Skip to main content
SpringerLink
Log in

Genetic Basis of Metastasis

  • Chapter
International Manual of Oncology Practice

  • 1300 Accesses

Abstract

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.

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 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Weinberg RA (2007) The biology of cancer, 1st edn. Garland Science, New York, USA.

    Google Scholar 

  2. Cai W, Chen X (2008) Multimodality molecular imaging of tumor angiogenesis. J Nucl Med 49(Suppl 2):113S–128S. doi:10.2967/jnumed.107.045922

    Article  PubMed  CAS  Google Scholar 

  3. Fein MR, Egeblad M (2013) Caught in the act: revealing the metastatic process by live imaging. Dis Model Mech 6(3):580–593. doi:10.1242/dmm.009282

    Article  PubMed Central  PubMed  Google Scholar 

  4. Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2(8):563–572. doi:10.1038/nrc865

    Article  PubMed  CAS  Google Scholar 

  5. Mehlen P, Puisieux A (2006) Metastasis: a question of life or death. Nat Rev Cancer 6(6):449–458. doi:10.1038/nrc1886

    Article  PubMed  CAS  Google Scholar 

  6. Schmidt-Kittler O, Ragg T, Daskalakis A, Granzow M, Ahr A, Blankenstein TJ, … Klein CA (2003) From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression. Proc Natl Acad Sci U S A 100(13):7737–7742. doi:10.1073/pnas.1331931100

  7. DeVita VT (2008) Cancer principles and practice of oncology, 8th edn. Lippincott Williams & Wilkins, Philadelphia

    Google Scholar 

  8. 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):72–77

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  9. DeVita V, Lawrence T, Rosenberg S (eds) (2008) Cancer prinicples & practice of oncology, 8th edn. Lippincott Williams & Wilkins, Philadelphia

    Google Scholar 

  10. Hellman S (2005) Premise, promise, paradigm and prophesy. Nat Clin Pract Oncol 2(7):325

    Article  PubMed  Google Scholar 

  11. 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):6109–6114

    PubMed  CAS  Google Scholar 

  12. 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 U S A 79(18):5547–5551

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  13. Weigelt B, Peterse JL, van’t Veer LJ (2005) Breast cancer metastasis: markers and models. Nat Rev Cancer 5(8):591–602. doi:10.1038/nrc1670

    Article  PubMed  CAS  Google Scholar 

  14. Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119(6):1420–1428. doi:10.1172/jci39104

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  15. Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890. doi:10.1016/j.cell.2009.11.007

    Article  PubMed  CAS  Google Scholar 

  16. van Zijl F, Krupitza G, Mikulits W (2011) Initial steps of metastasis: cell invasion and endothelial transmigration. Mutat Res 728(1–2):23–34. doi:10.1016/j.mrrev.2011.05.002

    Article  PubMed Central  PubMed  Google Scholar 

  17. 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):9078–9084

    Article  PubMed  CAS  Google Scholar 

  18. 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. doi:10.1016/j.bbcan.2008.07.002

    PubMed Central  PubMed  CAS  Google Scholar 

  19. 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):652–661

    Article  PubMed  CAS  Google Scholar 

  20. Friedl P, Wolf K (2003) Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 3(5):362–374. doi:10.1038/nrc1075

    Article  PubMed  CAS  Google Scholar 

  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. doi:10.1158/0008-5472.can-08-0784

    Article  PubMed  CAS  Google Scholar 

  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. doi:10.1158/0008-5472.can-10-0466

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  23. 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. doi:10.1083/jcb.200807195

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  24. Weinberg RA (2013) The biology of cancer (vol. 2), New York, USA.

    Google Scholar 

  25. Hockel M, Vaupel P (2001) Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93(4):266–276

    Article  PubMed  CAS  Google Scholar 

  26. Milani M, Harris AL (2008) Targeting tumour hypoxia in breast cancer. Eur J Cancer 44(18):2766–2773. doi:10.1016/j.ejca.2008.09.025

    Article  PubMed  CAS  Google Scholar 

  27. 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. doi:10.1002/ijc.22436

    Article  PubMed  CAS  Google Scholar 

  28. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, … Zlotnik A (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410(6824):50–56. doi:10.1038/35065016

  29. Zlotnik A (2006) Involvement of chemokine receptors in organ-specific metastasis. Contrib Microbiol 13:191–199. doi:10.1159/000092973

    Article  PubMed  CAS  Google Scholar 

  30. Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, … Massague J (2005) Genes that mediate breast cancer metastasis to lung. Nature 436(7050):518–524. doi:10.1038/nature03799

  31. Khan MA, Chen HC, Zhang D, Fu J (2013) Twist: a molecular target in cancer therapeutics. Tumour Biol 34(5):2497–2506. doi:10.1007/s13277-013-1002-x

    Article  PubMed  CAS  Google Scholar 

  32. 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. doi:10.1242/jcs.069443

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  33. Aguirre-Ghiso JA (2007) Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 7(11):834–846. doi:10.1038/nrc2256

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  34. Baccelli I, Trumpp A (2012) The evolving concept of cancer and metastasis stem cells. J Cell Biol 198(3):281–293. doi:10.1083/jcb.201202014

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  35. 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. doi:10.1186/bcr2333, Epub 2009 Jul 9

    Article  PubMed Central  PubMed  Google Scholar 

  36. 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. doi:10.1158/0008-5472.CAN-07-6874. Review

    Article  PubMed  CAS  Google Scholar 

  37. 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. doi:10.1002/stem.254

    PubMed Central  PubMed  CAS  Google Scholar 

  38. 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. doi:10.1016/j.surg.2011.07.005

    Article  PubMed  Google Scholar 

  39. 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. doi:10.1038/bjc.2012.49

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  40. 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):1253–1264

    Article  PubMed  CAS  Google Scholar 

  41. Zhang NH, Li J, Li Y, Zhang XT, Liao WT, Zhang JY, … Luo RC (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. doi:10.3892/etm.2012.527

  42. Debnath B, Xu S, Grande F, Garofalo A, Neamati N (2013) Small molecule inhibitors of CXCR4. Theranostics 3(1):47–75. doi:10.7150/thno.5376

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  43. Ramsey DM, McAlpine SR (2013) Halting metastasis through CXCR4 inhibition. Bioorg Med Chem Lett 23(1):20–25. doi:10.1016/j.bmcl.2012.10.138

    Article  PubMed  CAS  Google Scholar 

  44. 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. doi:10.1016/j.semcancer.2010.09.005

    Article  PubMed  CAS  Google Scholar 

  45. 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. doi:10.1158/1541-7786.mcr-09-0463

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  46. Kim M, Koh YJ, Kim KE, Koh BI, Nam DH, Alitalo K, … Koh GY (2010) CXCR4 signaling regulates metastasis of chemoresistant melanoma cells by a lymphatic metastatic niche. Cancer Res 70(24):10411–10421. doi:10.1158/0008-5472.can-10-2591

  47. Gros C, Fahy J, Halby L, Dufau I, Erdmann A, Gregoire JM,…Arimondo PB (2012) DNA methylation inhibitors in cancer: recent and future approaches. Biochimie 94(11):2280–2296. doi:10.1016/j.biochi.2012.07.025

  48. Wang Y, Shang Y (2013) Epigenetic control of epithelial-to-mesenchymal transition and cancer metastasis. Exp Cell Res 319(2):160–169. doi:10.1016/j.yexcr.2012.07.019

    Article  PubMed  CAS  Google Scholar 

  49. 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. doi:10.1038/sj.onc.1205699

    Article  PubMed  CAS  Google Scholar 

  50. Gray SG, Baird AM, O’Kelly F, Nikolaidis G, Almgren M, Meunier A, O’Byrne KJ (2012) Gemcitabine reactivates epigenetically silenced genes and functions as a DNA methyltransferase inhibitor. Int J Mol Med 30(6):1505–1511. doi:10.3892/ijmm.2012.1138

    PubMed  CAS  Google Scholar 

  51. Voutsadakis IA (2011) Molecular predictors of gemcitabine response in pancreatic cancer. World J Gastrointest Oncol 3(11):153–164. doi:10.4251/wjgo.v3.i11.153

    Article  PubMed Central  PubMed  Google Scholar 

  52. Blanchard F, Chipoy C (2005) Histone deacetylase inhibitors: new drugs for the treatment of inflammatory diseases? Drug Discov Today 10(3):197–204. doi:10.1016/s1359-6446(04)03309-4

    Article  PubMed  CAS  Google Scholar 

  53. Khan O, La Thangue NB (2012) HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol Cell Biol 90(1):85–94. doi:10.1038/icb.2011.100

    Article  PubMed  CAS  Google Scholar 

  54. Shabason JE, Tofilon PJ, Camphausen K (2010) HDAC inhibitors in cancer care. Oncology (Williston Park) 24(2):180–185

    Google Scholar 

  55. Massague J (2008) TGFbeta in cancer. Cell 134(2):215–230. doi:10.1016/j.cell.2008.07.001

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  56. 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. doi:10.1016/j.tcb.2010.06.006

    Article  PubMed  CAS  Google Scholar 

  57. 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. doi:10.4062/biomolther.2013.072

    Article  CAS  Google Scholar 

  58. 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. doi:10.1517/14728222.11.11.1473

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  59. 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. doi:10.1517/14728222.11.8.1103

    Article  PubMed  CAS  Google Scholar 

  60. Kakkar AK, Levine MN, Kadziola Z, Lemoine NR, Low V, Patel HK,…Williamson RC (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. doi:10.1200/jco.2004.10.002

  61. 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. doi:10.1093/annonc/mdr392

    PubMed  Google Scholar 

  62. 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. doi:10.1111/bjh.12381

    Article  PubMed  CAS  Google Scholar 

  63. 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):445–452

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  64. Mousa SA, Petersen LJ (2009) Anti-cancer properties of low-molecular-weight heparin: preclinical evidence. Thromb Haemost 102(2):258–267. doi:10.1160/th08-12-0832

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Medical Genetics, Faculty of Medicine, Turgut Ozal University, Anadolu Bulvari 16A Gimat, Ankara, Turkey

    Catherine A. Moroski-Erkul, Esin Demir, Esra Gunduz & Mehmet Gunduz M.D., Ph.D.

  2. Departments of Otolaryngology, Faculty of Medicine, Turgut Ozal University, Ankara, Turkey

    Mehmet Gunduz M.D., Ph.D.

Authors
  1. Catherine A. Moroski-Erkul
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Esin Demir
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Esra Gunduz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mehmet Gunduz M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mehmet Gunduz M.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Medical Oncology, University of Algarve, Faro, Portugal

    Ramon Andrade de Mello

  2. edificio 7, ala nascente, 3º andar, University of Algarve, Dept Cie Biomed edificio 7, ala nascente, 3º andar, Faro, Portugal

    Álvaro Tavares

  3. Medical Oncology, University of Athens, Athens, Greece

    Giannis Mountzios

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Moroski-Erkul, C.A., Demir, E., Gunduz, E., Gunduz, M. (2015). Genetic Basis of Metastasis. In: de Mello, R., Tavares, Á., Mountzios, G. (eds) International Manual of Oncology Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-21683-6_5

Download citation

Publish with us

Policies and ethics

Search

Navigation