer Research, 81(2), 400–413. https://doi.org/10.1158/0008-5472.CAN-20-1693

    Article  CAS  PubMed  Google Scholar 

  182. Lopez-Sánchez, L. M., Jimenez, C., Valverde, A., Hernandez, V., Peñarando, J., Martinez, A., …, & Rodriguez-Ariza, A. (2014). CoCl2, a Mimic of Hypoxia, Induces Formation of Polyploid Giant Cells with Stem Characteristics in Colon Cancer. PLOS ONE, 9(6), e99143. https://doi.org/10.1371/journal.pone.0099143

  183. Zhang, S., Zhang, D., Yang, Z., & Zhang, X. (2016). Tumor budding, micropapillary pattern, and polyploidy giant cancer cells in colorectal cancer: Current status and future prospects. Stem Cells International, 2016, e4810734. https://doi.org/10.1155/2016/4810734

    Article  CAS  Google Scholar 

  184. Kim, H. J., & Kim, J. (2021). OTUD6A is an Aurora Kinase A-Specific Deubiquitinase. International Journal of Molecular Sciences, 22(4), 1936. https://doi.org/10.3390/ijms22041936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Asteriti, I. A., Cesare, E. D., Mattia, F. D., Hilsenstein, V., Neumann, B., Cundari, E., …, & Guarguaglini, G. (2014). The Aurora-A inhibitor MLN8237 affects multiple mitotic processes and induces dose-dependent mitotic abnormalities and aneuploidy. Oncotarget, 5(15), 6229–6242. https://doi.org/10.18632/oncotarget.2190

  186. Liu, N., Hu, G., Wang, H., Li, Z., & Guo, Z. (2018). PLK1 inhibitor facilitates the suppressing effect of temozolomide on human brain glioma stem cells. Journal of Cellular and Molecular Medicine, 22(11), 5300–5310. https://doi.org/10.1111/jcmm.13793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Wang, X., Kuang, W., Ding, J., Li, J., Ji, M., Chen, W., …, & Yang, P. (2022). Systematic Identification of the RNA-Binding Protein STAU2 as a Key Regulator of Pancreatic Adenocarcinoma. Cancers, 14(15), 3629. https://doi.org/10.3390/cancers14153629

  188. Auffinger, B., Tobias, A. L., Han, Y., Lee, G., Guo, D., Dey, M., …, & Ahmed, A. U. (2014). Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy. Cell Death and Differentiation, 21(7), 1119–1131. https://doi.org/10.1038/cdd.2014.31

  189. Dey-Guha, I., Alves, C. P., Yeh, A. C., None, S., Sole, X., Darp, R., & Ramaswamy, S. (2015). A mechanism for asymmetric cell division resulting in proliferative asynchronicity. Molecular Cancer Research : MCR, 13(2). https://doi.org/10.1158/1541-7786.MCR-14-0474

  190. Charnley, M., Ludford-Menting, M., Pham, K., & Russell, S. M. (2019). A new role for Notch in the control of polarity and asymmetric cell division of developing T cells. Journal of Cell Science, 133(5), jcs235358. https://doi.org/10.1242/jcs.235358

    Article  CAS  PubMed  Google Scholar 

  191. Wc, Y., Mm, F., F, A., C, B., J, C., B, C., …, & T, H. (2015). Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency. Clinical cancer research : an official journal of the American Association for Cancer Research, 21(9). https://doi.org/10.1158/1078-0432.CCR-14-2808

  192. Hu, S., Fu, W., Li, T., Yuan, Q., Wang, F., Lv, G., …, & Lei, C. (2017). Antagonism of EGFR and Notch limits resistance to EGFR inhibitors and radiation by decreasing tumor-initiating cell frequency. Science Translational Medicine, 9(380), eaag0339. https://doi.org/10.1126/scitranslmed.aag0339

  193. Fu, W., Lei, C., Yu, Y., Liu, S., Li, T., Lin, F., …, & Hu, S. (2019). EGFR/Notch Antagonists Enhance the Response to Inhibitors of the PI3K-Akt Pathway by Decreasing Tumor-Initiating Cell Frequency. Clinical Cancer Research, 25(9), 2835–2847. https://doi.org/10.1158/1078-0432.CCR-18-2732

