Skip to main content

Advertisement

SpringerLink
Log in

Metastasis: an early event in cancer progression

  • Review – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Metastasis is the leading cause of death for a majority of cancer patients, and thus the need to understand the biology of metastasis becomes increasingly acute. When metastasis is initiated in tumor progression remains obscure. Better understanding of mechanisms regulating acquisition of metastatic ability in tumor cells will provide novel therapeutic targets and prevention of metastasis in clinics accompanied with the treatment of the primary tumor might be helpful in reducing metastasis-related mortality.

Methods

A literature search was performed in multiple electronic databases. Research papers from clinical reports to experimental studies on metastasis were analyzed.

Results

The article discusses tumor heterogeneity and genomic instability in the context of metastasis and tumor cell dissemination. And then we review biological mechanism of metastasis at an early stage in both intracellular (CSCs and CTCs) and extracellular (microenvironment) context. Finally, current development of anti-metastatic therapies is summarized.

Conclusions

Metastasis could be initiated at an early point of tumor progression. Therefore, early intervention on metastasis should be applied among cancer patients in clinical settings.

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

References

  • Aguirre-Ghiso JA, Liu D, Mignatti A, Kovalski K, Ossowski L (2001) Urokinase receptor and fibronectin regulate the ERK(MAPK) to p38(MAPK) activity ratios that determine carcinoma cell proliferation or dormancy in vivo. Mol Biol Cell 12(4):863–879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Al-Assar O, Demiciorglu F, Lunardi S, Gaspar-Carvalho MM, McKenna WG, Muschel RM et al (2014) Contextual regulation of pancreatic cancer stem cell phenotype and radioresistance by pancreatic stellate cells. Radiother Oncol 111(2):243–251

    Article  PubMed  Google Scholar 

  • Alderton GK (2015) Tumour microenvironment: driving relapse. Nat Rev Cancer 15(4):195

    Article  CAS  PubMed  Google Scholar 

  • Alix-Panabières C, Pantel K (2014) Challenges in circulating tumour cell research. Nat Rev Cancer 14(9):623–631

    Article  PubMed  CAS  Google Scholar 

  • Balic M, Lin H, Young L, Hawes D, Giuliano A, McNamara G et al (2006) Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res Off J Am Assoc Cancer Res 12(19):5615–5621. doi:10.1158/1078-0432.ccr-06-0169

    Article  CAS  Google Scholar 

  • Becker PS (2012) Dependence of acute myeloid leukemia on adhesion within the bone marrow microenvironment. Sci World J 2012:856467. doi:10.1100/2012/856467

    Article  CAS  Google Scholar 

  • Bedenne L, Michel P, Bouche O, Milan C, Mariette C, Conroy T et al (2007) Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol Off J Am Soc Clin Oncol 25(10):1160–1168. doi:10.1200/jco.2005.04.7118

    Article  CAS  Google Scholar 

  • Beliveau A, Mott JD, Lo A, Chen EI, Koller AA, Yaswen P et al (2010) Raf-induced MMP9 disrupts tissue architecture of human breast cells in three-dimensional culture and is necessary for tumor growth in vivo. Genes Dev 24(24):2800–2811. doi:10.1101/gad.1990410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bernards R, Weinberg RA (2002) Metastasis genes: a progression puzzle. Nature 418(6900):823

    Article  CAS  PubMed  Google Scholar 

  • Bissell MJ, Kenny PA, Radisky DC (2005) Microenvironmental regulators of tissue structure and function also regulate tumor induction and progression: the role of extracellular matrix and its degrading enzymes. Cold Spring Harb Symp Quant Biol 70:343–356. doi:10.1101/sqb.2005.70.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bissig H, Richter J, Desper R, Meier V, Schraml P, Schaffer AA et al (1999) Evaluation of the clonal relationship between primary and metastatic renal cell carcinoma by comparative genomic hybridization. Am J Pathol 155(1):267–274. doi:10.1016/s0002-9440(10)65120-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H et al (2010) Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467(7315):596–599. doi:10.1038/nature09454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bourzac K (2014) Biology: three known unknowns. Nature 509(7502):S69–S71. doi:10.1038/509S69a

