Journal of Biosciences

, Volume 41, Issue 3, pp 497–506 | Cite as

Therapeutic resistance and cancer recurrence mechanisms: Unfolding the story of tumour coming back

  • Mohammad Javad Dehghan Esmatabadi
  • Babak Bakhshinejad
  • Fatemeh Movahedi Motlagh
  • Sadegh BabashahEmail author
  • Majid SadeghizadehEmail author


Cancer recurrence is believed to be one of the major reasons for the failure of cancer treatment strategies. This biological phenomenon could arise from the incomplete eradication of tumour cells after chemo- and radiotherapy. Recent developments in the design of models reflecting cancer recurrence and in vivo imaging techniques have led researchers to gain a deeper and more detailed insight into the mechanisms underlying tumour relapse. Here, we provide an overview of three important drivers of recurrence including cancer stem cells (CSCs), neosis, and phoenix rising. The survival of cancer stem cells is well recognized as one of the primary causes of therapeutic resistance in malignant cells. CSCs have a relatively latent metabolism and show resistance to therapeutic agents through a variety of routes. Neosis has proven to be as an important mechanism behind tumour self-proliferation after treatment which gives rise to the expansion of tumour cells in the injured site via production of Raju cells. Phoenix rising is a pro-recurrence pathway through which apoptotic cancer cells send strong signals to the neighbouring diseased cells leading to their multiplication. The mechanisms involved in therapeutic resistance and tumour recurrence have not yet been fully understood and mostly remain unexplained. Without doubt, an improved understanding of the cellular machinery contributing to recurrence will pave the way for the development of novel, sophisticated and effective anti-tumour therapeutic strategies which can eradicate tumour without the threat of relapse.


Cancer recurrence cancer stem cells neosis phoenix rising therapeutic resistance tumour relapse 



We are indebted to all of those who provided rich insights into the field. Also, we apologize to the colleagues whose work could not be cited due to space limitations. This work was supported from Tarbiat Modares University, Tehran, Iran.


  1. Abdullah LN and Chow E 2013 Mechanisms of chemoresistance in cancer stem cells. Clin. Transl. Med. 2(1) 3. doi:  10.1186/2001-1326-2-3
  2. Alisi A, Cho WC, et al. 2013 Multidrug resistance and cancer stem cells in neuroblastoma and hepatoblastoma. Int. J. Mol. Sci. 14 24706–24725CrossRefPubMedPubMedCentralGoogle Scholar
  3. Allan AL, Vantyghem SA, et al. 2007 Tumor dormancy and cancer stem cells: implications for the biology and treatment of breast cancer metastasis. Breast Dis. 26 87–98CrossRefGoogle Scholar
  4. Alvero AB, Fu HH, et al. 2009 Stem-like ovarian cancer cells can serve as tumor vascular progenitors. Stem Cells 27 2405–2413CrossRefPubMedPubMedCentralGoogle Scholar
  5. Baker F, Denniston M, et al. 2005 Adult cancer survivors: how are they faring? Cancer 104 2565–2576CrossRefPubMedGoogle Scholar
  6. Bao S, Wu Q, et al. 2006 Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444 756–760CrossRefPubMedGoogle Scholar
  7. Bergmann A and Steller H 2010 Apoptosis, stem cells, and tissue regeneration. Sci Signal 3 re8CrossRefPubMedPubMedCentralGoogle Scholar
  8. Bussolati B, Bruno S, et al. 2008 Identification of a tumor-initiating stem cell population in human renal carcinomas. FASEB J 22 3696–3705CrossRefPubMedGoogle Scholar
  9. Bussolati B, Grange C, et al. 2009 Endothelial cell differentiation of human breast tumour stem/progenitor cells. J. Cell Mol. Med. 13 309–319Google Scholar
  10. Chen R, Nishimura MC, et al. 2010 A hierarchy of self-renewing tumor-initiating cell types in glioblastoma. Cancer Cell 17 362–375CrossRefPubMedGoogle Scholar
  11. Chen K, Huang YH, et al. 2013 Understanding and targeting cancer stem cells: therapeutic implications and challenges. Acta Pharmacol. Sin. 34 732–740CrossRefPubMedPubMedCentralGoogle Scholar
  12. Clarkson BD and Fried J 1971 Changing concepts of treatment in acute leukemia. Med. Clin. N. Am. 55 561–600CrossRefPubMedGoogle Scholar
  13. Clarkson B, Strife A, et al. 1970 Studies of cellular proliferation in human leukemia.IV. Behavior of normal hematopoietic cells in 3 adults with acute leukemia given continuous infusions of3 H-thymidine for 8 or 10 days. Cancer 26 1–19CrossRefPubMedGoogle Scholar
  14. Clevers H and Nusse R 2012 Wnt/beta-catenin signaling and disease. Cell 149 1192–1205CrossRefPubMedGoogle Scholar
  15. Dimri GP 2005 What has senescence got to do with cancer?’. Cancer Cell 7 505–512CrossRefPubMedPubMedCentralGoogle Scholar
  16. Dontu G, Abdallah W, et al. 2003 In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 17 1253–1270CrossRefPubMedPubMedCentralGoogle Scholar
  17. Felsher DW 2006 Tumor dormancy: death and resurrection of cancer as seen through transgenic mouse models. Cell Cycle 5 1808–1811CrossRefPubMedGoogle Scholar
  18. Furth J, Kahn MC, et al. 1937 The transmission of leukemia of mice with a single cell. Am. J. Cancer 31 276–282Google Scholar
  19. Galli R, Binda E, et al. 2004 Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 64 7011–7021CrossRefPubMedGoogle Scholar
  20. Gavosto F 1970 The proliferative kinetics of the acute leukaemias in relation to their treatment. Rev. Eur. Etud. Clin. Biol. 15 1042–1047PubMedGoogle Scholar
  21. Gewirtz DA 2014 The four faces of autophagy: implications for cancer therapy. Cancer Res. 74 647–651CrossRefPubMedGoogle Scholar
  22. Gurtner GC, Werner S, et al. 2008 Wound repair and regeneration. Nature 453 314–321CrossRefPubMedGoogle Scholar
  23. Han L, Shi S, et al. 2013 Cancer stem cells: therapeutic implications and perspectives in cancer therapy. Acta Pharm. Sin. B. 3 65–75CrossRefGoogle Scholar
  24. Huang EH, Hynes MJ, et al. 2009 Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res. 69 3382–3389CrossRefPubMedPubMedCentralGoogle Scholar