  194. Munster, P., Eckhardt, S. G., Patnaik, A., Shields, A. F., Tolcher, A. W., Davis, S. L., …, & Ferrarotto, R. (2015). Abstract C42: Safety and preliminary efficacy results of a first-in-human phase I study of the novel cancer stem cell (CSC) targeting antibody brontictuzumab (OMP-52M51, anti-Notch1) administered intravenously to patients with certain advanced solid tumors. Molecular Cancer Therapeutics, 14(12_Supplement_2), C42. https://doi.org/10.1158/1535-7163.TARG-15-C42

  195. Tanaka, S., Nakada, M., Yamada, D., Nakano, I., Todo, T., Ino, Y., …, & Hirao, A. (2015). Strong therapeutic potential of γ-secretase inhibitor MRK003 for CD44-high and CD133-low glioblastoma initiating cells. Journal of Neuro-Oncology, 121(2), 239–250. https://doi.org/10.1007/s11060-014-1630-z

  196. Du, F.-Y., Zhou, Q.-F., Sun, W.-J., & Chen, G.-L. (2019). Targeting cancer stem cells in drug discovery: Current state and future perspectives. World Journal of Stem Cells, 11(7), 398–420. https://doi.org/10.4252/wjsc.v11.i7.398

    Article  PubMed  PubMed Central  Google Scholar 

  197. Issa, M. E., Berndt, S., Carpentier, G., Pezzuto, J. M., & Cuendet, M. (2016). Bruceantin inhibits multiple myeloma cancer stem cell proliferation. Cancer Biology & Therapy, 17(9), 966–975. https://doi.org/10.1080/15384047.2016.1210737

    Article  CAS  Google Scholar 

  198. Liu, X., Wang, L., Cui, W., Yuan, X., Lin, L., Cao, Q., …, & Yang, J. (2016). Targeting ALDH1A1 by disulfiram/copper complex inhibits non-small cell lung cancer recurrence driven by ALDH-positive cancer stem cells. Oncotarget, 7(36), 58516–58530. https://doi.org/10.18632/oncotarget.11305

  199. Rodriguez-Torres, M., & Allan, A. L. (2016). Aldehyde dehydrogenase as a marker and functional mediator of metastasis in solid tumors. Clinical & Experimental Metastasis, 33(1), 97–113. https://doi.org/10.1007/s10585-015-9755-9

    Article  CAS  Google Scholar 

  200. Bernkopf, D. B., Daum, G., Brückner, M., & Behrens, J. (2018). Sulforaphane inhibits growth and blocks Wnt/β-catenin signaling of colorectal cancer cells. Oncotarget, 9(74), 33982–33994. https://doi.org/10.18632/oncotarget.26125

    Article  PubMed  PubMed Central  Google Scholar 

  201. Galuppo, R., Maynard, E., Shah, M., Daily, M. F., Chen, C., Spear, B. T., & Gedaly, R. (2014). Synergistic inhibition of HCC and liver cancer stem cell proliferation by targeting RAS/RAF/MAPK and WNT/β-catenin pathways. Anticancer Research, 34(4), 1709–1713.

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Liu, L., Zhi, Q., Shen, M., Gong, F.-R., Zhou, B. P., Lian, L., …, & Li, W. (2016). FH535, a β-catenin pathway inhibitor, represses pancreatic cancer xenograft growth and angiogenesis. Oncotarget, 7(30), 47145–47162. https://doi.org/10.18632/oncotarget.9975

  203. Lachenmayer, A., Alsinet, C., Savic, R., Cabellos, L., Toffanin, S., Hoshida, Y., …, & Llovet, J. M. (2012). Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 18(18), 4997–5007. https://doi.org/10.1158/1078-0432.CCR-11-2322

  204. Rahmani, F., Amerizadeh, F., Hassanian, S. M., Hashemzehi, M., Nasiri, S.-N., Fiuji, H., …, & Avan, A. (2019). PNU-74654 enhances the antiproliferative effects of 5-FU in breast cancer and antagonizes thrombin-induced cell growth via the Wnt pathway. Journal of Cellular Physiology, 234(8), 14123–14132. https://doi.org/10.1002/jcp.28104