    Article  CAS  PubMed  Google Scholar 

  • Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T (2005) Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression. Nat Rev Cancer 5(9):744–749. doi:10.1038/nrc1694

    Article  CAS  PubMed  Google Scholar 

  • Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes RC et al (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353(8):793–802. doi:10.1056/NEJMoa050434

    Article  CAS  PubMed  Google Scholar 

  • Catena R, Bhattacharya N, El Rayes T, Wang S, Choi H, Gao D et al (2013) Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1. Cancer Discov 3(5):578–589. doi:10.1158/2159-8290.cd-12-0476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Charafe-Jauffret E, Ginestier C, Iovino F, Tarpin C, Diebel M, Esterni B et al (2010) Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res 16(1):45–55. doi:10.1158/1078-0432.ccr-09-1630

    Article  CAS  Google Scholar 

  • Chen A, Cuevas I, Kenny PA, Miyake H, Mace K, Ghajar C et al (2009) Endothelial cell migration and vascular endothelial growth factor expression are the result of loss of breast tissue polarity. Cancer Res 69(16):6721–6729. doi:10.1158/0008-5472.can-08-4069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng L, Bostwick DG, Li G, Wang Q, Hu N, Vortmeyer AO et al (1999) Allelic imbalance in the clonal evolution of prostate carcinoma. Cancer 85(9):2017–2022

    Article  CAS  PubMed  Google Scholar 

  • Chinni SR, Sivalogan S, Dong Z, Filho JC, Deng X, Bonfil RD et al (2006) CXCL12/CXCR4 signaling activates Akt-1 and MMP-9 expression in prostate cancer cells: the role of bone microenvironment-associated CXCL12. Prostate 66(1):32–48. doi:10.1002/pros.20318

    Article  CAS  PubMed  Google Scholar 

  • Clevers H (ed) (2015) Tracking cancer stem cells: the intestine paradigm. 2015 AAAS Annual meeting (12–16 February 2015): aaas

  • Cohen SJ, Alpaugh RK, Gross S, O’Hara SM, Smirnov DA, Terstappen LW et al (2006) Isolation and characterization of circulating tumor cells in patients with metastatic colorectal cancer. Clin Colorectal Cancer 6(2):125–132

    Article  CAS  PubMed  Google Scholar 

  • Coussens LM, Fingleton B, Matrisian LM (2002) Matrix metalloproteinase inhibitors and cancer—trials and tribulations. Science 295(5564):2387–2392

    Article  CAS  PubMed  Google Scholar 

  • Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC et al (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351(8):781–791

    Article  CAS  PubMed  Google Scholar 

  • Croker AK, Goodale D, Chu J, Postenka C, Hedley BD, Hess DA et al (2009) High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic ability. J Cell Mol Med 13(8b):2236–2252. doi:10.1111/j.1582-4934.2008.00455.x

    Article  PubMed  Google Scholar 

  • Dieter SM, Ball CR, Hoffmann CM, Nowrouzi A, Herbst F, Zavidij O et al (2011) Distinct types of tumor-initiating cells form human colon cancer tumors and metastases. Cell Stem Cell 9(4):357–365. doi:10.1016/j.stem.2011.08.010

    Article  CAS  PubMed  Google Scholar 

  • Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ et al (2003) In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 17(10):1253–1270. doi:10.1101/gad.1061803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Emlet DR, Gupta P, Holgado-Madruga M, Del Vecchio CA, Mitra SS, Han S-Y et al (2014) Targeting a glioblastoma cancer stem-cell population defined by EGF receptor variant III. Cancer Res 74(4):1238–1249

    Article  CAS  PubMed  Google Scholar 

  • Engel J, Eckel R, Kerr J, Schmidt M, Fürstenberger G, Richter R et al (2003) The process of metastasisation for breast cancer. Eur J Cancer 39(12):1794–1806

