Skip to main content
SpringerLink
Log in

Biological and Clinical Evidence for Metabolic Dormancy in Solid Tumors Post Therapy

  • Chapter
  • First Online:
Tumor Dormancy and Recurrence

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Despite many advances in the understanding of cancer biology, patient survival has only modestly improved over the past few decades. This is partly due to the dismissal of an important phase of cancer progression called therapy-induced dormancy which arises during the course of (neo)adjuvant therapy. This review describes recent efforts in understanding the mechanisms that ‘dormant’ cancer cells adopt to survive and develop resistance prior to their relapse into secondary tumors. The focus is particularly on metabolic reprogramming that ensues as a consequence of tumor adaptation to therapy.

Noushin Nabavi and Susan L. Ettinger are co-first authors.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Aguirre-Ghiso JA (2007) Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 7(11):834–846. PubMed PMID: PMC2519109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Friedlander TW, Fong L (2014) The end of the beginning: circulating tumor cells as a biomarker in castration-resistant prostate cancer. J Clin Oncol 32(11):1104–1106. PubMed PMID: 24616311

    Article  CAS  PubMed  Google Scholar 

  3. Paget S (1889) The distribution of secondary growths in cancer of the breast. The Lancet. 133(3421):571–573

    Article  Google Scholar 

  4. Hinck L (2011) Tumor suppressors: heroes and villains? J Mammary Gland Biol Neoplasia 16(3):169–171. PubMed PMID: PMC4105358

    Article  PubMed  PubMed Central  Google Scholar 

  5. Jäger W, Xue H, Hayashi T, Janssen C, Awrey S, Wyatt AW et al (2015) Patient-derived bladder cancer xenografts in the preclinical development of novel targeted therapies. Oncotarget 6(25):21522–21532

    Article  PubMed  PubMed Central  Google Scholar 

  6. Eirew P, Steif A, Khattra J, Ha G, Yap D, Farahani H et al (2015) Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution. Nature 518(7539):422–426

    Article  CAS  PubMed  Google Scholar 

  7. Choi SYC, Lin D, Gout PW, Collins CC, Xu Y, Wang Y (2014) Lessons from patient-derived xenografts for better in vitro modeling of human cancer. Adv Drug Deliv Rev 79–80:222–237

    Article  PubMed  Google Scholar 

  8. Lin D, Xue H, Wang Y, Wu R, Watahiki A, Dong X et al (2014) Next generation patient-derived prostate cancer xenograft models. Asian J Androl 16(3):407–412

    Article  PubMed  PubMed Central  Google Scholar 

  9. Lin D, Wyatt AW, Xue H, Wang Y, Dong X, Haegert A et al (2014) High fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development. Cancer Res 74(4):1272–1283

    Article  CAS  PubMed  Google Scholar 

  10. Radzikowski J (2013) Resistance of dormant stages of planktonic invertebrates to adverse environmental conditions. J Plankton Res 35(4):707–723

    Article  Google Scholar 

  11. Archuleta RJ, Yvonne Hoppes P, Primm TP (2005) Mycobacterium Avium enters a state of metabolic dormancy in response to starvation. Tuberculosis 85(3):147–158

    Article  CAS  PubMed  Google Scholar 

  12. Chubukov V, Sauer U (2014) Environmental dependence of stationary-phase metabolism in Bacillus Subtilis and Escherichia coli. Appl Environ Microbiol 80(9):2901–2909

    Article  PubMed  PubMed Central  Google Scholar 

  13. Shimizu K (2014) Regulation Systems of Bacteria such as Escherichia coli in response to nutrient limitation and environmental stresses. Metabolites 4(1):1. doi:10.3390/metabo4010001

    Article  Google Scholar 

  14. Valcourt JR, Lemons JMS, Haley EM, Kojima M, Demuren OO, Coller HA (2012) Staying alive. Cell Cycle 11(9):1680–1696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. van der Toom EE, Verdone JE, Pienta KJ (2016) Disseminated tumor cells and dormancy in prostate cancer metastasis. Curr Opin Biotechnol 40:9–15

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lam H-M, Vessella RL, Morrissey C (2014) The role of the microenvironment—dormant prostate disseminated tumor cells in the bone marrow. Drug Discov Today Technol 11:41–47. PubMed PMID: PMC4412595

