The Darwinian Dynamics of Motility and Metastasis

  • Joshua D. SchiffmanEmail author
  • Richard M. White
  • Trevor A. Graham
  • Qihong Huang
  • Athena Aktipis


Cancer is a deadly disease, but it is rarely the primary tumor that kills patients. Most cancer deaths are due to metastasis, a complex and still poorly understood process. Metastatic cells may be particularly deadly not just because they can colonize new sites, but because they exhibit a much more plastic and adaptable phenotype compared to primary tumor cells. In this chapter we provide an overview of the evolution of metastasis. First, we review what is known about the mechanisms underlying cell motility/metastasis. Then we describe how evolution operates on cell motility, how evolution operates within tumors, how selection among micrometastases may be important and the role of co-evolution between tumor and stromal cells during metastasis. In addition to reviewing the literature, we describe a number of important insights from evolution that can help guide future work on the nature and dynamics of metastases. These include the application of ecological dispersal theory to the evolution of cell motility, the fact that somatic selection can favor plasticity in neoplastic cells, the possibility that selection among micrometastases may lead to the evolution of collective phenotypes that can extract resources from the host body, and the observation that the parameters of evolution may differ dramatically between primary tumors and metastases. By targeting the processes of evolution of cell motility, cell plasticity and the ability of cells to alter their environments, it may be possible for clinicians to substantially extend life and improve the quality of life for cancer patients. Evolutionary and ecological tools and approaches can help provide a basic framework for integrating what is already known about the evolution of metastasis and guiding future work on this topic.


Mestastis Evolution Cheating Motility Cancer 



We thank all the members of the Evolution of Metastasis working group at the Evolutionary Medicine Summer School at Mount Desert Island Biological Laboratories in Bar Harbor, Maine in August of 2012 for many insightful discussions.


  1. 1.
    Ambrus JL et al (1975) Causes of death in cancer patients. J Med 6(1):61–64PubMedGoogle Scholar
  2. 2.
    Nguyen LV et al (2012) Cancer stem cells: an evolving concept. Nat Rev Cancer 12(2):133–143PubMedGoogle Scholar
  3. 3.
    Greaves M (2013) Cancer stem cells as ‘units of selection’. Evol Appl 6(1):102–108PubMedCrossRefGoogle Scholar
  4. 4.
    Magee JA, Piskounova E, Morrison SJ (2012) Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell 21(3):283–296PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Fidler IJ (2003) The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 3(6):453–458PubMedCrossRefGoogle Scholar
  6. 6.
    Nguyen DX, Bos PD, Massague J (2009) Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9(4):274–284PubMedCrossRefGoogle Scholar
  7. 7.
    Comen E, Norton L (2012) Self-seeding in cancer. Recent Results Cancer Res 195:13–23PubMedCrossRefGoogle Scholar
  8. 8.
    Comen E, Norton L, Massague J (2011) Clinical implications of cancer self-seeding. Nat Rev Clin Oncol 8(6):369–377PubMedGoogle Scholar
  9. 9.
    Norton L, Massague J (2006) Is cancer a disease of self-seeding? Nat Med 12(8):875–878PubMedCrossRefGoogle Scholar
  10. 10.
    Houten L, Reilley AA (1980) An investigation of the cause of death from cancer. J Surg Oncol 13(2):111–116PubMedCrossRefGoogle Scholar
  11. 11.
    Valastyan S, Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147(2):275–292PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2(8):563–572PubMedCrossRefGoogle Scholar
  13. 13.
    Thiery JP et al (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890PubMedCrossRefGoogle Scholar
  14. 14.
    Carter AM, Pijnenborg R (2011) Evolution of invasive placentation with special reference to non-human primates. Best Pract Res Clin Obstet Gynaecol 25(3):249–257PubMedCrossRefGoogle Scholar
  15. 15.
    Guo S, Dipietro LA (2010) Factors affecting wound healing. J Dent Res 89(3):219–229PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Semenza GL (2000) HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 88(4):1474–1480PubMedGoogle Scholar
  17. 17.
    Humphries A, Wright NA (2008) Colonic crypt organization and tumorigenesis. Nat Rev Cancer 8(6):415–424PubMedCrossRefGoogle Scholar
  18. 18.
    Solanas G, Batlle E (2011) Control of cell adhesion and compartmentalization in the intestinal epithelium. Exp Cell Res 317(19):2695–2701PubMedCrossRefGoogle Scholar
  19. 19.
    Friedl P, Wolf K (2003) Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 3(5):362–374PubMedCrossRefGoogle Scholar
  20. 20.
    Sailem H et al (2014) Cross-talk between Rho and Rac GTPases drives deterministic exploration of cellular shape space and morphological heterogeneity. Open Biol 4:130132PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Sanz-Moreno V et al (2008) Rac activation and inactivation control plasticity of tumor cell movement. Cell 135(3):510–523PubMedCrossRefGoogle Scholar
  22. 22.
    Wilkinson S, Paterson HF, Marshall CJ (2005) Cdc42-MRCK and Rho-ROCK signalling cooperate in myosin phosphorylation and cell invasion. Nat Cell Biol 7(3):255–261PubMedCrossRefGoogle Scholar
  23. 23.
    Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3(10):721–732PubMedCrossRefGoogle Scholar
  24. 24.
    Elson DA et al (2000) Coordinate up-regulation of hypoxia inducible factor (HIF)-1alpha and HIF-1 target genes during multi-stage epidermal carcinogenesis and wound healing. Cancer Res 60(21):6189–6195PubMedGoogle Scholar
  25. 25.
    Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4(11):891–899PubMedCrossRefGoogle Scholar
  26. 26.
    Hsu PP, Sabatini DM (2008) Cancer cell metabolism: Warburg and beyond. Cell 134(5):703–707PubMedCrossRefGoogle Scholar
  27. 27.
    Sleeman JP et al (2012) Concepts of metastasis in flux: the stromal progression model. Semin Cancer Biol 22(3):174–186PubMedCrossRefGoogle Scholar
  28. 28.
    Jo M et al (2009) Reversibility of epithelial-mesenchymal transition (EMT) induced in breast cancer cells by activation of urokinase receptor-dependent cell signaling. J Biol Chem 284(34):22825–22833PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Jones S et al (2008) Comparative lesion sequencing provides insights into tumor evolution. Proc Natl Acad Sci U S A 105(11):4283–4288PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Navin N et al (2011) Tumour evolution inferred by single-cell sequencing. Nature 472(7341):90–94PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Yachida S et al (2010) Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467(7319):1114–1117PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Campbell PJ et al (2010) The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467(7319):1109–1113PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Wu X et al (2012) Clonal selection drives genetic divergence of metastatic medulloblastoma. Nature 482(7386):529–533PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Gerlinger M et al (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366(10):883–892PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Awad MM et al (2013) Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med 368(25):2395–2401PubMedCrossRefGoogle Scholar
  36. 36.
    Nguyen DX, Massague J (2007) Genetic determinants of cancer metastasis. Nat Rev Genet 8(5):341–352PubMedCrossRefGoogle Scholar
  37. 37.
    Klein CA (2009) Parallel progression of primary tumours and metastases. Nat Rev Cancer 9(4):302–312PubMedCrossRefGoogle Scholar
  38. 38.
    Kim MY et al (2009) Tumor self-seeding by circulating cancer cells. Cell 139(7):1315–1326PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Giancotti FG (2013) Mechanisms governing metastatic dormancy and reactivation. Cell 155(4):750–764PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Kleffel S, Schatton T (2013) Tumor dormancy and cancer stem cells: two sides of the same coin? Adv Exp Med Biol 734:145–179PubMedCrossRefGoogle Scholar
  41. 41.
    Yu Y, Zhu Z (2013) Cell dormancy and tumor refractory. Anticancer Agents Med Chem 13(2):199–202PubMedCrossRefGoogle Scholar
  42. 42.
    Barkan D, Green JE, Chambers AF (2010) Extracellular matrix: a gatekeeper in the transition from dormancy to metastatic growth. Eur J Cancer 46(7):1181–1188PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Aktipis CA, Maley CC, Pepper JW (2012) Dispersal evolution in neoplasms: the role of disregulated metabolism in the evolution of cell motility. Cancer Prev Res (Phila) 5(2):266–275CrossRefGoogle Scholar
  44. 44.
    Chen J et al (2011) Solving the puzzle of metastasis: the evolution of cell migration in neoplasms. PLoS One 6(4), e17933PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Mazzone M et al (2009) Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136(5):839–851PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Hockel M et al (1996) Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 56(19):4509–4515PubMedGoogle Scholar
  47. 47.
    Brizel DM et al (1996) Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res 56(5):941–943PubMedGoogle Scholar
  48. 48.
    Fukumura D, Jain RK (2007) Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization. Microvasc Res 74(2-3):72–84PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Hurwitz H et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342PubMedCrossRefGoogle Scholar
  50. 50.
    Mackey JR et al (2012) Controlling angiogenesis in breast cancer: a systematic review of anti-angiogenic trials. Cancer Treat Rev 38(6):673–688PubMedCrossRefGoogle Scholar
  51. 51.
    Ebos JM et al (2009) Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15(3):232–239PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Aktipis CA (2004) Know when to walk away: contingent movement and the evolution of cooperation. J Theor Biol 231(2):249–260PubMedCrossRefGoogle Scholar
  53. 53.
    Aktipis CA (2011) Is cooperation viable in mobile organisms? Simple Walk Away rule favors the evolution of cooperation in groups. Evol Hum Behav 32(4):263–276PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Nesse RM (2007) Runaway social selection for displays of partner value and altruism. Biol Theory 2(2):143–155CrossRefGoogle Scholar
  55. 55.
    Holmgren L, O’Reilly MS, Folkman J (1995) Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1(2):149–153PubMedCrossRefGoogle Scholar
  56. 56.
    Kitano H (2004) Biological robustness. Nat Rev Genet 5(11):826–837PubMedCrossRefGoogle Scholar
  57. 57.
    Tian T et al (2011) The origins of cancer robustness and evolvability. Integr Biol (Camb) 3(1):17–30CrossRefGoogle Scholar
  58. 58.
    Loeb LA (2011) Human cancers express mutator phenotypes: origin, consequences and targeting. Nat Rev Cancer 11(6):450–457PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Corcoran RB et al (2010) BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci Signal 3(149):ra84PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Willis L et al (2010) Breast cancer dormancy can be maintained by small numbers of micrometastases. Cancer Res 70(11):4310–4317PubMedCrossRefGoogle Scholar
  61. 61.
    Ratcliff WC et al (2012) Experimental evolution of multicellularity. Proc Natl Acad Sci U S A 109(5):1595–1600PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Sprouffske K et al (2013) An evolutionary explanation for the presence of cancer nonstem cells in neoplasms. Evol Appl 6(1):92–101PubMedCrossRefGoogle Scholar
  63. 63.
    Cordner R, Black KL, Wheeler CJ (2013) Exploitation of adaptive evolution in glioma treatment. CNS Oncol 2(2):171–179PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Bonavia R et al (2011) Heterogeneity maintenance in glioblastoma: a social network. Cancer Res 71(12):4055–4060PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Pyonteck SM et al (2012) Deficiency of the macrophage growth factor CSF-1 disrupts pancreatic neuroendocrine tumor development. Oncogene 31(11):1459–1467PubMedCrossRefGoogle Scholar
  66. 66.
    Lifsted T et al (1998) Identification of inbred mouse strains harboring genetic modifiers of mammary tumor age of onset and metastatic progression. Int J Cancer 77(4):640–644PubMedCrossRefGoogle Scholar
  67. 67.
    Allinen M et al (2004) Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 6(1):17–32PubMedCrossRefGoogle Scholar
  68. 68.
    Mueller BM et al (1992) Expression of tissue factor by melanoma cells promotes efficient hematogenous metastasis. Proc Natl Acad Sci U S A 89(24):11832–11836PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Kaplan RN et al (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438(7069):820–827PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Kreso A et al (2013) Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science 339(6119):543–548PubMedCrossRefGoogle Scholar
  71. 71.
    Araten DJ et al (2005) A quantitative measurement of the human somatic mutation rate. Cancer Res 65(18):8111–8117PubMedCrossRefGoogle Scholar
  72. 72.
    Elmore E, Kakunaga T, Barrett JC (1983) Comparison of spontaneous mutation rates of normal and chemically transformed human skin fibroblasts. Cancer Res 43(4):1650–1655PubMedGoogle Scholar
  73. 73.
    Kruglyak S et al (1998) Equilibrium distributions of microsatellite repeat length resulting from a balance between slippage events and point mutations. Proc Natl Acad Sci U S A 95(18):10774–10778PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Ushijima T et al (2003) Fidelity of the methylation pattern and its variation in the genome. Genome Res 13(5):868–874PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Bhattacharyya NP et al (1994) Mutator phenotypes in human colorectal carcinoma cell lines. Proc Natl Acad Sci U S A 91(14):6319–6323PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87(2):159–170PubMedCrossRefGoogle Scholar
  77. 77.
    Lengauer C, Kinzler KW, Vogelstein B (1997) Genetic instability in colorectal cancers. Nature 386(6625):623–627PubMedCrossRefGoogle Scholar
  78. 78.
    Issa JP (2004) CpG island methylator phenotype in cancer. Nat Rev Cancer 4(12):988–993PubMedCrossRefGoogle Scholar
  79. 79.
    Landan G et al (2012) Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues. Nat Genet 44(11):1207–1214PubMedCrossRefGoogle Scholar
  80. 80.
    Wright NA, Alison M (1984) The biology of epithelial cell populations. Oxford science publications, Oxford, Oxfordshire, New York: Clarendon Press; Oxford University PressGoogle Scholar
  81. 81.
    Charpin C et al (1988) Multiparametric evaluation (SAMBA) of growth fraction (monoclonal Ki67) in breast carcinoma tissue sections. Cancer Res 48(15):4368–4374PubMedGoogle Scholar
  82. 82.
    Vakkala M et al (1999) Apoptosis during breast carcinoma progression. Clin Cancer Res 5(2):319–324PubMedGoogle Scholar
  83. 83.
    Friberg S, Mattson S (1997) On the growth rates of human malignant tumors: implications for medical decision making. J Surg Oncol 65(4):284–297PubMedCrossRefGoogle Scholar
  84. 84.
    Simons BD, Clevers H (2011) Strategies for homeostatic stem cell self-renewal in adult tissues. Cell 145(6):851–862PubMedCrossRefGoogle Scholar
  85. 85.
    Beerenwinkel N et al (2007) Genetic progression and the waiting time to cancer. PLoS Comput Biol 3(11), e225PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Bozic I et al (2010) Accumulation of driver and passenger mutations during tumor progression. Proc Natl Acad Sci U S A 107(43):18545–18550PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Mascre G et al (2012) Distinct contribution of stem and progenitor cells to epidermal maintenance. Nature 489(7415):257–262PubMedCrossRefGoogle Scholar
  88. 88.
    Anderson AR et al (2006) Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment. Cell 127(5):905–915PubMedCrossRefGoogle Scholar
  89. 89.
    Yuan Y et al (2012) Quantitative image analysis of cellular heterogeneity in breast tumors complements genomic profiling. Sci Transl Med 4(157):157ra143PubMedCrossRefGoogle Scholar
  90. 90.
    Aktipis CA, Nesse RM (2013) Evolutionary foundations for cancer biology. Evol Appl 6(1):144–159PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Pienta KJ et al (2013) The cancer diaspora: metastasis beyond the seed and soil hypothesis. Clin Cancer Res 19(21):5849–5855PubMedCrossRefGoogle Scholar
  92. 92.
    Potter NE et al (2013) Single-cell mutational profiling and clonal phylogeny in cancer. Genome Res 23(12):2115–2125PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Livet J et al (2007) Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature 450(7166):56–62PubMedCrossRefGoogle Scholar
  94. 94.
    Dupuy AJ et al (2005) Mammalian mutagenesis using a highly mobile somatic Sleeping Beauty transposon system. Nature 436(7048):221–226PubMedCrossRefGoogle Scholar
  95. 95.
    White RM et al (2008) Transparent adult zebrafish as a tool for in vivo transplantation analysis. Cell Stem Cell 2(2):183–189PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Yu M et al (2013) Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339(6119):580–584PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Pantel K et al (1996) Frequency and prognostic significance of isolated tumour cells in bone marrow of patients with non-small-cell lung cancer without overt metastases. Lancet 347(9002):649–653PubMedCrossRefGoogle Scholar
  98. 98.
    Zong C et al (2012) Genome-wide detection of single-nucleotide and copy-number variations of a single human cell. Science 338(6114):1622–1626PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Drummond AJ et al (2012) Bayesian phylogenetics with BEAUti and the BEAST 1.7. Mol Biol Evol 29(8):1969–1973PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Sottoriva A et al (2013) Single-molecule genomic data delineate patient-specific tumor profiles and cancer stem cell organization. Cancer Res 73(1):41–49PubMedCrossRefGoogle Scholar
  101. 101.
    Lee JM et al (2013) Feasibility and safety of sequential research-related tumor core biopsies in clinical trials. Cancer 119(7):1357–1364PubMedCrossRefGoogle Scholar
  102. 102.
    Overman MJ et al (2013) Use of research biopsies in clinical trials: are risks and benefits adequately discussed? J Clin Oncol 31(1):17–22PubMedCrossRefGoogle Scholar
  103. 103.
    Peppercorn J (2013) Toward improved understanding of the ethical and clinical issues surrounding mandatory research biopsies. J Clin Oncol 31(1):1–2PubMedCrossRefGoogle Scholar
  104. 104.
    Ikushima H, Miyazono K (2010) TGFb signalling: a complex web in cancer progression. Nat Rev Cancer 10:415–424PubMedCrossRefGoogle Scholar
  105. 105.
    Massagué J (2008) TGFb in cancer. Cell 134:215–230PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Shi Y, Massagué J (2003) Mechanisms of TGF-b signaling from cell membrane to the nucleus. Cell 113:685–700PubMedCrossRefGoogle Scholar
  107. 107.
    Feng XH, Derynck R (2005) Specificity and versatility in TGF-b signaling through Smads. Annu Rev Cell Dev Biol 21:659–693PubMedCrossRefGoogle Scholar
  108. 108.
    Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-b family signalling. Nature 425:577–584PubMedCrossRefGoogle Scholar
  109. 109.
    Moustakas A, Heldin CH (2005) Non-Smad TGF-b signals. J Cell Sci 118:3573–3584PubMedCrossRefGoogle Scholar
  110. 110.
    Gherardi E et al (2006) Structural basis of hepatocyte growth factor/scatter factor and MET signalling. Proc Natl Acad Sci U S A 103:4046–4051PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Kirchhofer D et al (2004) Structural and functional basis of the serine protease-like hepatocyte growth factor β-chain in Met binding and signaling. J Biol Chem 279:39915–39924PubMedCrossRefGoogle Scholar
  112. 112.
    Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4:915.925CrossRefGoogle Scholar
  113. 113.
    Weidner KM et al (1996) Interaction between Gab1 and the c.Met receptor tyrosine kinase is responsible for epithelial morphogenesis. Nature 384:173–176PubMedCrossRefGoogle Scholar
  114. 114.
    Lai AZ, Abella JV, Park M (2009) Crosstalk in Met receptor oncogenesis. Trends Cell Biol 19:542–551PubMedCrossRefGoogle Scholar
  115. 115.
    Trusolino L, Bertotti A, Comoglio PM (2010) MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol 11:834–848PubMedCrossRefGoogle Scholar
  116. 116.
    Maroun CR, Naujokas MA, Holgado-Madruga M, Wong AJ, Park M (2000) The tyrosine phosphatase SHP.2 is required for sustained activation of extracellular signal-regulated kinase and epithelial morphogenesis downstream from the met receptor tyrosine kinase. Mol Cell Biol 20:8513–8525PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Paliouras GN, Naujokas MA, Park M (2009) Pak4, a novel Gab1 binding partner, modulates cell migration and invasion by the Met receptor. Mol Cell Biol 29:3018.3032PubMedCentralCrossRefGoogle Scholar
  118. 118.
    Schaeper U et al (2000) Coupling of Gab1 to c.Met, Grb2, and Shp2 mediates biological responses. J Cell Biol 149:1419–1432PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Schaeper U et al (2007) Distinct requirements for Gab1 in Met and EGF receptor signaling in vivo. Proc Natl Acad Sci U S A 104:15376–15381PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Beenken A, Mohammadi M (2009) The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 8:235–253PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Eswarakumar VP, Lax I, Schlessinger J (2005) Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 16:139–149PubMedCrossRefGoogle Scholar
  122. 122.
    Mohammadi M, Olsen SK, Ibrahimi OA (2005) Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev 16:107–137PubMedCrossRefGoogle Scholar
  123. 123.
    Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10:116–129PubMedCrossRefGoogle Scholar
  124. 124.
    Cao Y, Cao R, Hedlund EM (2008) R regulation of tumor angiogenesis and metastasis by FGF and PDGF signaling pathways. J Mol Med 86(7):785–789PubMedCrossRefGoogle Scholar
  125. 125.
    Cao R, Björndahl MA, Religa P, Clasper S, Garvin S, Galter D et al (2004) PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell 6(4):333–345PubMedCrossRefGoogle Scholar
  126. 126.
    Jechlinger M, Sommer A, Moriggl R, Seither P, Kraut N, Capodiecci P et al (2006) Autocrine PDGFR signaling promotes mammary cancer metastasis. J Clin Invest 116(6):1561–1570PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Pollak M (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8:915–928PubMedCrossRefGoogle Scholar
  128. 128.
    Pollak MN, Schernhammer ES, Hankinson SE (2004) Insulin-like growth factors and neoplasia. Nat Rev Cancer 4:505–518PubMedCrossRefGoogle Scholar
  129. 129.
    Ullrich A et al (1985) Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature 313:756–761PubMedCrossRefGoogle Scholar
  130. 130.
    Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R (2009) Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev 30:586–623PubMedCrossRefGoogle Scholar
  131. 131.
    LeRoith D (2000) Insulin-like growth factor I receptor signaling-overlapping or redundant pathways? Endocrinology 141:1287–1288PubMedGoogle Scholar
  132. 132.
    Xue C et al (2006) Epidermal growth factor receptor overexpression results in increased tumor cell motility in vivo coordinately with enhanced intravasation and metastasis. Cancer Res 66:192–197PubMedCrossRefGoogle Scholar
  133. 133.
    Lo HW, Hsu SC, Xia W et al (2007) Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer Res 67:9066–9076PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7:415–428PubMedCrossRefGoogle Scholar
  135. 135.
    Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelialmesenchymal transitions. Nat Rev Mol Cell Biol 7:131–142PubMedCrossRefGoogle Scholar
  136. 136.
    Grunert S, Jechlinger M, Beug H (2003) Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat Rev Mol Cell Biol 4:657–665PubMedCrossRefGoogle Scholar
  137. 137.
    Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9:265–273PubMedCrossRefGoogle Scholar
  138. 138.
    Wang W et al (2006) The activity status of cofilin is directly related to invasion, intravasation, and metastasis of mammary tumors. J Cell Biol 173:395–404PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Kurisu S, Suetsugu S, Yamazaki D, Yamaguchi H, Takenawa T (2005) Rac-WAVE2 signaling is involved in the invasive and metastatic phenotypes of murine melanoma cells. Oncogene 24:1309–1319PubMedCrossRefGoogle Scholar
  140. 140.
    Wang W et al (2004) Identification and testing of a gene expression signature of invasive carcinoma cells within primary mammary tumors. Cancer Res 64:8585–8594PubMedCrossRefGoogle Scholar
  141. 141.
    Gregory PA, Bert AG, Paterson EL et al (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10:593–601PubMedCrossRefGoogle Scholar
  142. 142.
    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 283:14910–14914PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Burk U, Schubert J, Wellner U et al (2008) A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep 9:582–589PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Park SM, Gaur AB, Lengyel E, Peter ME (2008) The miR-200 family determines the epithelial phenotype of cancer cells by targeting the Ecadherin repressors ZEB1 and ZEB2. Genes Dev 22:894–907PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Wellner U, Schubert J, Burk UC et al (2009) The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol 11:1487–1495PubMedCrossRefGoogle Scholar
  146. 146.
    Friedl P, Wolf K (2010) Plasticity of cell migration: a multiscale tuning model. J Cell Biol 188:11–19PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Wang W, Eddy R, Condeelis J (2007) The cofilin pathway in breast cancer invasion and metastasis. Nat Rev Cancer 7:429–440PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Olson MF, Sahai E (2008) The actin cytoskeleton in cancer cell motility. Clin Exp Metastasis 26:273–287PubMedCrossRefGoogle Scholar
  149. 149.
    Gupton SL, Gertler FB (2007) Filopodia: the fingers that do the walking. Sci STKE 2007(400):re5PubMedCrossRefGoogle Scholar
  150. 150.
    Vignjevic D, Montagnac G (2008) Reorganisation of the dendritic actin network during cancer cell migration and invasion. Semin Cancer Biol 18:12–22PubMedCrossRefGoogle Scholar
  151. 151.
    Buccione R, Caldieri G, Ayala I (2009) Invadopodia: specialized tumor cell structures for the focal degradation of the extracellular matrix. Cancer Metastasis Rev 28:137–149PubMedCrossRefGoogle Scholar
  152. 152.
    Vega FM, Ridley AJ (2008) Rho GTPases in cancer cell biology. FEBS Lett 582:2093–2101PubMedCrossRefGoogle Scholar
  153. 153.
    Sahai E, Marshall CJ (2002) RHO-GTPases and cancer. Nat Rev Cancer 2:133–142PubMedCrossRefGoogle Scholar
  154. 154.
    Jaffe AB, Hall A (2005) Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 21:247–269PubMedCrossRefGoogle Scholar
  155. 155.
    Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420:629–635PubMedCrossRefGoogle Scholar
  156. 156.
    Burridge K, Wennerberg K (2004) Rho and Rac take center stage. Cell 116:167–179PubMedCrossRefGoogle Scholar
  157. 157.
    Narumiya S, Tanji M, Ishizaki T (2009) Rho signaling, ROCK and mDia1, in transformation, metastasis and invasion. Cancer Metastasis Rev 28:65–76PubMedCrossRefGoogle Scholar
  158. 158.
    Hall A (2005) Rho GTPases and the control of cell behaviour. Biochem Soc Trans 33:891–895PubMedCrossRefGoogle Scholar
  159. 159.
    Ridley AJ (2006) Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol 16:522–529PubMedCrossRefGoogle Scholar
  160. 160.
    Zondag GC, Evers EE, ten Klooster JP, Janssen L, van der Kammen RA, Collard JG (2000) Oncogenic Ras downregulates Rac activity, which leads to increased Rho activity and epithelial-mesenchymal transition. J Cell Biol 149:775–782PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Hordijk PL, ten Klooster JP, van der Kammen RA, Michiels F, Oomen LC, Collard JG (1997) Inhibition of invasion of epithelial cells by Tiam1-Rac signaling. Science 278:1464–1466PubMedCrossRefGoogle Scholar
  162. 162.
    Sander EE, ten Klooster JP, van Delft S, van der Kammen RA, Collard JG (1999) Rac downregulates Rho activity: reciprocal balance between both GTPases determines cellular morphology and migratory behavior. J Cell Biol 147:1009–1022PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Pertz O, Hodgson L, Klemke RL, Hahn KM (2006) Spatiotemporal dynamics of RhoA activity in migrating cells. Nature 440:1069–1072PubMedCrossRefGoogle Scholar
  164. 164.
    Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A (1992) The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 70:401–410PubMedCrossRefGoogle Scholar
  165. 165.
    Cozzolino M, Stagni V, Spinardi L et al (2003) p120 catenin is required for growth factor-dependent cell motility and scattering in epithelial cells. Mol Biol Cell 14:1964–1977PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Anastasiadis PZ (1773) p120-ctn: a nexus for contextual signaling via Rho GTPases. Biochim Biophys Acta 2007:34–46Google Scholar
  167. 167.
    Bellovin DI, Bates RC, Muzikansky A, Rimm DL, Mercurio AM (2005) Altered localization of p120 catenin during epithelial to mesenchymal transition of colon carcinoma is prognostic for aggressive disease. Cancer Res 65:10938–10945PubMedCrossRefGoogle Scholar
  168. 168.
    Pinner S, Sahai E (2008) PDK1 regulates cancer cell motility by antagonizing inhibition of ROCK1 by RhoE. Nat Cell Biol 10:127–137PubMedCrossRefGoogle Scholar
  169. 169.
    Wicki A, Lehembre F, Wick N, Hantusch B, Kerjaschki D, Christofori G (2006) Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton. Cancer Cell 9:261–272PubMedCrossRefGoogle Scholar
  170. 170.
    Wicki A, Christofori G (2007) The potential role of podoplanin in tumour invasion. Br J Cancer 96:1–5PubMedCrossRefGoogle Scholar
  171. 171.
    Schacht V, Dadras SS, Johnson LA, Jackson DG, Hong YK, Detmar M (2005) Up-regulation of the lymphatic marker podoplanin, a mucin-type transmembrane glycoprotein, in human squamous cell carcinomas and germ cell tumors. Am J Pathol 166:913–921PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Atsumi N, Ishii G, Kojima M, Sanada M, Fujii S, Ochiai A (2008) Podoplanin, a novel marker of tumor-initiating cells in human squamous cell carcinoma A431. Biochem Biophys Res Commun 373:36–41PubMedCrossRefGoogle Scholar
  173. 173.
    Scholl FG, Gamallo C, Vilaro S, Quintanilla M (1999) Identification of PA2.26 antigen as a novel cell-surface mucin-type glycoprotein that induces plasma membrane extensions and increased motility in keratinocytes. J Cell Sci 112:4601–4613PubMedGoogle Scholar
  174. 174.
    Poujade M, Grasland-Mongrain E, Hertzog A et al (2007) Collective migration of an epithelial monolayer in response to a model wound. Proc Natl Acad Sci U S A 104:15988–15993PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Wolf K, Wu YI, Liu Y et al (2007) Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion. Nat Cell Biol 9:893–904PubMedCrossRefGoogle Scholar
  176. 176.
    De Wever O, Mareel M (2003) Role of tissue stroma in cancer cell invasion. J Pathol 200:429–447PubMedCrossRefGoogle Scholar
  177. 177.
    Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011–1027PubMedCrossRefGoogle Scholar
  178. 178.
    Wissmann C, Detmar M (2006) Pathways targeting tumor lymphangiogenesis. Clin Cancer Res 12:6865–6868PubMedCrossRefGoogle Scholar
  179. 179.
    Mantovani A, Sica A et al (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686PubMedCrossRefGoogle Scholar
  180. 180.
    Mantovani A, Romero P, Palucka AK et al (2008) Tumour immunity: effector response to tumour and role of the microenvironment. Lancet 371:771–783PubMedCrossRefGoogle Scholar
  181. 181.
    Talmadge JE, Donkor M, Scholar E (2007) Inflammatory cell infiltration of tumors: Jekyll or Hyde. Cancer Metastasis Rev 26:373–400PubMedCrossRefGoogle Scholar
  182. 182.
    Lewis CE, Pollard JW (2006) Distinct role of macrophages in different tumor microenvironments. Cancer Res 66:605–612PubMedCrossRefGoogle Scholar
  183. 183.
    Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124:263–266PubMedCrossRefGoogle Scholar
  184. 184.
    Wyckoff JB, Wang Y, Lin EY et al (2007) Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res 67:2649–2656PubMedCrossRefGoogle Scholar
  185. 185.
    De Wever O, Demetter P, Mareel M et al (2008) Stromal myofibroblasts are drivers of invasive cancer growth. Int J Cancer 123:2229–2238PubMedCrossRefGoogle Scholar
  186. 186.
    Krishnamachary B et al (2006) Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Res 66:2725–2731Google Scholar
  187. 187.
    Sahlgren C et al (2008) Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci U S A 105(17):6392–6397Google Scholar
  188. 188.
    Evans AJ et al (2007) VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail. Mol Cell Biol 27:157–169Google Scholar
  189. 189.
    Staller P et al (2003) Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 425:307–311Google Scholar
  190. 190.
    Ceradini DJ et al (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nature Med 10:858–864Google Scholar
  191. 191.
    Barriga EH, Maxwell PH, Reyes AE, Mayor R. The hypoxia factor Hif-1α controls neural crest chemotaxis and epithelial to mesenchymal transition. J Cell Biol. 2013 May 27;201(5):759-76. doi:  10.1083/jcb.201212100. PubMed PMID: 23712262; PubMed Central PMCID: PMC3664719.Google Scholar

Copyright information

© Springer-Verlag New York 2016

Authors and Affiliations

  • Joshua D. Schiffman
    • 1
    Email author
  • Richard M. White
    • 2
  • Trevor A. Graham
    • 3
  • Qihong Huang
    • 4
  • Athena Aktipis
    • 3
    • 5
  1. 1.Departments of Pediatrics and Oncological Sciences, Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA
  2. 2.Departments of Cancer Biology and Genetics and Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical CollegeNew YorkUSA
  3. 3.Center for Evolution and CancerUniversity of California San FranciscoSan FranciscoUSA
  4. 4.The Wistar InstitutePhiladelphiaUSA
  5. 5.Department of PsychologyArizona State UniversityTempeUSA

Personalised recommendations