    Article  CAS  PubMed  Google Scholar 

  • Eyles J, Puaux AL, Wang X, Toh B, Prakash C, Hong M et al (2010) Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J Clin Investig 120(6):2030–2039. doi:10.1172/jci42002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fehm T, Braun S, Muller V, Janni W, Gebauer G, Marth C et al (2006) A concept for the standardized detection of disseminated tumor cells in bone marrow from patients with primary breast cancer and its clinical implementation. Cancer 107(5):885–892

    Article  PubMed  Google Scholar 

  • Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA et al (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363(9):809–819. doi:10.1056/NEJMoa1002011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Furger KA, Menon RK, Tuck AB, Bramwell VH, Chambers AF (2001) The functional and clinical roles of osteopontin in cancer and metastasis. Curr Mol Med 1(5):621–632

    Article  CAS  PubMed  Google Scholar 

  • Gao H, Chakraborty G, Lee-Lim AP, Mo Q, Decker M, Vonica A et al (2012) The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell 150(4):764–779. doi:10.1016/j.cell.2012.06.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao F, Zhao ZL, Zhao WT, Fan QR, Wang SC, Li J et al (2013) miR-9 modulates the expression of interferon-regulated genes and MHC class I molecules in human nasopharyngeal carcinoma cells. Biochem Biophys Res Commun 431(3):610–616. doi:10.1016/j.bbrc.2012.12.097

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez-Angulo AM, Litton JK, Broglio KR, Meric-Bernstam F, Rakkhit R, Cardoso F et al (2009) High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive, node-negative tumors 1 cm or smaller. J Clin Oncol Off J Am Soc Clin Oncol 27(34):5700–5706. doi:10.1200/jco.2009.23.2025

    Article  Google Scholar 

  • Govaert KM, Emmink BL, Nijkamp MW, Cheung ZJ, Steller EJ, Fatrai S et al (2014) Hypoxia after liver surgery imposes an aggressive cancer stem cell phenotype on residual tumor cells. Ann Surg 259(4):750–759

    Article  PubMed  Google Scholar 

  • Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G et al (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10(5):593–601. doi:10.1038/ncb1722

    Article  CAS  PubMed  Google Scholar 

  • Guo W, Xue J, Shi J, Li N, Shao Y, Yu X et al (2010) Proteomics analysis of distinct portal vein tumor thrombi in hepatocellular carcinoma patients. J Proteome Res 9(8):4170–4175

    Article  CAS  PubMed  Google Scholar 

  • Gutschner T, Diederichs S (2012) The hallmarks of cancer: a long non-coding RNA point of view. RNA Biol 9(6):703–719. doi:10.4161/rna.20481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harmer MH (ed) (1978) TNM classification of malignant tumours. The Union

  • Hayes DF, Smerage JB (2009) Circulating tumor cells. Progr Mol Biol Transl Sci 95:95–112

    Article  Google Scholar 

  • Hood JL, San RS, Wickline SA (2011) Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res 71(11):3792–3801. doi:10.1158/0008-5472.can-10-4455

    Article  CAS  PubMed  Google Scholar 

  • Hu Y, Yu X, Liu S, Liu S (2013) Cancer stem cells: a shifting subpopulation of cells with stemness? Med Hypotheses 80(5):649–655

    Article  CAS  PubMed  Google Scholar 

  • Huang S, Chen Y, Podsypanina K, Li Y (2008) Comparison of expression profiles of metastatic versus primary mammary tumors in MMTV-Wnt-1 and MMTV-Neu transgenic mice. Neoplasia (New York, NY) 10(2):118–124

    Article  CAS  Google Scholar 

  • Humphries B, Yang C (2015) The microRNA-200 family: small molecules with novel roles in cancer development, progression and therapy. Oncotarget 6(9):6472–6498

    Article  PubMed  PubMed Central  Google Scholar 

  • Husemann Y, Geigl JB, Schubert F, Musiani P, Meyer M, Burghart E et al (2008) Systemic spread is an early step in breast cancer. Cancer Cell 13(1):58–68. doi:10.1016/j.ccr.2007.12.003

    Article  PubMed  CAS  Google Scholar 

  • Ignatiadis M, Xenidis N, Perraki M, Apostolaki S, Politaki E, Kafousi M et al (2007) Different prognostic value of cytokeratin-19 mRNA positive circulating tumor cells according to estrogen receptor and HER2 status in early-stage breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 25(33):5194–5202. doi:10.1200/jco.2007.11.7762

    Article  Google Scholar 

  • Jackisch C, Scappaticci FA, Heinzmann D, Bisordi F, Schreitmüller T, Gv M et al (2015) Neoadjuvant breast cancer treatment as a sensitive setting for trastuzumab biosimilar development and extrapolation. Future Oncol 11(1):61–71

    Article  CAS  PubMed  Google Scholar 

  • Ji P, Diederichs S, Wang W, Boing S, Metzger R, Schneider PM et al (2003) MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 22(39):8031–8041. doi:10.1038/sj.onc.1206928

    Article  PubMed  CAS  Google Scholar 

  • Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schutte J et al (2012) 1 versus 3 years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA 307(12):1265–1272. doi:10.1001/jama.2012.347

    Article  CAS  PubMed  Google Scholar 

  • Jung EK, Leung E, Barker D (2016) Synthesis and biological activity of pyrrole analogues of combretastatin A-4. Bioorg Med Chem Lett 26(13):3001–3005. doi:10.1016/j.bmcl.2016.05.026

    Article  CAS  PubMed  Google Scholar 

  • Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C et al (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3(6):537–549

    Article  CAS  PubMed  Google Scholar 

  • Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C et al (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438(7069):820–827. doi:10.1038/nature04186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim MY, Oskarsson T, Acharyya S, Nguyen DX, Zhang XH, Norton L et al (2009) Tumor self-seeding by circulating cancer cells. Cell 139(7):1315–1326. doi:10.1016/j.cell.2009.11.025

    Article  PubMed  PubMed Central  Google Scholar 

  • Klein CA (2009) Parallel progression of primary tumours and metastases. Nat Rev Cancer 9(4):302–312. doi:10.1038/nrc2627

    Article  CAS  PubMed  Google Scholar 

  • Klein CA, Hölzel D (2006) Systemic cancer progression and tumor dormancy: mathematical models meet single cell genomics. Cell Cycle 5(16):1788–1798

    Article  CAS  PubMed  Google Scholar 

  • Klein CA, Blankenstein TJ, Schmidt-Kittler O, Petronio M, Polzer B, Stoecklein NH et al (2002) Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer. Lancet (London, England) 360(9334):683–689. doi:10.1016/s0140-6736(02)09838-0

    Article  CAS  Google Scholar 

  • Kogo R, Shimamura T, Mimori K, Kawahara K, Imoto S, Sudo T et al (2011) Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res 71(20):6320–6326. doi:10.1158/0008-5472.can-11-1021

    Article  CAS  PubMed  Google Scholar 

  • Koppelmans V, de Groot M, de Ruiter MB, Boogerd W, Seynaeve C, Vernooij MW et al (2014) Global and focal white matter integrity in breast cancer survivors 20 years after adjuvant chemotherapy. Hum Brain Mapp 35(3):889–899

    Article  PubMed  Google Scholar 

  • Korpal M, Lee ES, Hu G, Kang Y (2008) The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem 283(22):14910–14914. doi:10.1074/jbc.C800074200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koscielny S, Tubiana M, Le MG, Valleron AJ, Mouriesse H, Contesso G et al (1984) Breast cancer: relationship between the size of the primary tumour and the probability of metastatic dissemination. Br J Cancer 49(6):709–715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krebs MG, Sloane R, Priest L, Lancashire L, Hou J-M, Greystoke A et al (2011) Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. J Clin Oncol 29(12):1556–1563

    Article  PubMed  Google Scholar 

  • Kucia M, Reca R, Miekus K, Wanzeck J, Wojakowski W, Janowska-Wieczorek A et al (2005) Trafficking of normal stem cells and metastasis of cancer stem cells involve similar mechanisms: pivotal role of the SDF-1-CXCR4 axis. Stem Cells 23(7):879–894. doi:10.1634/stemcells.2004-0342

    Article  CAS  PubMed  Google Scholar 

  • Kuukasjarvi T, Karhu R, Tanner M, Kahkonen M, Schaffer A, Nupponen N et al (1997) Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer. Cancer Res 57(8):1597–1604

    CAS  PubMed  Google Scholar 

  • Lamouille S, Xu J, Derynck R (2014) Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol 15(3):178–196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA (2014) Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res 2014:149185

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Li J, Chen L, Zhang X, Zhang Y, Liu H, Sun B et al. (2014) Detection of circulating tumor cells in hepatocellular carcinoma using antibodies against asialoglycoprotein receptor, carbamoyl phosphate synthetase 1 and pan-cytokeratin. PloS One 9(4):e96185. doi:10.1371/journal.pone.0096185

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lim E, Metzger-Filho O, Winer EP (2012) The natural history of hormone receptor-positive breast cancer. Oncology 26(688–694):696

    Google Scholar 

  • Ling H, Vincent K, Pichler M, Fodde R, Berindan-Neagoe I, Slack FJ et al. (2015) Junk DNA and the long non-coding RNA twist in cancer genetics. Oncogene 34(39):5003–5011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H et al (2011) The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med 17(2):211–215. doi:10.1038/nm.2284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu S, Guo W, Shi J, Li N, Yu X, Xue J et al (2012) MicroRNA-135a contributes to the development of portal vein tumor thrombus by promoting metastasis in hepatocellular carcinoma. J Hepatol 56(2):389–396. doi:10.1016/j.jhep.2011.08.008

    Article  CAS  PubMed  Google Scholar 

  • Liu S, Li N, Yu X, Xiao X, Cheng K, Hu J et al (2013) Expression of intercellular adhesion molecule 1 by hepatocellular carcinoma stem cells and circulating tumor cells. Gastroenterology 144(5):1031–41.e10. doi:10.1053/j.gastro.2013.01.046

    Article  PubMed  CAS  Google Scholar 

  • Loberg RD, Bradley DA, Tomlins SA, Chinnaiyan AM, Pienta KJ (2007) The lethal phenotype of cancer: the molecular basis of death due to malignancy. CA Cancer J Clin 57(4):225–241

    Article  PubMed  Google Scholar 

  • Lu X, Mu E, Wei Y, Riethdorf S, Yang Q, Yuan M et al (2011) VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging alpha4beta1-positive osteoclast progenitors. Cancer Cell 20(6):701–714. doi:10.1016/j.ccr.2011.11.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu H, Clauser KR, Tam WL, Fröse J, Ye X, Eaton EN et al (2014a) A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat Cell Biol 16(11):1105–1117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu H, Yan CH, Bian Y, Chen Z, Van Waes C (2014b) CK2 phosphorylates and inhibits tumor suppressor TAp73 function to promote cancer stem cell gene expression and phenotype in head and neck cancer. Cancer Res 74(19):1925

    Article  Google Scholar 

  • Martin SS, Ridgeway AG, Pinkas J, Lu Y, Reginato MJ, Koh EY et al (2004) A cytoskeleton-based functional genetic screen identifies Bcl-xL as an enhancer of metastasis, but not primary tumor growth. Oncogene 23(26):4641–4645. doi:10.1038/sj.onc.1207595

    Article  CAS  PubMed  Google Scholar 

  • Mitelman F, Johansson B, Mertens F (2007) The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer 7(4):233–245. doi:10.1038/nrc2091

    Article  CAS  PubMed  Google Scholar 

  • Moreira IS, Fernandes PA, Ramos MJ (2007) Vascular endothelial growth factor (VEGF) inhibition—a critical review. Anti Cancer Agents Med Chem 7(2):223–245

    Article  CAS  Google Scholar 

  • Mueller MM, Fusenig NE (2004) Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4(11):839–849

    Article  CAS  PubMed  Google Scholar 

  • Nagle JA, Ma Z, Byrne MA, White MF, Shaw LM (2004) Involvement of insulin receptor substrate 2 in mammary tumor metastasis. Mol Cell Biol 24(22):9726–9735. doi:10.1128/mcb.24.22.9726-9735.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L et al (2007) Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450(7173):1235–1239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nasulewicz A, Wietrzyk J, Wolf FI, Dzimira S, Madej J, Maier JA et al (2004) Magnesium deficiency inhibits primary tumor growth but favors metastasis in mice. Biochim Biophys Acta 1739(1):26–32. doi:10.1016/j.bbadis.2004.08.003

    Article  CAS  PubMed  Google Scholar 

  • Nishimura E (2014) Melanoma heterogeneity and cancer stem cell. Gan to kagaku ryoho Cancer Chemother 41(4):433–436

    Google Scholar 

  • Oskarsson T, Batlle E, Massague J (2014) Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell 14(3):306–321. doi:10.1016/j.stem.2014.02.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  Google Scholar 

  • Pang R, Law WL, Chu AC, Poon JT, Lam CS, Chow AK et al (2010) A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell 6(6):603–615. doi:10.1016/j.stem.2010.04.001

    Article  CAS  PubMed  Google Scholar 

  • Pantel K, Brakenhoff RH (2004) Dissecting the metastatic cascade. Nat Rev Cancer 4(6):448–456. doi:10.1038/nrc1370

    Article  CAS  PubMed  Google Scholar 

  • Pantel K, Muller V, Auer M, Nusser N, Harbeck N, Braun S (2003) Detection and clinical implications of early systemic tumor cell dissemination in breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res 9(17):6326–6334

    CAS  Google Scholar 

  • Pantel K, Brakenhoff RH, Brandt B (2008) Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer 8(5):329–340. doi:10.1038/nrc2375

    Article  CAS  PubMed  Google Scholar 

  • Papayannopoulou T (2004) Current mechanistic scenarios in hematopoietic stem/progenitor cell mobilization. Blood 103(5):1580–1585. doi:10.1182/blood-2003-05-1595

    Article  CAS  PubMed  Google Scholar 

  • Pavlidis N, Khaled H, Gaafar R (2015) A mini review on cancer of unknown primary site: a clinical puzzle for the oncologists. J Adv Res 6(3):375–382

    Article  PubMed  Google Scholar 

  • Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G et al (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18(6):883–891. doi:10.1038/nm.2753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Piergentili R, Carradori S, Gulia C, De Monte C, Cristini C, Grande P et al (2014) Bladder cancer: innovative approaches beyond the diagnosis. Curr Med Chem 21(20):2219–2236

    Article  CAS  PubMed  Google Scholar 

  • Podsypanina K, Politi K, Beverly LJ, Varmus HE (2008a) Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras. Proc Natl Acad Sci USA 105(13):5242–5247. doi:10.1073/pnas.0801197105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Podsypanina K, Du Y-CN, Jechlinger M, Beverly LJ, Hambardzumyan S, Varmus H (2008b) Seeding and propagation of untransformed mouse mammary cells in the lung. Science 321(5897):1841–1844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Popiolek M, Rider JR, Andrén O, Andersson S-O, Holmberg L, Adami H-O et al (2013) Natural history of early, localized prostate cancer: a final report from three decades of follow-up. Eur Urol 63(3):428–435

    Article  PubMed  Google Scholar 

  • Qin T, Yuan Z, Peng R, Bai B, Shi Y, Teng X et al (2013) HER2-positive breast cancer patients receiving trastuzumab treatment obtain prognosis comparable with that of HER2-negative breast cancer patients. Oncol Targets Ther 6:341–347. doi:10.2147/ott.s40851

    Article  CAS  Google Scholar 

  • Rana S, Malinowska K, Zoller M (2013) Exosomal tumor microRNA modulates premetastatic organ cells. Neoplasia (New York, NY) 15(3):281–295

    Article  CAS  Google Scholar 

  • Resovi A, Pinessi D, Chiorino G, Taraboletti G (2014) Current understanding of the thrombospondin-1 interactome. Matrix Biol J Int Soc Matrix Biol 37:83–91. doi:10.1016/j.matbio.2014.01.012