  205. Wei, W., Chua, M.-S., Grepper, S., & So, S. (2010). Small molecule antagonists of Tcf4/β-catenin complex inhibit the growth of HCC cells in vitro and in vivo. International Journal of Cancer, 126(10), 2426–2436. https://doi.org/10.1002/ijc.24810

    Article  CAS  PubMed  Google Scholar 

  206. Fields, A. P., & Regala, R. P. (2007). Protein kinase C iota: Human oncogene, prognostic marker and therapeutic target. Pharmacological Research, 55(6), 487–497. https://doi.org/10.1016/j.phrs.2007.04.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Wang, S., Cai, J., Zhang, S., Dong, M., Zhang, L., Xu, Y., …, & Chen, S. (2021). Loss of polarity protein Par3, via transcription factor Snail, promotes bladder cancer metastasis. Cancer Science, 112(7), 2625–2641. https://doi.org/10.1111/cas.14920

  208. Ohashi, S., Sakashita, G., Ban, R., Nagasawa, M., Matsuzaki, H., Murata, Y., …, & Urano, T. (2006). Phospho-regulation of human protein kinase Aurora-A: analysis using anti-phospho-Thr288 monoclonal antibodies. Oncogene, 25(59), 7691–7702. https://doi.org/10.1038/sj.onc.1209754

  209. Manfredi, M. G., Ecsedy, J. A., Chakravarty, A., Silverman, L., Zhang, M., Hoar, K. M., …, & Sells, T. B. (2011). Characterization of Alisertib (MLN8237), an investigational small-molecule inhibitor of aurora A kinase using novel in vivo pharmacodynamic assays. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 17(24), 7614–7624. https://doi.org/10.1158/1078-0432.CCR-11-1536

  210. Lerner, R. G., Grossauer, S., Kadkhodaei, B., Meyers, I., Sidorov, M., Koeck, K., …, & Petritsch, C. K. (2015). Targeting a Plk1-Controlled Polarity Checkpoint in Therapy-Resistant Glioblastoma-Propagating Cells. Cancer Research, 75(24), 5355–5366. https://doi.org/10.1158/0008-5472.CAN-14-3689

  211. Wang, R., & Liu, C. (2019). All-trans retinoic acid therapy induces asymmetric division of glioma stem cells from the U87MG cell line. Oncology Letters, 18(4), 3646–3654. https://doi.org/10.3892/ol.2019.10691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Tallman, M. S., Andersen, J. W., Schiffer, C. A., Appelbaum, F. R., Feusner, J. H., Ogden, A., …, & Wiernik, P. H. (1997). All-trans-Retinoic Acid in Acute Promyelocytic Leukemia. New England Journal of Medicine, 337(15), 1021–1028. https://doi.org/10.1056/NEJM199710093371501

  213. Qian, Y., Shi, L., & Luo, Z. (2020). Long non-coding RNAs in cancer: Implications for diagnosis, prognosis, and therapy. Frontiers in Medicine, 7, 612393. https://doi.org/10.3389/fmed.2020.612393

    Article  PubMed  PubMed Central  Google Scholar 

  214. Gibellini, L., Pinti, M., Nasi, M., Montagna, J. P., De Biasi, S., Roat, E., …, & Cossarizza, A. (2011). Quercetin and Cancer Chemoprevention. Evidence-Based Complementary and Alternative Medicine, 2011, 1–15. https://doi.org/10.1093/ecam/neq053

  215. Zahavi, D., & Weiner, L. (2020). Monoclonal antibodies in cancer therapy. Antibodies, 9(3), 34. https://doi.org/10.3390/antib9030034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Hajirasouliha, I., Mahmoody, A., & Raphael, B. J. (2014). A combinatorial approach for analyzing intra-tumor heterogeneity from high-throughput sequencing data. Bioinformatics, 30(12), i78–i86. https://doi.org/10.1093/bioinformatics/btu284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Marjanovic, N. D., Hofree, M., Chan, J. E., Canner, D., Wu, K., Trakala, M., …, & Tammela, T. (2020). Emergence of a High-Plasticity Cell State during Lung Cancer Evolution. Cancer Cell, 38(2), 229–246.e13. https://doi.org/10.1016/j.ccell.2020.06.012