  25. Huang Q, Li F, et al. 2011 Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat. Med. 17 860–866CrossRefPubMedPubMedCentralGoogle Scholar
  26. Hueng D-Y, Sytwu H-K, et al. 2011 Isolation and characterization of tumor stem-like cells from human meningiomas. J. Neuro-Oncol. 104 45–53CrossRefGoogle Scholar
  27. Jager R and Fearnhead HO 2012 Dead Cells Talking’: The Silent Form of Cell Death Is Not so Quiet. Biochem. Res. Int. 2012, 453838PubMedPubMedCentralGoogle Scholar
  28. Jordan CT, Guzman ML, et al. 2006 Cancer stem cells. N. Engl. J. Med. 355 1253–1261CrossRefPubMedGoogle Scholar
  29. Khan MI, Czarnecka AM, et al. 2015 Current approaches in identification and isolation of human renal cell carcinoma cancer stem cells. Stem Cell Res. Ther. 6 178CrossRefPubMedPubMedCentralGoogle Scholar
  30. Killmann SA, Cronkite EP, et al. 1963 Estimation of phases of the life cycle of leukemic cells from labeling in human beings in vivo with tritiated thymidine. Lab. Investig. 12 671–684PubMedGoogle Scholar
  31. Kondo T, Setoguchi T, et al. 2004 Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc. Natl. Acad. Sci. USA 101 781–786CrossRefPubMedPubMedCentralGoogle Scholar
  32. Kroemer G 2015 Autophagy: a druggable process that is deregulated in aging and human disease. J. Clin. Invest. 125 1–4CrossRefPubMedPubMedCentralGoogle Scholar
  33. Li F, Huang Q, et al. 2010 Apoptotic cells activate the ‘phoenix rising’ pathway to promote wound healing and tissue regeneration. Sci Signal. 3 ra13PubMedPubMedCentralGoogle Scholar
  34. Liu J, Ma L, et al. 2013 Spheroid body-forming cells in the human gastric cancer cell line MKN-45 possess cancer stem cell properties. Int. J. Oncol. 42 453–459PubMedGoogle Scholar
  35. Liu C, Li CY, et al. 2014 Mathematical modeling of the Phoenix Rising pathway. PLoS Comput. Biol. 10 e1003461CrossRefPubMedPubMedCentralGoogle Scholar
  36. Manohar PR 2015 Descriptions and Classification of Cancer in the Classical Ayurvedic Texts. Indian Nat. Sci. Acad. 50 187–195Google Scholar
  37. Martin P, D'Souza D, et al. 2003 Wound Healing in the PU.1 Null Mouse—Tissue Repair Is Not Dependent on Inflammatory Cells. Curr. Biol. 13 1122–1128CrossRefPubMedGoogle Scholar
  38. Medema JP 2013 Cancer stem cells: the challenges ahead. Nat. Cell Biol. 15 338–344CrossRefPubMedGoogle Scholar
  39. Mosser DM and Edwards JP 2008 Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8 958–969CrossRefPubMedPubMedCentralGoogle Scholar
  40. Navolanic PM, Akula SM and McCubrey JA 2004 Neosis and its potential role in cancer development and chemoresistance. Cancer Biol. Ther. 2 219–220CrossRefGoogle Scholar
  41. O'Connor ML, Xiang D, et al. 2014 Cancer stem cells: A contentious hypothesis now moving forward. Cancer Lett. 344 180–187CrossRefPubMedGoogle Scholar
  42. Ojha R, Bhattacharyya S, et al. 2015 Autophagy in Cancer Stem Cells: A Potential Link Between Chemoresistance, Recurrence, and Metastasis. Biores Open Access 4 97–108CrossRefPubMedPubMedCentralGoogle Scholar
  43. Pastrana E, Silva-Vargas V, et al. 2011 Eyes wide open: a critical review of sphere-formation as an assay for stem cells. Cell Stem Cell 8 486–498CrossRefPubMedPubMedCentralGoogle Scholar
  44. Pavlidis N and Karpozilos A 2011 The History of Oncology by Theo Wagener. Ann. Oncol. 22 1933–1935CrossRefGoogle Scholar
  45. Rahman M, Deleyrolle L, et al. 2011 The cancer stem cell hypothesis: failures and pitfalls. Neurosurgery 68 531–545. discussion 545CrossRefPubMedGoogle Scholar
  46. Rajaraman R, Rajaraman MM, et al. 2005 Neosis--a paradigm of self-renewal in cancer. Cell Biol. Int. 29 1084–1097CrossRefPubMedGoogle Scholar
  47. Rajaraman R, Guernsey DL, et al. 2006 Stem cells, senescence, neosis and self-renewal in cancer. Cancer Cell Int. 6 25CrossRefPubMedPubMedCentralGoogle Scholar
