Genetic Basis of Metastasis

  • Catherine A. Moroski-Erkul
  • Esin Demir
  • Esra Gunduz
  • Mehmet GunduzEmail author


The variation between and among the many types of cancer presents a formidable challenge both to practicing clinicians and medical researchers. There are several characteristics that are common to all cancers such as unrestrained proliferation and evasion of cell death. Another common feature is that of metastasis. Metastasis is “initiated” when primary tumor cells acquire the ability to invade surrounding tissues and eventually develop secondary tumors in distant locations. This process appears to rely not only on changes at the genetic level of tumor cells themselves but also from their interaction with surrounding stromal cells and the immune system. The genetic and molecular changes that give rise to metastatic change are of special interest due to the significant decline in a patient’s prognosis after metastasis has occured. A host of genes and pathways involved in several pathways have been implicated in this process, several of which will be reviewed in detail.


Genetics Cancer Metastasis EMT 


  1. 1.
    Aguirre-Ghiso JA (2007) Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 7(11):834–846. Scholar
  2. 2.
    Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, Kasimir-Bauer S (2009) Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res 11(4):R46. Epub 2009 Jul 9CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Baccelli I, Trumpp A (2012) The evolving concept of cancer and metastasis stem cells. J Cell Biol 198(3):281–293. Scholar
  4. 4.
    Barbolina MV, Kim M, Liu Y, Shepard J, Belmadani A, Miller RJ, Shea LD, Stack MS (2010) Microenvironmental regulation of chemokine (C-X-C-motif) receptor 4 in ovarian carcinoma. Mol Cancer Res 8(5):653–664. Scholar
  5. 5.
    Barthel SR, Gavino JD, Descheny L, Dimitroff CJ (2007) Targeting selectins and selectin ligands in inflammation and cancer. Expert Opin Ther Targets 11(11):1473–1491. Scholar
  6. 6.
    Blanchard F, Chipoy C (2005) Histone deacetylase inhibitors: new drugs for the treatment of inflammatory diseases? Drug Discov Today 10(3):197–204. Scholar
  7. 7.
    Borsig L, Vlodavsky I, Ishai-Michaeli R, Torri G, Vismara E (2011) Sulfated hexasaccharides attenuate metastasis by inhibition of P-selectin and heparanase. Neoplasia 13(5):445–452CrossRefGoogle Scholar
  8. 8.
    Burger JA (2010) Chemokines and chemokine receptors in chronic lymphocytic leukemia (CLL): from understanding the basics towards therapeutic targeting. Semin Cancer Biol 20(6):424–430. Scholar
  9. 9.
    Cai W, Chen X (2008) Multimodality molecular imaging of tumor angiogenesis. J Nucl Med 49(Suppl 2):113S–128S. Scholar
  10. 10.
    Cancer Prinicples & Practice of Oncology (2008) (V. DeVita, MD, T. Lawrence, MD PhD & S. Rosenberg, MD PhD Eds. 8th ed.): Lippincott Williams & WilkinsGoogle Scholar
  11. 11.
    Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2(8):563–572. Scholar
  12. 12.
    Christman JK (2002) 5-Azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene 21(35):5483–5495. Scholar
  13. 13.
    Debnath B, Xu S, Grande F, Garofalo A, Neamati N (2013) Small molecule inhibitors of CXCR4. Theranostics 3(1):47–75. Scholar
  14. 14.
    DeVita VT, MD (2008) Cancer principles and practice of oncology, 8th edn. Lippincott Williams & Wilkins PhiladelphiaGoogle Scholar
  15. 15.
    El-Hariry I, Pignatelli M, Lemoine NR (2001) FGF-1 and FGF-2 regulate the expression of E-cadherin and catenins in pancreatic adenocarcinoma. Int J Cancer 94(5):652–661CrossRefGoogle Scholar
  16. 16.
    Fan X, Khaki L, Zhu TS, Soules ME, Talsma CE, Gul N, Koh C, Zhang J, Li YM, Maciaczyk J, Nikkhah G, Dimeco F, Piccirillo S, Vescovi AL, Eberhart CG (2010) NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells 28(1):5–16. Scholar
  17. 17.
    Fein MR, Egeblad M (2013) Caught in the act: revealing the metastatic process by live imaging. Dis Model Mech 6(3):580–593. Scholar
  18. 18.
    Fong Y, Coit DG, Woodruff JM, Brennan MF (1993) Lymph node metastasis from soft tissue sarcoma in adults. Analysis of data from a prospective database of 1772 sarcoma patients. Ann Surg 217(1):72–77CrossRefGoogle Scholar
  19. 19.