    Article  PubMed  PubMed Central  Google Scholar 

  17. Shiozawa Y, Eber MR, Berry JE, Taichman RS (2015) Bone marrow as a metastatic niche for disseminated tumor cells from solid tumors. BoneKEy Rep 4:689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Amoêdo Nívea D, Valencia Juan P, Rodrigues Mariana F, Galina A, Rumjanek FD (2013) How does the metabolism of tumour cells differ from that of normal cells. Biosci Rep 33(6):e00080. PubMed PMID: PMC3828821

    PubMed  PubMed Central  Google Scholar 

  19. Cantor JR, Sabatini DM (2012) Cancer cell metabolism: one hallmark, many faces. Cancer Discov 2(10):881–898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Warburg O (1956) On the origin of cancer cells. Science 123(3191):309–314

    Article  CAS  PubMed  Google Scholar 

  21. Hay N (2016) Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy? Nat Rev Cancer 16(10):635–649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mattaini KR, Sullivan MR, Vander Heiden MG (2016) The importance of serine metabolism in cancer. J Cell Biol 214(3):249–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Locasale JW (2013) Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer 13(8):572–583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Phang JM, Liu W, Hancock CN, Fischer JW (2015) Proline metabolism and cancer: emerging links to glutamine and collagen. Curr Opin Clin Nutr Metab Care 18(1):71–77. PubMed PMID: 00075197-201501000-00012

    Article  CAS  PubMed  Google Scholar 

  26. Olivares O, Däbritz JHM, King A, Gottlieb E, Halsey C (2015) Research into cancer metabolomics: towards a clinical metamorphosis. Semin Cell Dev Biol 43:52–64

    Article  PubMed  Google Scholar 

  27. Phang JM, Liu W, Hancock C (2013) Bridging epigenetics and metabolism: role of non-essential amino acids. Epigenetics 8(3):231–236. PubMed PMID: PMC3669115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Beerman I, Seita J, Inlay Matthew A, Weissman Irving L, Rossi DJ (2014) Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell 15(1):37–50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pietras EM, Lakshminarasimhan R, Techner J-M, Fong S, Flach J, Binnewies M et al (2014) Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons. J Exp Med 211(2):245–262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sosa MS, Bragado P, Debnath J, Aguirre-Ghiso JA (2013) Regulation of tumor cell dormancy by tissue microenvironments and autophagy. Adv Exp Med Biol 734:73–89. PubMed PMID: PMC3651695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Neill T, Schaefer L, Iozzo RV (2014) Instructive roles of extracellular matrix on autophagy. Am J Pathol 184(8):2146–2153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ito K, Suda T (2014) Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol 15(4):243–256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ward PS, Thompson CB (2012) Signaling in control of cell growth and metabolism. Cold Spring Harbor Perspect Biol 4(7):a006783. PubMed PMID: PMC3385956

    Article  Google Scholar 

  34. Krall AS, Xu S, Graeber TG, Braas D, Christofk HR (2016) Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. Nat Commun 7:11457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yang M, Vousden KH (2016) Serine and one-carbon metabolism in cancer. Nat Rev Cancer 16(10):650–662

    Article  CAS  PubMed  Google Scholar 

  36. Ducker Gregory S, Rabinowitz JD (2017) One-carbon metabolism in health and disease. Cell Metab 25(1):27–42

    Article  CAS  PubMed  Google Scholar 

  37. Saqcena M, Menon D, Patel D, Mukhopadhyay S, Chow V, Foster DA (2013) Amino acids and mtor mediate distinct metabolic checkpoints in mammalian G1 cell cycle. PLoS One 8(8):e74157. PubMed PMID: PMC3747087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sahu N, Dela Cruz D, Gao M, Sandoval W, Haverty Peter M, Liu J et al (2016) Proline starvation induces unresolved ER stress and hinders mTORC1-dependent tumorigenesis. Cell Metab 24(5):753–761

    Article  CAS  PubMed  Google Scholar 

  39. Tsun Z-Y, Possemato R (2015) Amino acid management in cancer. Semin Cell Dev Biol 43:22–32. PubMed PMID: PMC4800996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Phillips MM, Sheaff MT, Szlosarek PW (2013) Targeting arginine-dependent cancers with arginine-degrading enzymes: opportunities and challenges. Cancer Res Treat 45(4):251–262