  48. Rajaraman R, Guernsey D, et al. 2007 Neosis-A parasexual somatic reduction division in cancer. Int. J. Hum. Genet. 7 29Google Scholar
  49. Rasheed ZA, Kowalski J, et al. 2011 Concise review: Emerging concepts in clinical targeting of cancer stem cells. Stem Cells 29 883–887CrossRefPubMedPubMedCentralGoogle Scholar
  50. Ricci-Vitiani L, Pallini R, et al. 2010 Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468 824–828CrossRefPubMedGoogle Scholar
  51. Roninson IB, Broude EV, et al. 2001 If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells. Drug Resist. Updat. 4 303–313CrossRefPubMedGoogle Scholar
  52. Sakariassen PØ, Immervoll H, et al. 2007 Cancer stem cells as mediators of treatment resistance in brain tumors: status and controversies. Neoplasia 9 882–892CrossRefPubMedPubMedCentralGoogle Scholar
  53. Shen G, Shen F, et al. 2008a Identification of cancer stem-like cells in the C6 glioma cell line and the limitation of current identification methods. In Vitro Cell. Dev. Biol. Anim. 44 280–289CrossRefPubMedGoogle Scholar
  54. Shen R, Ye Y, et al. 2008b Precancerous stem cells can serve as tumor vasculogenic progenitors. PLoS One 3 e1652CrossRefPubMedPubMedCentralGoogle Scholar
  55. Singh A and Settleman J 2010 EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29 4741–4751CrossRefPubMedPubMedCentralGoogle Scholar
  56. Singh SK, Hawkins C, et al. 2004 Identification of human brain tumour initiating cells. Nature 432 396–401CrossRefPubMedGoogle Scholar
  57. Singh R, George J, et al. 2010 Role of senescence and mitotic catastrophe in cancer therapy. Cell Div. 5 4CrossRefPubMedPubMedCentralGoogle Scholar
  58. Sui X, Chen R, et al. 2013 Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis. 4, e838CrossRefPubMedGoogle Scholar
  59. Sundaram M, Guernsey DL, et al. 2004 Neosis: a novel type of cell division in cancer. Cancer Biol. Ther. 3 207–218CrossRefPubMedGoogle Scholar
  60. Tsuruo T, Naito M, et al. 2003 Molecular targeting therapy of cancer: drug resistance, apoptosis and survival signal. Cancer Sci. 94 15–21CrossRefPubMedGoogle Scholar
  61. Vunjak-Novakovic G and Scadden DT 2011 Biomimetic platforms for human stem cell research. Cell Stem Cell. 8 252–261CrossRefPubMedPubMedCentralGoogle Scholar
  62. Wang SS, Jiang J, et al. 2015 Links between cancer stem cells and epithelial-mesenchymal transition. Onco. Targets Ther. 8 2973–2980PubMedPubMedCentralGoogle Scholar
  63. Welte Y, Adjaye J, et al. 2010 Cancer stem cells in solid tumors: elusive or illusive? Cell Commun. Signal. 8 6CrossRefPubMedPubMedCentralGoogle Scholar
  64. Yanamoto S, Kawasaki G, et al. 2011 Isolation and characterization of cancer stem-like side population cells in human oral cancer cells. Oral Oncol. 47 855–860CrossRefPubMedGoogle Scholar
  65. Zhang S, Mercado-Uribe I, et al. 2014 Generation of cancer stem-like cells through the formation of polyploid giant cancer cells. Oncogene 33 116–128CrossRefPubMedGoogle Scholar
  66. Zhao Y, Dong J, et al. 2010 Endothelial cell transdifferentiation of human glioma stem progenitor cells in vitro. Brain Res. Bull. 82 308–312CrossRefPubMedGoogle Scholar
  67. Zhong Y, Guan K, et al. 2010 Spheres derived from the human SK-RC-42 renal cell carcinoma cell line are enriched in cancer stem cells. Cancer Lett. 299 150–160CrossRefPubMedGoogle Scholar

Copyright information

© Indian Academy of Sciences 2016

Authors and Affiliations

  • Mohammad Javad Dehghan Esmatabadi
    • 1
  • Babak Bakhshinejad
    • 1
  • Fatemeh Movahedi Motlagh
    • 2
  • Sadegh Babashah
    • 1
    Email author
  • Majid Sadeghizadeh
    • 1
    Email author
  1. 1.Department of Molecular Genetics, Faculty of Biological SciencesTarbiat Modares UniversityTehranIran
  2. 2.Department of GeneticsSabzevar University of Medical SciencesSabzevarIran

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