    Francipane MG, Alea MP, Lombardo Y, Todaro M, Medema JP, Stassi G (2008) Crucial role of interleukin-4 in the survival of colon cancer stem cells. Cancer Res 68(11):4022–4025. ReviewCrossRefPubMedGoogle Scholar
  20. 20.
    Friedl P, Wolf K (2003) Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 3(5):362–374. Scholar
  21. 21.
    Friedl P, Wolf K (2008) Tube travel: the role of proteases in individual and collective cancer cell invasion. Cancer Res 68(18):7247–7249. Scholar
  22. 22.
    Giampieri S, Pinner S, Sahai E (2010) Intravital imaging illuminates transforming growth factor beta signaling switches during metastasis. Cancer Res 70(9):3435–3439. Scholar
  23. 23.
    Gil-Bernabe AM, Lucotti S, Muschel RJ (2013) Coagulation and metastasis: what does the experimental literature tell us? Br J Haematol 162(4):433–441. Scholar
  24. 24.
    Gray SG, Baird AM, O’Kelly F, Nikolaidis G, Almgren M, Meunier A et al (2012) Gemcitabine reactivates epigenetically silenced genes and functions as a DNA methyltransferase inhibitor. Int J Mol Med 30(6):1505–1511. Scholar
  25. 25.
    Gros C, Fahy J, Halby L, Dufau I, Erdmann A, Gregoire JM et al (2012) DNA methylation inhibitors in cancer: recent and future approaches. Biochimie 94(11):2280–2296. Scholar
  26. 26.
    Harris JF, Chambers AF, Hill RP, Ling V (1982) Metastatic variants are generated spontaneously at a high rate in mouse KHT tumor. Proc Natl Acad Sci USA 79(18):5547–5551CrossRefGoogle Scholar
  27. 27.
    Hazan RB, Norton L (1998) The epidermal growth factor receptor modulates the interaction of E-cadherin with the actin cytoskeleton. J Biol Chem 273(15):9078–9084CrossRefGoogle Scholar
  28. 28.
    Hellman S (2005) Premise, promise, paradigm and prophesy. Nat Clin Pract Oncol 2(7):325CrossRefGoogle Scholar
  29. 29.
    Hiller DJ, Meschonat C, Kim R, Li BD, Chu QD (2011) Chemokine receptor CXCR4 level in primary tumors independently predicts outcome for patients with locally advanced breast cancer. Surgery 150(3):459–465. Scholar
  30. 30.
    Hockel M, Vaupel P (2001) Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93(4):266–276CrossRefGoogle Scholar
  31. 31.
    Iiizumi M, Liu W, Pai SK, Furuta E, Watabe K (2008) Drug development against metastasis-related genes and their pathways: a rationale for cancer therapy. Biochim Biophys Acta 1786(2):87–104. Scholar
  32. 32.
    Kakkar AK, Levine MN, Kadziola Z, Lemoine NR, Low V, Patel HK et al (2004) Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol 22(10):1944–1948. Scholar
  33. 33.
    Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119(6):1420–1428. Scholar
  34. 34.
    Khan MA, Chen HC, Zhang D, Fu J (2013) Twist: a molecular target in cancer therapeutics. Tumour Biol 34(5):2497–2506. Scholar
  35. 35.
    Khan O, La Thangue NB (2012) HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol Cell Biol 90(1):85–94. Scholar
  36. 36.
    Kim M, Koh YJ, Kim KE, Koh BI, Nam DH, Alitalo K et al (2010) CXCR4 signaling regulates metastasis of chemoresistant melanoma cells by a lymphatic metastatic niche. Cancer Res 70(24):10411–10421. Scholar
  37. 37.
    Ludwig RJ, Schon MP, Boehncke WH (2007) P-selectin: a common therapeutic target for cardiovascular disorders, inflammation and tumour metastasis. Expert Opin Ther Targets 11(8):1103–1117. Scholar
  38. 38.
    Mandala M, Falanga A, Roila F (2011) Management of venous thromboembolism (VTE) in cancer patients: ESMO clinical practice guidelines. Ann Oncol 22(Suppl 6):vi85–vi92. Scholar
  39. 39.
    Massague J (2008) TGFbeta in Cancer. Cell 134(2):215–230. Scholar
  40. 40.
    Mehlen P, Puisieux A (2006) Metastasis: a question of life or death. Nat Rev Cancer 6(6):449–458. Scholar
  41. 41.
    Milani M, Harris AL (2008) Targeting tumour hypoxia in breast cancer. Eur J Cancer 44(18):2766–2773. Scholar
  42. 42.
    Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD et al (2005) Genes that mediate breast cancer metastasis to lung. Nature 436(7050):518–524. Scholar
  43. 43.
    Mousa SA, Petersen LJ (2009) Anti-cancer properties of low-molecular-weight heparin: preclinical evidence. Thromb Haemost 102(2):258–267. Scholar
  44. 44.
    Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME et al (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410(6824):50–56. Scholar
  45. 45.
    Pardali E, Goumans MJ, ten Dijke P (2010) Signaling by members of the TGF-beta family in vascular morphogenesis and disease. Trends Cell Biol 20(9):556–567. Scholar
  46. 46.
    Popple A, Durrant LG, Spendlove I, Rolland P, Scott IV, Deen S, Ramage JM (2012) The chemokine, CXCL12, is an independent predictor of poor survival in ovarian cancer. Br J Cancer 106(7):1306–1313. Scholar
  47. 47.
    Ramsey DM, McAlpine SR (2013) Halting metastasis through CXCR4 inhibition. Bioorg Med Chem Lett 23(1):20–25. Scholar
  48. 48.
    Riechelmann H, Sauter A, Golze W, Hanft G, Schroen C, Hoermann K, Erhardt T, Gronau S (2008) Phase I trial with the CD44v6-targeting immunoconjugate bivatuzumab mertansine in head and neck squamous cell carcinoma. Oral Oncol 44(9):823–829. Epub 2008 Jan 18
  49. 49.
    Sabeh F, Shimizu-Hirota R, Weiss SJ (2009) Protease-dependent versus -independent cancer cell invasion programs: three-dimensional amoeboid movement revisited. J Cell Biol 185(1):11–19. Scholar
  50. 50.
    Schmidt-Kittler O, Ragg T, Daskalakis A, Granzow M, Ahr A, Blankenstein TJ et al (2003) From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression. Proc Natl Acad Sci USA 100(13):7737–7742. Scholar
  51. 51.
    Shabason JE, Tofilon PJ, Camphausen K (2010) HDAC inhibitors in cancer care. Oncology (Williston Park) 24(2):180–185Google Scholar
  52. 52.
    Sheen YY, Kim MJ, Park SA, Park SY, Nam JS (2013) Targeting the transforming growth factor-beta signaling in cancer therapy. Biomol Ther (Seoul) 21(5):323–331. Scholar
  53. 53.
    Stoletov K, Kato H, Zardouzian E, Kelber J, Yang J, Shattil S, Klemke R (2010) Visualizing extravasation dynamics of metastatic tumor cells. J Cell Sci 123(Pt 13):2332–2341. Scholar
  54. 54.
    Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890. Scholar
  55. 55.
    Trastour C, Benizri E, Ettore F, Ramaioli A, Chamorey E, Pouyssegur J, Berra E (2007) HIF-1alpha and CA IX staining in invasive breast carcinomas: prognosis and treatment outcome. Int J Cancer 120(7):1451–1458. Scholar
  56. 56.
    van Zijl F, Krupitza G, Mikulits W (2011) Initial steps of metastasis: cell invasion and endothelial transmigration. Mutat Res 728(1-2):23–34. Scholar
  57. 57.
    Voutsadakis IA (2011) Molecular predictors of gemcitabine response in pancreatic cancer. World J Gastrointest Oncol 3(11):153–164. Scholar
  58. 58.
    Waghorne C, Thomas M, Lagarde A, Kerbel RS, Breitman ML (1988) Genetic evidence for progressive selection and overgrowth of primary tumors by metastatic cell subpopulations. Cancer Res 48(21):6109–6114PubMedGoogle Scholar
  59. 59.
    Wang Y, Shang Y (2013) Epigenetic control of epithelial-to-mesenchymal transition and cancer metastasis. Exp Cell Res 319(2):160–169. Scholar
  60. 60.
    Weigelt B, Peterse JL, van’t Veer LJ (2005) Breast cancer metastasis: markers and models. Nat Rev Cancer 5(8):591–602. Scholar
  61. 61.
    Weinberg RA (2013) The biology of cancer, vol 2. Garland Science, New YorkGoogle Scholar
  62. 62.
    Weinberg RA (2007) The biology of cancer, 1st edn. Garland Science, New YorkGoogle Scholar
  63. 63.
    Yao X, Zhou L, Han S, Chen Y (2011) High expression of CXCR4 and CXCR7 predicts poor survival in gallbladder cancer. J Int Med Res 39(4):1253–1264CrossRefGoogle Scholar
  64. 64.
    Zhang NH, Li J, Li Y, Zhang XT, Liao WT, Zhang JY et al (2012) Co-expression of CXCR4 and CD133 proteins is associated with poor prognosis in stage II-III colon cancer patients. Exp Ther Med 3(6):973–982. Scholar
  65. 65.
    Zlotnik A (2006) Involvement of chemokine receptors in organ-specific metastasis. Contrib Microbiol 13:191–199. Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Catherine A. Moroski-Erkul
    • 1
    • 2
  • Esin Demir
    • 3
    • 2
  • Esra Gunduz
    • 4
    • 2
  • Mehmet Gunduz
    • 4
    • 2
    • 5
    Email author
  1. 1.Intellia Therapeutics, IncCambridgeUSA
  2. 2.Departments of Medical GeneticsTurgut Ozal UniversityAnkaraTurkey
  3. 3.Koc UniversityIstanbulTurkey
  4. 4.Wakayama Medical UniversityWakayamaJapan
  5. 5.Otolaryngology, Faculty of MedicineTurgut Ozal UniversityAnkaraTurkey

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