  218. Wooten, M., Ranjan, R., & Chen, X. (2020). Asymmetric histone inheritance in asymmetrically dividing stem cells. Trends in Genetics, 36(1), 30–43. https://doi.org/10.1016/j.tig.2019.10.004

    Article  CAS  PubMed  Google Scholar 

  219. Zion, E. H., Chandrasekhara, C., & Chen, X. (2020). Asymmetric inheritance of epigenetic states in asymmetrically dividing stem cells. Current Opinion in Cell Biology, 67, 27–36. https://doi.org/10.1016/j.ceb.2020.08.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Zion, E., & Chen, X. (2021). Breaking symmetry: The asymmetries in epigenetic inheritance. The Biochemist, 43(1), 14–19. https://doi.org/10.1042/bio_2020_110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. French, R., & Pauklin, S. (2021). Epigenetic regulation of cancer stem cell formation and maintenance. International Journal of Cancer, 148(12), 2884–2897. https://doi.org/10.1002/ijc.33398

    Article  CAS  PubMed  Google Scholar 

  222. Suzuki, A., Yamanaka, T., Hirose, T., Manabe, N., Mizuno, K., Shimizu, M., …, & Ohno, S. (2001). Atypical Protein Kinase C Is Involved in the Evolutionarily Conserved Par Protein Complex and Plays a Critical Role in Establishing Epithelia-Specific Junctional Structures. Journal of Cell Biology, 152(6), 1183–1196. https://doi.org/10.1083/jcb.152.6.1183

  223. Wu, M.-J., Chen, Y.-S., Kim, M. R., Chang, C.-C., Gampala, S., Zhang, Y., …, & Chang, C.-J. (2019). Epithelial-Mesenchymal Transition Directs Stem Cell Polarity via Regulation of Mitofusin. Cell Metabolism, 29(4), 993–1002.e6. https://doi.org/10.1016/j.cmet.2018.11.004

Download references

Acknowledgements

We acknowledge Ms. Sucheta Mondal for her help in writing this review. We are also thankful to Dr. Jayanta Chakraborty, Director, Chittaranjan National Cancer Institute.

Funding

This work was supported by SERB sponsored projects (EEQ/2020/000601 and CRG/2021/007813). We wish to acknowledge the funding organization CSIR for their financial support.

Author information

Author notes

  1. Priya Samanta and Arijit Bhowmik contributed equally to this work.

Authors and Affiliations

  1. Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute (CNCI), 37, Shyama Prasad Mukherjee Rd, Bakul Bagan, Bhowanipore, Kolkata, West Bengal, 700026, India

    Priya Samanta, Arijit Bhowmik, Souradeep Biswas, Rupali Sarkar, Rituparna Ghosh, Shampa Pakhira, Mrinmoyee Mondal, Soummadeep Sen, Prosenjit Saha & Subhadip Hajra

Authors
  1. Priya Samanta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arijit Bhowmik
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Souradeep Biswas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rupali Sarkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rituparna Ghosh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shampa Pakhira
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mrinmoyee Mondal
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Soummadeep Sen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Prosenjit Saha
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Subhadip Hajra
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: P.SM and A.B; literature search and data analysis: P.SM and A.B, Writing—original draft preparation: P.SM, A.B, S.B, R.S, R.G, S.P, M.M, S.S, P.S and S.H; Writing—review and editing: S.B, R.S, R.G, S.P, M.M, S.S, P.S and S.H; Funding acquisition: P.S and S.H.

Corresponding authors

Correspondence to Arijit Bhowmik or Subhadip Hajra.

Ethics declarations

Ethical Approval

Not Applicable

Consent to Participate

Not Applicable

Consent to Publish

Not Applicable

Competing Interests

The authors confirm that this article content has no competing interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Samanta, P., Bhowmik, A., Biswas, S. et al. Therapeutic Effectiveness of Anticancer Agents Targeting Different Signaling Molecules Involved in Asymmetric Division of Cancer Stem Cell. Stem Cell Rev and Rep 19, 1283–1306 (2023). https://doi.org/10.1007/s12015-023-10523-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-023-10523-3

Keywords

Search

Navigation