    Article  CAS  Google Scholar 

  • Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F et al (2012) EMT and dissemination precede pancreatic tumor formation. Cell 148(1–2):349–361. doi:10.1016/j.cell.2011.11.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E et al (2012) Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 13(3):239–246. doi:10.1016/s1470-2045(11)70393-x

    Article  CAS  PubMed  Google Scholar 

  • Sarvi S, Mackinnon AC, Avlonitis N, Bradley M, Rintoul RC, Rassl DM et al (2014) CD133+ cancer stem-like cells in small cell lung cancer are highly tumorigenic and chemoresistant but sensitive to a novel neuropeptide antagonist. Cancer Res 74(5):1554–1565

    Article  CAS  PubMed  Google Scholar 

  • Schardt JA, Meyer M, Hartmann CH, Schubert F, Schmidt-Kittler O, Fuhrmann C et al (2005) Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer. Cancer Cell 8(3):227–239. doi:10.1016/j.ccr.2005.08.003

    Article  CAS  PubMed  Google Scholar 

  • Schmidt F, Efferth T (2016) Tumor heterogeneity, single-cell sequencing, and drug resistance. Pharmaceuticals (Basel, Switzerland). doi:10.3390/ph9020033

    PubMed  Google Scholar 

  • 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. doi:10.1073/pnas.1331931100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seton-Rogers S (2015) Non-coding RNA: stressed to bits. Nat Rev Cancer 15(6):320

    Article  CAS  PubMed  Google Scholar 

  • Shaked Y, McAllister S, Fainaru O, Almog N (2014) Tumor dormancy and the angiogenic switch: possible implications of bone marrow-derived cells. Curr Pharm Des 20(30):4920–4933

    Article  CAS  PubMed  Google Scholar 

  • Shannon KE, Keene JL, Settle SL, Duffin TD, Nickols MA, Westlin M et al (2004) Anti-metastatic properties of RGD-peptidomimetic agents S137 and S247. Clin Exp Metastasis 21(2):129–138

    Article  CAS  PubMed  Google Scholar 

  • Shen CH, Kim SH, Trousil S, Frederick DT, Piris A, Yuan P et al (2016) Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma. Nat Med. doi:10.1038/nm.4155

    Google Scholar 

  • Shlush LI, Zandi S, Mitchell A, Chen WC, Brandwein JM, Gupta V et al (2014) Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 506(7488):328–333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shuqun C, Mengchao W, Han C, Feng S, Jiahe Y, Guanghui D et al (2007) Tumor thrombus types influence the prognosis of hepatocellular carcinoma with the tumor thrombi in the portal vein. Hepatogastroenterology 54(74):499–502

    PubMed  Google Scholar 

  • Sosa MS, Avivar-Valderas A, Bragado P, Wen HC, Aguirre-Ghiso JA (2011) ERK1/2 and p38alpha/beta signaling in tumor cell quiescence: opportunities to control dormant residual disease. Clin Cancer Res Off J Am Assoc Cancer Res 17(18):5850–5857. doi:10.1158/1078-0432.ccr-10-2574

    Article  CAS  Google Scholar 

  • Sosa MS, Bragado P, Aguirre-Ghiso JA (2014) Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat Rev Cancer 14(9):611–622. doi:10.1038/nrc3793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steeg PS (2006) Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12(8):895–904. doi:10.1038/nm1469

    Article  CAS  PubMed  Google Scholar 

  • Stoecklein NH, Hosch SB, Bezler M, Stern F, Hartmann CH, Vay C et al (2008) Direct genetic analysis of single disseminated cancer cells for prediction of outcome and therapy selection in esophageal cancer. Cancer Cell 13(5):441–453. doi:10.1016/j.ccr.2008.04.005

    Article  CAS  PubMed  Google Scholar 

  • Takebe N, Harris PJ, Warren RQ, Ivy SP (2011) Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat Rev Clin Oncol 8(2):97–106

    Article  CAS  PubMed  Google Scholar 

  • Tanase K, Thies ED, Mäder U, Reiners C, Verburg FA (2015) The TNM system (version 7) is the most accurate staging system for the prediction of loss of life expectancy in differentiated thyroid cancer. Clin Endocrinol (Oxf). doi:10.1111/cen.12765