    Article  PubMed  PubMed Central  Google Scholar 

  41. Patil MD, Bhaumik J, Babykutty S, Banerjee UC, Fukumura D (2016) Arginine dependence of tumor cells: targeting a chink in cancer/’s armor. Oncogene 35(38):4957–4972

    Article  CAS  PubMed  Google Scholar 

  42. Chiang C-H, Chang M-Y, Hsu J-J, Chiu T-H, Lee K-F, Ts-Ta H et al (1999) Tumor vascular pattern and blood flow impedance in the differential diagnosis of leiomyoma and adenomyosis by color doppler sonography. J Assist Reprod Genet 16(5):268–275. PubMed PMID: PMC3455709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Antonescu C (2014) Malignant vascular tumors—an update. Mod Pathol 27(S1):S30–SS8

    Article  CAS  PubMed  Google Scholar 

  44. Urra H, Dufey E, Avril T, Chevet E, Hetz C (2016) Endoplasmic reticulum stress and the hallmarks of cancer. Trends Cancer 2(5):252–262

    Article  PubMed  Google Scholar 

  45. Tsai YC, Weissman AM (2010) The unfolded protein response, degradation from the endoplasmic reticulum, and cancer. Genes Cancer 1(7):764–778. PubMed PMID: PMC3039444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Powell E, Piwnica-Worms D, Piwnica-Worms H (2014) Contribution of p53 to metastasis. Cancer Discov 4(4):405–414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Montagner M, Enzo E, Forcato M, Zanconato F, Parenti A, Rampazzo E et al (2012) SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors. Nature 487(7407):380–384

    Article  CAS  PubMed  Google Scholar 

  48. Adam AP, George A, Schewe D, Bragado P, Iglesias BV, Ranganathan AC et al (2009) Computational identification of a p38SAPK-regulated transcription factor network required for tumor cell quiescence. Cancer Res 69(14):5664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Aguirre-Ghiso JA, Estrada Y, Liu D, Ossowski L (2003) ERK-MAPK activity as a determinant of tumor growth and dormancy; regulation by p38-SAPK. Cancer Res 63(7):1684

    CAS  PubMed  Google Scholar 

  50. Tesio M, Tang Y, Müdder K, Saini M, von Paleske L, Macintyre E et al (2015) Hematopoietic stem cell quiescence and function are controlled by the CYLD–TRAF2–p38MAPK pathway. J Exp Med 212(4):525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ludin A, Gur-Cohen S, Golan K, Kaufmann KB, Itkin T, Medaglia C et al (2014) Reactive oxygen species regulate hematopoietic stem cell self-renewal, migration and development, as well as their bone marrow microenvironment. Antioxid Redox Signal 21(11):1605–1619. PubMed PMID: PMC4175025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bigarella CL, Liang R, Ghaffari S (2014) Stem cells and the impact of ROS signaling. Development 141(22):4206–4218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Huang J, Nguyen-McCarty M, Hexner EO, Danet-Desnoyers G, Klein PS (2012) Maintenance of hematopoietic stem cells through regulation of Wnt and mTOR pathways. Nat Med 18(12):1778–1785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Scognamiglio R, Cabezas-Wallscheid N, Thier Marc C, Altamura S, Reyes A, Prendergast Áine M et al (2016) Myc depletion induces a pluripotent dormant state mimicking diapause. Cell 164(4):668–680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Laurenti E, Wilson A, Trumpp A (2009) Myc’s other life: stem cells and beyond. Curr Opin Cell Biol 21(6):844–854

    Article  CAS  PubMed  Google Scholar 

  56. Yeh AC, Ramaswamy S (2015) Mechanisms of cancer cell dormancy—another hallmark of cancer? Cancer Res 75(23):5014–5022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Rodgers JT, King KY, Brett JO, Cromie MJ, Charville GW, Maguire KK et al (2014) mTORC1 controls the adaptive transition of quiescent stem cells from G0 to GAlert. Nature 510(7505):393–396

