Skip to main content

Migratory Strategies of Normal and Malignant Stem Cells

  • Protocol
  • First Online:
Stem Cell Migration

Part of the book series: Methods in Molecular Biology ((MIMB,volume 750))

Abstract

The regulated migration of stem cells is critical for organogenesis during development and for tissue ­homeostasis and repair during adulthood. Human bone marrow (BM) represents an accessible reservoir containing regenerative cell types from hematopoietic, endothelial, and mesenchymal-stromal lineages that together coordinate hematopoiesis and promote the repair of damaged vasculature and tissues throughout the body. Thus, a detailed understanding of lineage-specific stem cell mobilization, homing, and subsequent engraftment in areas of injury or disease is of critical importance to the rational development of novel cell-mediated regenerative therapies. Stem cell trafficking via the circulation from site of origin to peripheral tissues requires fundamental molecular pathways governing (1) niche-specific deadhesion of progenitor cells; (2) chemoattraction to guide progenitor cell homing; and (3) interstitial navigation and adhesion/retention of recruited progenitor cells. This overview chapter summarizes the diversity of migratory strategies employed by hematopoietic, endothelial, and mesenchymal-stromal progenitor cells during repair and regeneration after tissue damage. Further elucidation of stem cell homing and migration pathways will allow greater application of stem cells for targeted cell therapy and/or drug delivery for tissue repair. Strikingly similar migratory mechanisms appear to govern the in vivo migration of recently characterized cancer stem cells (CSC) in leukemias and solid tumors, indicating that conserved principles of stem cell migration and niche specificity will provide new information to target CSC in anticancer therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Weissman, I. L. (2000) Stem cells: units of development, units of regeneration, and units in evolution Cell 100, 157–68.

    PubMed  CAS  Google Scholar 

  2. Laird, D. J., von Andrian, U. H., and Wagers, A. J. (2008) Stem cell trafficking in tissue development, growth, and disease Cell 132, 612–30.

    PubMed  CAS  Google Scholar 

  3. Morrison, S. J. and Spradling, A. C. (2008) Stem cells and niches: mechanisms that promote stem cell maintenance throughout life Cell 132, 598–611.

    CAS  Google Scholar 

  4. Massberg, S., Schaerli, P., Knezevic-Maramica, I., Kollnberger, M., Tubo, N., Moseman, E. A., Huff, I. V., Junt, T., Wagers, A. J., Mazo, I. B., and von Andrian, U. H. (2007) Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues Cell 131, 994–1008.

    PubMed  CAS  Google Scholar 

  5. Asahara, T., Murohara, T., Sullivan, A., Silver, M., van der Zee, R., Li, T., Witzenbichler, B., Schatteman, G., and Isner, J. M. (1997) Isolation of putative progenitor endothelial cells for angiogenesis Science 275, 964–7.

    CAS  Google Scholar 

  6. Yoder, M. C., Mead, L. E., Prater, D., Krier, T. R., Mroueh, K. N., Li, F., Krasich, R., Temm, C. J., Prchal, J. T., and Ingram, D. A. (2007) Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals Blood 109, 1801–9.

    CAS  Google Scholar 

  7. Crisan, M., Yap, S., Casteilla, L., Chen, C. W., Corselli, M., Park, T. S., Andriolo, G., Sun, B., Zheng, B., Zhang, L., Norotte, C., Teng, P. N., Traas, J., Schugar, R., Deasy, B. M., Badylak, S., Buhring, H. J., Giacobino, J. P., Lazzari, L., Huard, J., and Peault, B. (2008) A perivascular origin for mesenchymal stem cells in multiple human organs Cell Stem Cell 3, 301–13.

    CAS  Google Scholar 

  8. Uccelli, A., Moretta, L., and Pistoia, V. (2008) Mesenchymal stem cells in health and disease Nat Rev Immunol.

    Google Scholar 

  9. Spaggiari, G. M., Capobianco, A., Abdelrazik, H., Becchetti, F., Mingari, M. C., and Moretta, L. (2008) Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2 Blood 111, 1327–33.

    Google Scholar 

  10. Au, P., Tam, J., Fukumura, D., and Jain, R. K. (2008) Bone marrow-derived mesenchymal stem cells facilitate engineering of long-lasting functional vasculature Blood 111, 4551–8.

    CAS  Google Scholar 

  11. Hess, D., Li, L., Martin, M., Sakano, S., Hill, D., Strutt, B., Thyssen, S., Gray, D. A., and Bhatia, M. (2003) Bone marrow-derived stem cells initiate pancreatic regeneration Nat Biotechnol 21, 763–70.

    CAS  Google Scholar 

  12. Lee, R. H., Seo, M. J., Reger, R. L., Spees, J. L., Pulin, A. A., Olson, S. D., and Prockop, D. J. (2006) Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice Proc Natl Acad Sci USA 103, 17438–43.

    CAS  Google Scholar 

  13. Zhou, P., Hohm, S., Capoccia, B., Wirthlin, L., Hess, D., Link, D., and Nolta, J. (2008) Immunodeficient mouse models to study human stem cell-mediated tissue repair Methods Mol Biol 430, 213–25.

    CAS  Google Scholar 

  14. Kaplan, R. N., Rafii, S., and Lyden, D. (2006) Preparing the “soil”: the premetastatic niche Cancer Res 66, 11089–93.

    PubMed  CAS  Google Scholar 

  15. Avecilla, S. T., Hattori, K., Heissig, B., Tejada, R., Liao, F., Shido, K., Jin, D. K., Dias, S., Zhang, F., Hartman, T. E., Hackett, N. R., Crystal, R. G., Witte, L., Hicklin, D. J., Bohlen, P., Eaton, D., Lyden, D., de Sauvage, F., and Rafii, S. (2004) Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis Nat Med 10, 64–71.

    CAS  Google Scholar 

  16. Heissig, B., Hattori, K., Dias, S., Friedrich, M., Ferris, B., Hackett, N. R., Crystal, R. G., Besmer, P., Lyden, D., Moore, M. A., Werb, Z., and Rafii, S. (2002) Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand Cell 109, 625–37.

    PubMed  CAS  Google Scholar 

  17. Heissig, B., Ohki, Y., Sato, Y., Rafii, S., Werb, Z., and Hattori, K. (2005) A role for niches in hematopoietic cell development Hematology 10, 247–53.

    CAS  Google Scholar 

  18. Kollet, O., Dar, A., Shivtiel, S., Kalinkovich, A., Lapid, K., Sztainberg, Y., Tesio, M., Samstein, R. M., Goichberg, P., Spiegel, A., Elson, A., and Lapidot, T. (2006) Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells Nat Med 12, 657–64.

    CAS  Google Scholar 

  19. Broxmeyer, H. E., Hangoc, G., Cooper, S., Campbell, T., Ito, S., and Mantel, C. (2007) AMD3100 and CD26 modulate mobilization, engraftment, and survival of hematopoietic stem and progenitor cells mediated by the SDF-1/CXCL12-CXCR4 axis Ann N Y Acad Sci 1106, 1–19.

    PubMed  CAS  Google Scholar 

  20. Campbell, T. B., Hangoc, G., Liu, Y., Pollok, K., and Broxmeyer, H. E. (2007) Inhibition of CD26 in human cord blood CD34+ cells enhances their engraftment of nonobese diabetic/severe combined immunodeficiency mice Stem Cells Dev 16, 347–54.

    PubMed  CAS  Google Scholar 

  21. Christopherson, K. W., 2nd, Hangoc, G., and Broxmeyer, H. E. (2002) Cell surface peptidase CD26/dipeptidylpeptidase IV ­regulates CXCL12/stromal cell-derived factor-1 alpha-mediated chemotaxis of human cord blood CD34+ progenitor cells J Immunol 169, 7000–8.

    PubMed  CAS  Google Scholar 

  22. Christopherson, K. W., 2nd, Hangoc, G., Mantel, C. R., and Broxmeyer, H. E. (2004) Modulation of hematopoietic stem cell homing and engraftment by CD26 Science 305, 1000–3.

    Google Scholar 

  23. Stier, S., Ko, Y., Forkert, R., Lutz, C., Neuhaus, T., Grunewald, E., Cheng, T., Dombkowski, D., Calvi, L. M., Rittling, S. R., and Scadden, D. T. (2005) Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size J Exp Med 201, 1781–91.

    CAS  Google Scholar 

  24. Calvi, L. M., Adams, G. B., Weibrecht, K. W., Weber, J. M., Olson, D. P., Knight, M. C., Martin, R. P., Schipani, E., Divieti, P., Bringhurst, F. R., Milner, L. A., Kronenberg, H. M., and Scadden, D. T. (2003) Osteoblastic cells regulate the haematopoietic stem cell niche Nature 425, 841–6.

    CAS  Google Scholar 

  25. Levesque, J. P., Hendy, J., Winkler, I. G., Takamatsu, Y., and Simmons, P. J. (2003) Granulocyte colony-stimulating factor induces the release in the bone marrow of proteases that cleave c-KIT receptor (CD117) from the surface of hematopoietic progenitor cells Exp Hematol 31, 109–17.

    PubMed  CAS  Google Scholar 

  26. Levesque, J. P., Hendy, J., Takamatsu, Y., Simmons, P. J., and Bendall, L. J. (2003) Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide J Clin Invest 111, 187–96.

    PubMed  CAS  Google Scholar 

  27. Liles, W. C., Broxmeyer, H. E., Rodger, E., Wood, B., Hubel, K., Cooper, S., Hangoc, G., Bridger, G. J., Henson, G. W., Calandra, G., and Dale, D. C. (2003) Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist Blood 102, 2728–30.

    PubMed  CAS  Google Scholar 

  28. Broxmeyer, H. E., Orschell, C. M., Clapp, D. W., Hangoc, G., Cooper, S., Plett, P. A., Liles, W. C., Li, X., Graham-Evans, B., Campbell, T. B., Calandra, G., Bridger, G., Dale, D. C., and Srour, E. F. (2005) Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist J Exp Med 201, 1307–18.

    PubMed  CAS  Google Scholar 

  29. Hess, D. A., Bonde, J., Craft, T. P., Wirthlin, L., Hohm, S., Lahey, R., Todt, L. M., Dipersio, J. F., Devine, S. M., and Nolta, J. A. (2007) Human progenitor cells rapidly mobilized by AMD3100 repopulate NOD/SCID mice with increased frequency in ­comparison to cells from the same donor mobilized by granulocyte colony stimulating factor Biol Blood Marrow Transplant 13, 398–411.

    PubMed  CAS  Google Scholar 

  30. Shepherd, R. M., Capoccia, B. J., Devine, S. M., Dipersio, J., Trinkaus, K. M., Ingram, D., and Link, D. C. (2006) Angiogenic cells can be rapidly mobilized and efficiently harvested from the blood following treatment with AMD3100 Blood 108, 3662–7.

    Google Scholar 

  31. Capoccia, B. J., Shepherd, R. M., and Link, D. C. (2006) G-CSF and AMD3100 mobilize monocytes into the blood that stimulate angiogenesis in vivo through a paracrine mechanism Blood 108, 2438–45.

    PubMed  CAS  Google Scholar 

  32. Pitchford, S. C., Furze, R. C., Jones, C. P., Wengner, A. M., and Rankin, S. M. (2009) Differential mobilization of subsets of progenitor cells from the bone marrow Cell Stem Cell 4, 62–72.

    CAS  Google Scholar 

  33. Broxmeyer, H. E., Kohli, L., Kim, C. H., Lee, Y., Mantel, C., Cooper, S., Hangoc, G., Shaheen, M., Li, X., and Clapp, D. W. (2003) Stromal cell-derived factor-1/CXCL12 directly enhances survival/antiapoptosis of myeloid progenitor cells through CXCR4 and G(alpha)i proteins and enhances engraftment of competitive, repopulating stem cells J Leukoc Biol 73, 630–8.

    PubMed  CAS  Google Scholar 

  34. Broxmeyer, H. E., Cooper, S., Kohli, L., Hangoc, G., Lee, Y., Mantel, C., Clapp, D. W., and Kim, C. H. (2003) Transgenic expression of stromal cell-derived factor-1/CXC chemokine ligand 12 enhances myeloid progenitor cell survival/antiapoptosis in vitro in response to growth factor withdrawal and enhances myelopoiesis in vivo J Immunol 170, 421–9.

    PubMed  CAS  Google Scholar 

  35. Lee, Y., Gotoh, A., Kwon, H. J., You, M., Kohli, L., Mantel, C., Cooper, S., Hangoc, G., Miyazawa, K., Ohyashiki, K., and Broxmeyer, H. E. (2002) Enhancement of intracellular signaling associated with hematopoietic progenitor cell survival in response to SDF-1/CXCL12 in synergy with other cytokines Blood 99, 4307–17.

    PubMed  CAS  Google Scholar 

  36. Jo, D. Y., Rafii, S., Hamada, T., and Moore, M. A. (2000) Chemotaxis of primitive hematopoietic cells in response to stromal cell-derived factor-1 J Clin Invest 105, 101–11.

    Google Scholar 

  37. Naiyer, A. J., Jo, D. Y., Ahn, J., Mohle, R., Peichev, M., Lam, G., Silverstein, R. L., Moore, M. A., and Rafii, S. (1999) Stromal derived factor-1-induced chemokinesis of cord blood CD34(+) cells (long-term culture-initiating cells) through endothelial cells is mediated by E-selectin Blood 94, 4011–9.

    PubMed  CAS  Google Scholar 

  38. Mohle, R., Bautz, F., Rafii, S., Moore, M. A., Brugger, W., and Kanz, L. (1998) The chemokine receptor CXCR-4 is expressed on CD34+ hematopoietic progenitors and ­leukemic cells and mediates transendothelial migration induced by stromal cell-derived factor-1 Blood 91, 4523–30.

    Google Scholar 

  39. Kollet, O., Petit, I., Kahn, J., Samira, S., Dar, A., Peled, A., Deutsch, V., Gunetti, M., Piacibello, W., Nagler, A., and Lapidot, T. (2002) Human CD34(+)CXCR4(−) sorted cells harbor intracellular CXCR4, which can be functionally expressed and provide NOD/SCID repopulation Blood 100, 2778–86.

    PubMed  CAS  Google Scholar 

  40. Kollet, O., Spiegel, A., Peled, A., Petit, I., Byk, T., Hershkoviz, R., Guetta, E., Barkai, G., Nagler, A., and Lapidot, T. (2001) Rapid and efficient homing of human CD34(+)CD38(−/low)CXCR4(+) stem and progenitor cells to the bone marrow and spleen of NOD/SCID and NOD/SCID/B2m(null) mice Blood 97, 3283–91.

    PubMed  CAS  Google Scholar 

  41. Peled, A., Kollet, O., Ponomaryov, T., Petit, I., Franitza, S., Grabovsky, V., Slav, M. M., Nagler, A., Lider, O., Alon, R., Zipori, D., and Lapidot, T. (2000) The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34(+) cells: role in transendothelial/stromal migration and engraftment of NOD/SCID mice Blood 95, 3289–96.

    PubMed  CAS  Google Scholar 

  42. Peled, A., Grabovsky, V., Habler, L., Sandbank, J., Arenzana-Seisdedos, F., Petit, I., Ben-Hur, H., Lapidot, T., and Alon, R. (1999) The chemokine SDF-1 stimulates integrin-mediated arrest of CD34(+) cells on vascular endothelium under shear flow J Clin Invest 104, 1199–211.

    PubMed  CAS  Google Scholar 

  43. Peled, A., Petit, I., Kollet, O., Magid, M., Ponomaryov, T., Byk, T., Nagler, A., Ben-Hur, H., Many, A., Shultz, L., Lider, O., Alon, R., Zipori, D., and Lapidot, T. (1999) Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4 Science 283, 845–8.

    Google Scholar 

  44. Hattori, K., Heissig, B., Tashiro, K., Honjo, T., Tateno, M., Shieh, J. H., Hackett, N. R., Quitoriano, M. S., Crystal, R. G., Rafii, S., and Moore, M. A. (2001) Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells Blood 97, 3354–60.