    Google Scholar 

  • Todaro M, Gaggianesi M, Catalano V, Benfante A, Iovino F, Biffoni M et al (2014) CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell 14(3):342–356

    Article  CAS  PubMed  Google Scholar 

  • Van’t Veer LJ, Dai H, Van De Vijver MJ, He YD, Hart AA, Mao M et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415(6871):530–536

    Article  Google Scholar 

  • Wang X, Adjei AA (2015) Lung cancer and metastasis: new opportunities and challenges. Cancer Metastasis Rev. doi:10.1007/s10555-015-9562-4

    Google Scholar 

  • Weckermann D, Polzer B, Ragg T, Blana A, Schlimok G, Arnholdt H et al (2009) Perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer. J Clin Oncol Off J Am Soc Clin Oncol 27(10):1549–1556. doi:10.1200/jco.2008.17.0563

    Article  Google Scholar 

  • Weng D, Penzner JH, Song B, Koido S, Calderwood SK, Gong J (2012) Metastasis is an early event in mouse mammary carcinomas and is associated with cells bearing stem cell markers. Breast Cancer Res BCR 14(1):R18. doi:10.1186/bcr3102

    Article  CAS  PubMed  Google Scholar 

  • Wood SL, Pernemalm M, Crosbie PA, Whetton AD (2014) The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets. Cancer Treat Rev 40(4):558–566

    Article  CAS  PubMed  Google Scholar 

  • Wu X, Northcott PA, Dubuc A, Dupuy AJ, Shih DJ, Witt H et al (2012) Clonal selection drives genetic divergence of metastatic medulloblastoma. Nature 482(7386):529–533. doi:10.1038/nature10825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang ZF, Ho DW, Ng MN, Lau CK, Yu WC, Ngai P et al (2008) Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell 13(2):153–166. doi:10.1016/j.ccr.2008.01.013

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Liu S, Hu T, Liu S, He Y, Sun S (2009a) Up-regulated microRNA-143 transcribed by nuclear factor kappa B enhances hepatocarcinoma metastasis by repressing fibronectin expression. Hepatology (Baltimore, MD) 50(2):490–499. doi:10.1002/hep.23008

    Article  CAS  Google Scholar 

  • Zhang XH, Wang Q, Gerald W, Hudis CA, Norton L, Smid M et al (2009b) Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell 16(1):67–78. doi:10.1016/j.ccr.2009.05.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Yang P, Sun T, Li D, Xu X, Rui Y et al (2013) miR-126 and miR-126* repress recruitment of mesenchymal stem cells and inflammatory monocytes to inhibit breast cancer metastasis. Nat Cell Biol 15(3):284–294. doi:10.1038/ncb2690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zimmer AS, Steeg PS (2015) Meaningful prevention of breast cancer metastasis: candidate therapeutics, preclinical validation, and clinical trial concerns. J Mol Med 93(1):13–29

    Article  CAS  PubMed  Google Scholar 

Download references

Author contribution

HYJ reviewed the literature and drafted the manuscript. Y.XY and X.GX analyzed the literature and revised the manuscript. L.SR provided the conception of the review and approved the final version of the manuscript.

Funding

This work was supported by the China National Funds for Distinguished Young Scientists (Grant No: 81425019) and specially appointed Professor of Shanghai (Grant No: GZ2015009) to S.R Liu.

Author information

Authors and Affiliations

  1. Clinical Research Center, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China

    Yijun Hu & Guixia Xu

  2. Department of Laboratory Diagnostics, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China

    Yijun Hu & Shanrong Liu

  3. Department of Anesthesiology, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China

    Xiya Yu

Authors
  1. Yijun Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiya Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guixia Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shanrong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shanrong Liu.

Ethics declarations

Conflict of interest

The authors have declared no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hu, Y., Yu, X., Xu, G. et al. Metastasis: an early event in cancer progression. J Cancer Res Clin Oncol 143, 745–757 (2017). https://doi.org/10.1007/s00432-016-2279-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-016-2279-0

Keywords

Search

Navigation