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Hurst RE, Bastian A, Bailey-Downs L, Ihnat MA (2016) Targeting dormant micrometastases: rationale, evidence to date and clinical implications. Ther Adv Med Oncol 8(2):126–137. PubMed PMID: PMC4753353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Won EJ, Kim H-R, Park R-Y, Choi S-Y, Shin JH, Suh S-P et al (2015) Direct confirmation of quiescence of CD34+CD38- leukemia stem cell populations using single cell culture, their molecular signature and clinicopathological implications. BMC Cancer 15:217. PubMed PMID: PMC4391681

    Article  PubMed  PubMed Central  Google Scholar 

  60. 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 Int 2016:1740936. PubMed PMID: PMC4932171

    PubMed  PubMed Central  Google Scholar 

  61. Buczacki S, Davies RJ, Winton DJ (2011) Stem cells, quiescence and rectal carcinoma: an unexplored relationship and potential therapeutic target. Br J Cancer 105(9):1253–1259. PubMed PMID: PMC3241542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Suresh R, Ali S, Ahmad A, Philip PA, Sarkar FH (2016) The role of cancer stem cells in recurrent and drug-resistant lung cancer. In: Ahmad A, Gadgeel SM (eds) Lung cancer and personalized medicine: novel therapies and clinical management. Springer, Cham, pp 57–74

    Chapter  Google Scholar 

  63. Han L, Shi S, Gong T, Zhang Z, Sun X (2013) Cancer stem cells: therapeutic implications and perspectives in cancer therapy. Acta Pharm Sin B 3(2):65–75

    Article  Google Scholar 

  64. Goss PE, Chambers AF (2010) Does tumour dormancy offer a therapeutic target? Nat Rev Cancer 10(12):871–877

    Article  CAS  PubMed  Google Scholar 

  65. Loi S, Dafni U, Karlis D et al (2016) Effects of estrogen receptor and human epidermal growth factor receptor-2 levels on the efficacy of trastuzumab: a secondary analysis of the hera trial. JAMA Oncol 2(8):1040–1047

    Article  PubMed  Google Scholar 

  66. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353(16):1659–1672. PubMed PMID: 16236737

    Article  CAS  PubMed  Google Scholar 

  67. Sweeney CJ, Chen Y-H, Carducci M, Liu G, Jarrard DF, Eisenberger M et al (2015) Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 373(8):737–746. PubMed PMID: 26244877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Financial Support

This work was supported by the Canadian Institutes of Health Research (Y.W.), BC Cancer Foundation Mesothelioma Research Fund/Mitacs Accelerate Postdoctoral Fellowship Fund (N.N., Y.W., C.C.C.), and the Terry Fox New Frontiers Program on Prostate Cancer Progression (C.C.C., Y.W.).

Conflicts of Interest

The authors confirm that there are no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Experimental Therapeutics and Department of Urologic Sciences, BC Cancer Agency and University of British Columbia, Vancouver, BC, Canada

    Noushin Nabavi & Yuzhuo Wang

  2. Laboratory for Advanced Genome Analysis, Vancouver Prostate Centre, Vancouver, BC, Canada

    Susan L. Ettinger

  3. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada

    Susan L. Ettinger

  4. School of Life, Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, Buckinghamshire, UK

    Francesco Crea

  5. Laboratory for Advanced Genome Analysis, Vancouver Prostate Centre, 2660 Oak St, Vancouver, BC, Canada, V6H 3Z6

    Colin C. Collins

  6. Department of Urologic Sciences, University of British Columbia, 2329 West Mall, Vancouver, BC, Canada, V6T 1Z4

    Colin C. Collins

Authors
  1. Noushin Nabavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susan L. Ettinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesco Crea
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuzhuo Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Colin C. Collins
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yuzhuo Wang or Colin C. Collins .

Editor information

Editors and Affiliations

  1. Department of Experimental Therapeutics and Department of Urologic Sciences, BC Cancer Agency and University of British Columbia, Vancouver, British Columbia, Canada

    Yuzhuo Wang

  2. School of Life, Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, Buckinghamshire, United Kingdom

    Francesco Crea

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Nabavi, N., Ettinger, S.L., Crea, F., Wang, Y., Collins, C.C. (2017). Biological and Clinical Evidence for Metabolic Dormancy in Solid Tumors Post Therapy. In: Wang, Y., Crea, F. (eds) Tumor Dormancy and Recurrence. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-319-59242-8_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-59242-8_2

  • Published:

  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-59240-4

  • Online ISBN: 978-3-319-59242-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation