Skip to main content

The Darwinian Dynamics of Motility and Metastasis

Abstract

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.

Keywords

  • Mestastis
  • Evolution
  • Cheating
  • Motility
  • Cancer

This is a preview of subscription content, access via your institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-1-4939-6460-4_8
  • Chapter length: 42 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   149.00
Price excludes VAT (USA)
  • ISBN: 978-1-4939-6460-4
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   199.99
Price excludes VAT (USA)
Hardcover Book
USD   199.99
Price excludes VAT (USA)
Fig. 8.1
Fig. 8.2

References

  1. Ambrus JL et al (1975) Causes of death in cancer patients. J Med 6(1):61–64

    CAS  PubMed  Google Scholar 

  2. Nguyen LV et al (2012) Cancer stem cells: an evolving concept. Nat Rev Cancer 12(2):133–143

    CAS  PubMed  Google Scholar 

  3. Greaves M (2013) Cancer stem cells as ‘units of selection’. Evol Appl 6(1):102–108

    PubMed  CrossRef  Google Scholar 

  4. Magee JA, Piskounova E, Morrison SJ (2012) Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell 21(3):283–296

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  5. Fidler IJ (2003) The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 3(6):453–458

    CAS  PubMed  CrossRef  Google Scholar 

  6. Nguyen DX, Bos PD, Massague J (2009) Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9(4):274–284

    CAS  PubMed  CrossRef  Google Scholar 

  7. Comen E, Norton L (2012) Self-seeding in cancer. Recent Results Cancer Res 195:13–23

    PubMed  CrossRef  Google Scholar 

  8. Comen E, Norton L, Massague J (2011) Clinical implications of cancer self-seeding. Nat Rev Clin Oncol 8(6):369–377

    PubMed  Google Scholar 

  9. Norton L, Massague J (2006) Is cancer a disease of self-seeding? Nat Med 12(8):875–878

    CAS  PubMed  CrossRef  Google Scholar 

  10. Houten L, Reilley AA (1980) An investigation of the cause of death from cancer. J Surg Oncol 13(2):111–116

    CAS  PubMed  CrossRef  Google Scholar 

  11. Valastyan S, Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147(2):275–292

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

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

    CAS  PubMed  CrossRef  Google Scholar 

  13. Thiery JP et al (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890

    CAS  PubMed  CrossRef  Google Scholar 

  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):249–257

    PubMed  CrossRef  Google Scholar 

  15. Guo S, Dipietro LA (2010) Factors affecting wound healing. J Dent Res 89(3):219–229

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  16. Semenza GL (2000) HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 88(4):1474–1480

    CAS  PubMed  Google Scholar 

  17. Humphries A, Wright NA (2008) Colonic crypt organization and tumorigenesis. Nat Rev Cancer 8(6):415–424

    CAS  PubMed  CrossRef  Google Scholar 

  18. Solanas G, Batlle E (2011) Control of cell adhesion and compartmentalization in the intestinal epithelium. Exp Cell Res 317(19):2695–2701

    CAS  PubMed  CrossRef  Google Scholar 

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

    CAS  PubMed  CrossRef  Google Scholar 

  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 4:130132

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  21. Sanz-Moreno V et al (2008) Rac activation and inactivation control plasticity of tumor cell movement. Cell 135(3):510–523

    CAS  PubMed  CrossRef  Google Scholar 

  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):255–261

    CAS  PubMed  CrossRef  Google Scholar 

  23. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3(10):721–732

    CAS  PubMed  CrossRef  Google Scholar 

  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):6189–6195

    CAS  PubMed  Google Scholar 

  25. Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4(11):891–899

    CAS  PubMed  CrossRef  Google Scholar 

  26. Hsu PP, Sabatini DM (2008) Cancer cell metabolism: Warburg and beyond. Cell 134(5):703–707

    CAS  PubMed  CrossRef  Google Scholar 

  27. Sleeman JP et al (2012) Concepts of metastasis in flux: the stromal progression model. Semin Cancer Biol 22(3):174–186

    CAS  PubMed  CrossRef  Google Scholar 

  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):22825–22833

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  29. Jones S et al (2008) Comparative lesion sequencing provides insights into tumor evolution. Proc Natl Acad Sci U S A 105(11):4283–4288

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  30. Navin N et al (2011) Tumour evolution inferred by single-cell sequencing. Nature 472(7341):90–94

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  31. Yachida S et al (2010) Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467(7319):1114–1117

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  32. Campbell PJ et al (2010) The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467(7319):1109–1113

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  33. Wu X et al (2012) Clonal selection drives genetic divergence of metastatic medulloblastoma. Nature 482(7386):529–533

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  34. Gerlinger M et al (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366(10):883–892

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  35. Awad MM et al (2013) Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med 368(25):2395–2401

    CAS  PubMed  CrossRef  Google Scholar 

  36. Nguyen DX, Massague J (2007) Genetic determinants of cancer metastasis. Nat Rev Genet 8(5):341–352

    CAS  PubMed  CrossRef  Google Scholar 

  37. Klein CA (2009) Parallel progression of primary tumours and metastases. Nat Rev Cancer 9(4):302–312

    CAS  PubMed  CrossRef  Google Scholar 

  38. Kim MY et al (2009) Tumor self-seeding by circulating cancer cells. Cell 139(7):1315–1326

    PubMed  PubMed Central  CrossRef  Google Scholar 

  39. Giancotti FG (2013) Mechanisms governing metastatic dormancy and reactivation. Cell 155(4):750–764

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  40. Kleffel S, Schatton T (2013) Tumor dormancy and cancer stem cells: two sides of the same coin? Adv Exp Med Biol 734:145–179

    CAS  PubMed  CrossRef  Google Scholar 

  41. Yu Y, Zhu Z (2013) Cell dormancy and tumor refractory. Anticancer Agents Med Chem 13(2):199–202

    CAS  PubMed  CrossRef  Google Scholar 

  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):1181–1188

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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):266–275

    CrossRef  Google Scholar 

  44. Chen J et al (2011) Solving the puzzle of metastasis: the evolution of cell migration in neoplasms. PLoS One 6(4), e17933

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  45. Mazzone M et al (2009) Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136(5):839–851

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  46. Hockel M et al (1996) Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 56(19):4509–4515

    CAS  PubMed  Google Scholar 

  47. Brizel DM et al (1996) Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res 56(5):941–943

    CAS  PubMed  Google Scholar 

  48. Fukumura D, Jain RK (2007) Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization. Microvasc Res 74(2-3):72–84

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  49. Hurwitz H et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342

    CAS  PubMed  CrossRef  Google Scholar 

  50. Mackey JR et al (2012) Controlling angiogenesis in breast cancer: a systematic review of anti-angiogenic trials. Cancer Treat Rev 38(6):673–688

    CAS  PubMed  CrossRef  Google Scholar 

  51. Ebos JM et al (2009) Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15(3):232–239

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  52. Aktipis CA (2004) Know when to walk away: contingent movement and the evolution of cooperation. J Theor Biol 231(2):249–260

    PubMed  CrossRef  Google Scholar 

  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):263–276

    PubMed  PubMed Central  CrossRef  Google Scholar 

  54. Nesse RM (2007) Runaway social selection for displays of partner value and altruism. Biol Theory 2(2):143–155

    CrossRef  Google Scholar 

  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):149–153

    CAS  PubMed  CrossRef  Google Scholar 

  56. Kitano H (2004) Biological robustness. Nat Rev Genet 5(11):826–837

    CAS  PubMed  CrossRef  Google Scholar 

  57. Tian T et al (2011) The origins of cancer robustness and evolvability. Integr Biol (Camb) 3(1):17–30

    CAS  CrossRef  Google Scholar 

  58. Loeb LA (2011) Human cancers express mutator phenotypes: origin, consequences and targeting. Nat Rev Cancer 11(6):450–457

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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):ra84

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  60. Willis L et al (2010) Breast cancer dormancy can be maintained by small numbers of micrometastases. Cancer Res 70(11):4310–4317

    CAS  PubMed  CrossRef  Google Scholar 

  61. Ratcliff WC et al (2012) Experimental evolution of multicellularity. Proc Natl Acad Sci U S A 109(5):1595–1600

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  62. Sprouffske K et al (2013) An evolutionary explanation for the presence of cancer nonstem cells in neoplasms. Evol Appl 6(1):92–101

    PubMed  CrossRef  Google Scholar 

  63. Cordner R, Black KL, Wheeler CJ (2013) Exploitation of adaptive evolution in glioma treatment. CNS Oncol 2(2):171–179

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  64. Bonavia R et al (2011) Heterogeneity maintenance in glioblastoma: a social network. Cancer Res 71(12):4055–4060

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  65. Pyonteck SM et al (2012) Deficiency of the macrophage growth factor CSF-1 disrupts pancreatic neuroendocrine tumor development. Oncogene 31(11):1459–1467

    CAS  PubMed  CrossRef  Google Scholar 

  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):640–644

    CAS  PubMed  CrossRef  Google Scholar 

  67. Allinen M et al (2004) Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 6(1):17–32

    CAS  PubMed  CrossRef  Google Scholar 

  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):11832–11836

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  69. Kaplan RN et al (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438(7069):820–827

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  70. Kreso A et al (2013) Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science 339(6119):543–548

    CAS  PubMed  CrossRef  Google Scholar 

  71. Araten DJ et al (2005) A quantitative measurement of the human somatic mutation rate. Cancer Res 65(18):8111–8117

    CAS  PubMed  CrossRef  Google Scholar 

  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):1650–1655

    CAS  PubMed  Google Scholar 

  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):10774–10778

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  74. Ushijima T et al (2003) Fidelity of the methylation pattern and its variation in the genome. Genome Res 13(5):868–874

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  75. Bhattacharyya NP et al (1994) Mutator phenotypes in human colorectal carcinoma cell lines. Proc Natl Acad Sci U S A 91(14):6319–6323

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  76. Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87(2):159–170

    CAS  PubMed  CrossRef  Google Scholar 

  77. Lengauer C, Kinzler KW, Vogelstein B (1997) Genetic instability in colorectal cancers. Nature 386(6625):623–627

    CAS  PubMed  CrossRef  Google Scholar 

  78. Issa JP (2004) CpG island methylator phenotype in cancer. Nat Rev Cancer 4(12):988–993

    CAS  PubMed  CrossRef  Google Scholar 

  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):1207–1214

    CAS  PubMed  CrossRef  Google Scholar 

  80. Wright NA, Alison M (1984) The biology of epithelial cell populations. Oxford science publications, Oxford, Oxfordshire, New York: Clarendon Press; Oxford University Press

    Google Scholar 

  81. Charpin C et al (1988) Multiparametric evaluation (SAMBA) of growth fraction (monoclonal Ki67) in breast carcinoma tissue sections. Cancer Res 48(15):4368–4374

    CAS  PubMed  Google Scholar 

  82. Vakkala M et al (1999) Apoptosis during breast carcinoma progression. Clin Cancer Res 5(2):319–324

    CAS  PubMed  Google Scholar 

  83. Friberg S, Mattson S (1997) On the growth rates of human malignant tumors: implications for medical decision making. J Surg Oncol 65(4):284–297

    CAS  PubMed  CrossRef  Google Scholar 

  84. Simons BD, Clevers H (2011) Strategies for homeostatic stem cell self-renewal in adult tissues. Cell 145(6):851–862

    CAS  PubMed  CrossRef  Google Scholar 

  85. Beerenwinkel N et al (2007) Genetic progression and the waiting time to cancer. PLoS Comput Biol 3(11), e225

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  86. Bozic I et al (2010) Accumulation of driver and passenger mutations during tumor progression. Proc Natl Acad Sci U S A 107(43):18545–18550

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  87. Mascre G et al (2012) Distinct contribution of stem and progenitor cells to epidermal maintenance. Nature 489(7415):257–262

    CAS  PubMed  CrossRef  Google Scholar 

  88. Anderson AR et al (2006) Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment. Cell 127(5):905–915

    CAS  PubMed  CrossRef  Google Scholar 

  89. Yuan Y et al (2012) Quantitative image analysis of cellular heterogeneity in breast tumors complements genomic profiling. Sci Transl Med 4(157):157ra143

    PubMed  CrossRef  Google Scholar 

  90. Aktipis CA, Nesse RM (2013) Evolutionary foundations for cancer biology. Evol Appl 6(1):144–159

    PubMed  PubMed Central  CrossRef  Google Scholar 

  91. Pienta KJ et al (2013) The cancer diaspora: metastasis beyond the seed and soil hypothesis. Clin Cancer Res 19(21):5849–5855

    PubMed  CrossRef  Google Scholar 

  92. Potter NE et al (2013) Single-cell mutational profiling and clonal phylogeny in cancer. Genome Res 23(12):2115–2125

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  93. Livet J et al (2007) Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature 450(7166):56–62

    CAS  PubMed  CrossRef  Google Scholar 

  94. Dupuy AJ et al (2005) Mammalian mutagenesis using a highly mobile somatic Sleeping Beauty transposon system. Nature 436(7048):221–226

    CAS  PubMed  CrossRef  Google Scholar 

  95. White RM et al (2008) Transparent adult zebrafish as a tool for in vivo transplantation analysis. Cell Stem Cell 2(2):183–189

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  96. Yu M et al (2013) Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339(6119):580–584

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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):649–653

    CAS  PubMed  CrossRef  Google Scholar 

  98. Zong C et al (2012) Genome-wide detection of single-nucleotide and copy-number variations of a single human cell. Science 338(6114):1622–1626

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  99. Drummond AJ et al (2012) Bayesian phylogenetics with BEAUti and the BEAST 1.7. Mol Biol Evol 29(8):1969–1973

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  100. Sottoriva A et al (2013) Single-molecule genomic data delineate patient-specific tumor profiles and cancer stem cell organization. Cancer Res 73(1):41–49

    CAS  PubMed  CrossRef  Google Scholar 

  101. Lee JM et al (2013) Feasibility and safety of sequential research-related tumor core biopsies in clinical trials. Cancer 119(7):1357–1364

    CAS  PubMed  CrossRef  Google Scholar 

  102. Overman MJ et al (2013) Use of research biopsies in clinical trials: are risks and benefits adequately discussed? J Clin Oncol 31(1):17–22

    PubMed  CrossRef  Google Scholar 

  103. Peppercorn J (2013) Toward improved understanding of the ethical and clinical issues surrounding mandatory research biopsies. J Clin Oncol 31(1):1–2

    PubMed  CrossRef  Google Scholar 

  104. Ikushima H, Miyazono K (2010) TGFb signalling: a complex web in cancer progression. Nat Rev Cancer 10:415–424

    CAS  PubMed  CrossRef  Google Scholar 

  105. Massagué J (2008) TGFb in cancer. Cell 134:215–230

    PubMed  PubMed Central  CrossRef  CAS  Google Scholar 

  106. Shi Y, Massagué J (2003) Mechanisms of TGF-b signaling from cell membrane to the nucleus. Cell 113:685–700

    CAS  PubMed  CrossRef  Google Scholar 

  107. Feng XH, Derynck R (2005) Specificity and versatility in TGF-b signaling through Smads. Annu Rev Cell Dev Biol 21:659–693

    CAS  PubMed  CrossRef  Google Scholar 

  108. Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-b family signalling. Nature 425:577–584

    CAS  PubMed  CrossRef  Google Scholar 

  109. Moustakas A, Heldin CH (2005) Non-Smad TGF-b signals. J Cell Sci 118:3573–3584

    CAS  PubMed  CrossRef  Google Scholar 

  110. Gherardi E et al (2006) Structural basis of hepatocyte growth factor/scatter factor and MET signalling. Proc Natl Acad Sci U S A 103:4046–4051

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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 279:39915–39924

    CAS  PubMed  CrossRef  Google Scholar 

  112. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4:915.925

    CrossRef  CAS  Google Scholar 

  113. Weidner KM et al (1996) Interaction between Gab1 and the c.Met receptor tyrosine kinase is responsible for epithelial morphogenesis. Nature 384:173–176

    CAS  PubMed  CrossRef  Google Scholar 

  114. Lai AZ, Abella JV, Park M (2009) Crosstalk in Met receptor oncogenesis. Trends Cell Biol 19:542–551

    CAS  PubMed  CrossRef  Google Scholar 

  115. Trusolino L, Bertotti A, Comoglio PM (2010) MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol 11:834–848

    CAS  PubMed  CrossRef  Google Scholar 

  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 20:8513–8525

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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 29:3018.3032

    PubMed Central  CrossRef  CAS  Google Scholar 

  118. Schaeper U et al (2000) Coupling of Gab1 to c.Met, Grb2, and Shp2 mediates biological responses. J Cell Biol 149:1419–1432

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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 104:15376–15381

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  120. Beenken A, Mohammadi M (2009) The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 8:235–253

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  121. Eswarakumar VP, Lax I, Schlessinger J (2005) Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 16:139–149

    CAS  PubMed  CrossRef  Google Scholar 

  122. Mohammadi M, Olsen SK, Ibrahimi OA (2005) Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev 16:107–137

    CAS  PubMed  CrossRef  Google Scholar 

  123. Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10:116–129

    CAS  PubMed  CrossRef  Google Scholar 

  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):785–789

    CAS  PubMed  CrossRef  Google Scholar 

  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):333–345

    CAS  PubMed  CrossRef  Google Scholar 

  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):1561–1570

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  127. Pollak M (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8:915–928

    CAS  PubMed  CrossRef  Google Scholar 

  128. Pollak MN, Schernhammer ES, Hankinson SE (2004) Insulin-like growth factors and neoplasia. Nat Rev Cancer 4:505–518

    CAS  PubMed  CrossRef  Google Scholar 

  129. Ullrich A et al (1985) Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature 313:756–761

    CAS  PubMed  CrossRef  Google Scholar 

  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 30:586–623

    CAS  PubMed  CrossRef  Google Scholar 

  131. LeRoith D (2000) Insulin-like growth factor I receptor signaling-overlapping or redundant pathways? Endocrinology 141:1287–1288

    CAS  PubMed  Google Scholar 

  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 66:192–197

    CAS  PubMed  CrossRef  Google Scholar 

  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 67:9066–9076

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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 7:415–428

    CAS  PubMed  CrossRef  Google Scholar 

  135. Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelialmesenchymal transitions. Nat Rev Mol Cell Biol 7:131–142

    CAS  PubMed  CrossRef  Google Scholar 

  136. Grunert S, Jechlinger M, Beug H (2003) Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat Rev Mol Cell Biol 4:657–665

    PubMed  CrossRef  CAS  Google Scholar 

  137. Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9:265–273

    CAS  PubMed  CrossRef  Google Scholar 

  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 173:395–404

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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 24:1309–1319

    CAS  PubMed  CrossRef  Google Scholar 

  140. Wang W et al (2004) Identification and testing of a gene expression signature of invasive carcinoma cells within primary mammary tumors. Cancer Res 64:8585–8594

    CAS  PubMed  CrossRef  Google Scholar 

  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 10:593–601

    CAS  PubMed  CrossRef  Google Scholar 

  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 283:14910–14914

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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 9:582–589

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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 22:894–907

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  145. Wellner U, Schubert J, Burk UC et al (2009) The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol 11:1487–1495

    CAS  PubMed  CrossRef  Google Scholar 

  146. Friedl P, Wolf K (2010) Plasticity of cell migration: a multiscale tuning model. J Cell Biol 188:11–19

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  147. Wang W, Eddy R, Condeelis J (2007) The cofilin pathway in breast cancer invasion and metastasis. Nat Rev Cancer 7:429–440

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  148. Olson MF, Sahai E (2008) The actin cytoskeleton in cancer cell motility. Clin Exp Metastasis 26:273–287

    PubMed  CrossRef  Google Scholar 

  149. Gupton SL, Gertler FB (2007) Filopodia: the fingers that do the walking. Sci STKE 2007(400):re5

    PubMed  CrossRef  Google Scholar 

  150. Vignjevic D, Montagnac G (2008) Reorganisation of the dendritic actin network during cancer cell migration and invasion. Semin Cancer Biol 18:12–22

    CAS  PubMed  CrossRef  Google Scholar 

  151. Buccione R, Caldieri G, Ayala I (2009) Invadopodia: specialized tumor cell structures for the focal degradation of the extracellular matrix. Cancer Metastasis Rev 28:137–149

    PubMed  CrossRef  Google Scholar 

  152. Vega FM, Ridley AJ (2008) Rho GTPases in cancer cell biology. FEBS Lett 582:2093–2101

    CAS  PubMed  CrossRef  Google Scholar 

  153. Sahai E, Marshall CJ (2002) RHO-GTPases and cancer. Nat Rev Cancer 2:133–142

    PubMed  CrossRef  Google Scholar 

  154. Jaffe AB, Hall A (2005) Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 21:247–269

    CAS  PubMed  CrossRef  Google Scholar 

  155. Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420:629–635

    CAS  PubMed  CrossRef  Google Scholar 

  156. Burridge K, Wennerberg K (2004) Rho and Rac take center stage. Cell 116:167–179

    CAS  PubMed  CrossRef  Google Scholar 

  157. Narumiya S, Tanji M, Ishizaki T (2009) Rho signaling, ROCK and mDia1, in transformation, metastasis and invasion. Cancer Metastasis Rev 28:65–76

    CAS  PubMed  CrossRef  Google Scholar 

  158. Hall A (2005) Rho GTPases and the control of cell behaviour. Biochem Soc Trans 33:891–895

    CAS  PubMed  CrossRef  Google Scholar 

  159. Ridley AJ (2006) Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol 16:522–529

    CAS  PubMed  CrossRef  Google Scholar 

  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 149:775–782

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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 278:1464–1466

    CAS  PubMed  CrossRef  Google Scholar 

  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 147:1009–1022

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  163. Pertz O, Hodgson L, Klemke RL, Hahn KM (2006) Spatiotemporal dynamics of RhoA activity in migrating cells. Nature 440:1069–1072

    CAS  PubMed  CrossRef  Google Scholar 

  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 70:401–410

    CAS  PubMed  CrossRef  Google Scholar 

  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 14:1964–1977

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  166. Anastasiadis PZ (1773) p120-ctn: a nexus for contextual signaling via Rho GTPases. Biochim Biophys Acta 2007:34–46

    Google Scholar 

  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 65:10938–10945

    CAS  PubMed  CrossRef  Google Scholar 

  168. Pinner S, Sahai E (2008) PDK1 regulates cancer cell motility by antagonizing inhibition of ROCK1 by RhoE. Nat Cell Biol 10:127–137

    CAS  PubMed  CrossRef  Google Scholar 

  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 9:261–272

    CAS  PubMed  CrossRef  Google Scholar 

  170. Wicki A, Christofori G (2007) The potential role of podoplanin in tumour invasion. Br J Cancer 96:1–5

    CAS  PubMed  CrossRef  Google Scholar 

  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 166:913–921

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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 373:36–41

    CAS  PubMed  CrossRef  Google Scholar 

  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 112:4601–4613

    CAS  PubMed  Google Scholar 

  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 104:15988–15993

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  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 9:893–904

    CAS  PubMed  CrossRef  Google Scholar 

  176. De Wever O, Mareel M (2003) Role of tissue stroma in cancer cell invasion. J Pathol 200:429–447

    PubMed  CrossRef  CAS  Google Scholar 

  177. Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011–1027

    CAS  PubMed  CrossRef  Google Scholar 

  178. Wissmann C, Detmar M (2006) Pathways targeting tumor lymphangiogenesis. Clin Cancer Res 12:6865–6868

    CAS  PubMed  CrossRef  Google Scholar 

  179. Mantovani A, Sica A et al (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686

    CAS  PubMed  CrossRef  Google Scholar 

  180. Mantovani A, Romero P, Palucka AK et al (2008) Tumour immunity: effector response to tumour and role of the microenvironment. Lancet 371:771–783

    CAS  PubMed  CrossRef  Google Scholar 

  181. Talmadge JE, Donkor M, Scholar E (2007) Inflammatory cell infiltration of tumors: Jekyll or Hyde. Cancer Metastasis Rev 26:373–400

    PubMed  CrossRef  Google Scholar 

  182. Lewis CE, Pollard JW (2006) Distinct role of macrophages in different tumor microenvironments. Cancer Res 66:605–612

    CAS  PubMed  CrossRef  Google Scholar 

  183. Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124:263–266

    CAS  PubMed  CrossRef  Google Scholar 

  184. Wyckoff JB, Wang Y, Lin EY et al (2007) Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res 67:2649–2656

    CAS  PubMed  CrossRef  Google Scholar 

  185. De Wever O, Demetter P, Mareel M et al (2008) Stromal myofibroblasts are drivers of invasive cancer growth. Int J Cancer 123:2229–2238

    PubMed  CrossRef  CAS  Google Scholar 

  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 66:2725–2731

    Google Scholar 

  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):6392–6397

    Google Scholar 

  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 27:157–169

    Google Scholar 

  189. Staller P et al (2003) Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 425:307–311

    Google Scholar 

  190. Ceradini DJ et al (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nature Med 10:858–864

    Google Scholar 

  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 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joshua D. Schiffman M.D. .

Editor information

Editors and Affiliations

Appendix: Molecular Pathways Underlying Cell Motility

Appendix: Molecular Pathways Underlying Cell Motility

TGF-β is a major regulatory molecule in cell migration and invasion. TGF-β binds to and activates its receptors TβRI and TβRII [104107]. Receptor activation leads to Smad complex translocation from cytoplasm to nucleus and activates the expression of transcription factors such as ZEB1, ZEB2, SNAI1, SNAI2, TWIST, which promote cell migration and invasion [104107]. TGF-β can also turn on non-Smad cell signaling such as GTPase RhoA and phosphoinositide-3-kinase (PI3K) pathways through TβRI and TβRII, which then activate cell migration [108, 109].

Other cell surface receptors including hepatocyte growth factor receptor c-MET, fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGF), insulin-like growth factor receptor (IGF1R), epidermal growth factor receptor (EGFR), also regulate the cell motility and detachment. Hepatocyte growth factor (HGF) binds to its receptor c-MET and induces receptor dimerization and activation [110, 111]. Activation of c-Met recruits multiple cellular proteins and turn on cell signaling cascades including RAC1 cell division control protein 42 (CDC42) and p21 activated kinase PAK, which promotes cell migration [112119]. Fibroblast growth factor FGFs bind and activate their receptors FGFRs, which then activates RAS and PI3K pathway to promote cell migration [120123]. Platelet-derived growth factor PDGF binds to its receptor PDGFR-β and activates downstream signaling pathways such as PI3K through phosphorylation, which then enhance cell motility [124126]. Insulin-like growth factor IGF1 receptor IGF1R assembles a protein complex including IRS-1 upon binding to IGF1, which also promotes the expression of transcription factors that regulate cell detachment [127, 128]. IGF1R activation also turns on PI3K signaling pathway, which promotes cell migration [127131]. Epidermal growth factor (EGF) can also activate its receptor EGFR and downstream PI3K and PLC signaling pathways as well as the expression of transcription factor Twist [132, 133].

The effects of these cell surface receptors and signaling molecule activation are detachment and motility of tumor cells. The activation of transcription factors such as SNAI1, SNAI2, TWIST, ZEB1 and ZEB2 suppresses the expression of E-cadherin, a major component of epithelial adherens junctions [134]. Loss of E-cadherin function is one of the characteristics of epithelial-mesenchymal transition (EMT), which promotes tumor cell detachment, migration and invasion from primary tumor to neighboring tissues [135137]. In concert with cell detachment, the activation of PI3K and PLC pathways promotes actin polymerization and cell movement [138140].

Cell detachment and movement can also be regulated epigenetically. MicroRNAs are 21–23 nucleotide long small noncoding RNAs and can serve as mediators between cell surface receptors and their downstream transcription factors. MiR-200 family members are regulated by TGFβ pathways and suppress ZEB1 and ZEB2 [141145]. The coordination of the activation of pathways that promote cell detachment and movement and the suppression of pathways that inhibit cell movement causes tumor cells to migrate and invade.

Cell migration includes single cell migration and collective cell migration. Both forms of migration contribute to the seeding of tumor cells in secondary organs and eventual growth of metastases [146]. The signaling pathways critical for single cell migration regulate reorganization of actin cytoskeleton and membrane protrusion formation such as invadopodia, lamillipodia and filopodia [19, 147151]. Rho GTPases play important roles in these processes [152156] (Table 8.1). GTPases are activated in GTP-binding state and inactive in GDP-binding state. RhoA is one of the GTPases that activate cell migration. It activates downstream ROCK kinases that promote actin stress fiber formation [152157]. Other GTPases promote cell migration through different mechanisms. Rac1 regulates lamillipodia by activating PAK kinases whereas Cdc42 promotes filopodia formation by activating PAK kinases [158, 159]. The activation of GTPases is controlled by GTPase-activating proteins (GAPs), guanine nucleotide exchange factors (GEFs) and guanosine nucleotide dissociation inhibitors (GDIs). Activation and inactivation of RhoA requires RhoGAP p190-RhoGAP and RhoGEF Vav2 [160164]. Rac1 function of promoting cell movement is regulated by RhoGEF Dock3 [21]. p120-catenin serves as a GDI for both RhoA and Rac to suppress their activities [165167]. The activation or suppression of GTPase and their regulators are regulated by cell signaling pathways. For example, PDK1 functions as a mediator between PI3K signaling and RhoA activity [168]. The activation of these signaling molecules allows tumor cells to migrate through collagen fibers in the tumor microenvironment.

In contrast of single cell migration, cells in collective migration move in sheets and strands while maintaining cell-cell junctions. Such movement requires the coordination of cell adhesion and cell migration. It has been shown that cell surface protein podoplanin is able to mediate such movement [169] (Table 8.1). Podoplanin is expressed in cancer cells of multiple types such as breast, lung, ovary, squamous cell carcinoma, etc. that locate on the outer layer of invasion front [170172]. Podoplanin expression is sufficient for cells to form filapodia-like protrusion and display collective migration [173]. When a podoplanin transgenic mouse model is crossed with RipTag pancreatic cancer mouse model, pancreatic cancer cells in this model exhibit collective cell invasion without epithelial-mesenchymal transition, demonstrating the podoplanin has distinct mechanisms than those of single cell migration [169]. In addition, stroma cells are required for collective-invasion cells to go through extracellular matrix [174]. An in vitro cell culture model demonstrated that fibroblasts exhibit protease activities and remodel matrix for the collective-invasion cells to move through extracellular matrix [174]. This is in contrast with capabilities of single migration cancer cells that exhibit protease activity themselves [175].

Tumor microenvironment is also critical for cancer cells migration and invasion. The communications between cells in tumor environment and cancer cells provide the signals and facilitate cancer cell movement [176]. Cells in tumor microenvironment include endothelial cells, immune cells, myofibroblasts, nerve cells, adipocytes, etc. [176]. Endothelial cells form blood and lymphatic vessels in tumor microenvironment [177, 178]. Both endothelial cells and tumor cells express cell surface receptors such as VEGFR, c-MET, IGFR, etc which stimulate vessel formation in endothelial cells [177, 178]. These blood and lymphatic vessels serve as conduits for cancer cells to eventually leave primary tumor sites. Immune cells such as leukocytes, monocytes and tumor-associated macrophages secrete chemokines IL-1, IL-6, TNFα, CXCL12, MMPs, uPA, which promote inflammatory reaction for invasion, break down basement membranes and facilitate tumor cell migration and invasion [179184]. Myofibroblasts produce signaling molecules such as TGFβ, IGF1, FGF to promote cancer cell migration and invasion [185]. Hypoxia environment in tumors also create an ecosystem to promote cell migration. Hypoxia-mediated gene expression plays an important role in this process. Hypoxia-inducible factor (HIF) family of transcription factors promotes both cell detachment and motility by the suppression of E-cadherin expression and activation of chemotaxis factorsCXCR4/SDF-1 [186191] (Table 8.1). Tumor microenvironment and the cells in the surroundings provide additional signals and environment supporting tumor cell growth, migration and invasion.

Rights and permissions

Reprints and Permissions

Copyright information

© 2016 Springer-Verlag New York

About this chapter

Cite this chapter

Schiffman, J.D., White, R.M., Graham, T.A., Huang, Q., Aktipis, A. (2016). The Darwinian Dynamics of Motility and Metastasis. In: Maley, C., Greaves, M. (eds) Frontiers in Cancer Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-6460-4_8

Download citation