    PubMed  CAS  Google Scholar 

  45. Lapidot, T., Dar, A., and Kollet, O. (2005) How do stem cells find their way home? Blood 106, 1901–10.

    PubMed  CAS  Google Scholar 

  46. Ponomaryov, T., Peled, A., Petit, I., Taichman, R. S., Habler, L., Sandbank, J., Arenzana-Seisdedos, F., Magerus, A., Caruz, A., Fujii, N., Nagler, A., Lahav, M., Szyper-Kravitz, M., Zipori, D., and Lapidot, T. (2000) Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function J Clin Invest 106, 1331–9.

    PubMed  CAS  Google Scholar 

  47. Zhao, Y., Zhan, Y., Burke, K. A., and Anderson, W. F. (2005) Soluble factor(s) from bone marrow cells can rescue lethally irradiated mice by protecting endogenous hematopoietic stem cells Exp Hematol 33, 428–34.

    PubMed  CAS  Google Scholar 

  48. Kawabata, K., Ujikawa, M., Egawa, T., Kawamoto, H., Tachibana, K., Iizasa, H., Katsura, Y., Kishimoto, T., and Nagasawa, T. (1999) A cell-autonomous requirement for CXCR4 in long-term lymphoid and myeloid reconstitution Proc Natl Acad Sci USA 96, 5663–7.

    PubMed  CAS  Google Scholar 

  49. Ma, Q., Jones, D., and Springer, T. A. (1999) The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment Immunity 10, 463–71.

    PubMed  CAS  Google Scholar 

  50. Kollet, O., Shivtiel, S., Chen, Y. Q., Suriawinata, J., Thung, S. N., Dabeva, M. D., Kahn, J., Spiegel, A., Dar, A., Samira, S., Goichberg, P., Kalinkovich, A., Arenzana-Seisdedos, F., Nagler, A., Hardan, I., Revel, M., Shafritz, D. A., and Lapidot, T. (2003) HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver J Clin Invest 112, 160–9.

    PubMed  CAS  Google Scholar 

  51. Ratajczak, M. Z., Kucia, M., Reca, R., Majka, M., Janowska-Wieczorek, A., and Ratajczak, J. (2004) Stem cell plasticity revisited: CXCR4-positive cells expressing mRNA for early muscle, liver and neural cells ‘hide out’ in the bone marrow Leukemia 18, 29–40.

    PubMed  CAS  Google Scholar 

  52. Stumm, R. K., Rummel, J., Junker, V., Culmsee, C., Pfeiffer, M., Krieglstein, J., Hollt, V., and Schulz, S. (2002) A dual role for the SDF-1/CXCR4 chemokine receptor system in adult brain: isoform-selective regulation of SDF-1 expression modulates CXCR4-dependent neuronal plasticity and cerebral leukocyte recruitment after focal ischemia J Neurosci 22, 5865–78.

    PubMed  CAS  Google Scholar 

  53. Petit, I., Goichberg, P., Spiegel, A., Peled, A., Brodie, C., Seger, R., Nagler, A., Alon, R., and Lapidot, T. (2005) Atypical PKC-zeta regulates SDF-1-mediated migration and development of human CD34+ progenitor cells J Clin Invest 115, 168–76.

    PubMed  CAS  Google Scholar 

  54. Cancelas, J. A., Lee, A. W., Prabhakar, R., Stringer, K. F., Zheng, Y., and Williams, D. A. (2005) Rac GTPases differentially integrate signals regulating hematopoietic stem cell localization Nat Med 11, 886–91.

    CAS  Google Scholar 

  55. Gu, Y., Filippi, M. D., Cancelas, J. A., Siefring, J. E., Williams, E. P., Jasti, A. C., Harris, C. E., Lee, A. W., Prabhakar, R., Atkinson, S. J., Kwiatkowski, D. J., and Williams, D. A. (2003) Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases Science 302, 445–9.

    Google Scholar 

  56. Brooke, G., Tong, H., Levesque, J. P., and Atkinson, K. (2008) Molecular trafficking mechanisms of multipotent mesenchymal stem cells derived from human bone marrow and placenta Stem Cells Dev 17, 929–40.

    CAS  Google Scholar 

  57. Uccelli, A., Moretta, L., and Pistoia, V. (2008) Mesenchymal stem cells in health and disease Nat Rev Immunol 8, 726–36.

    CAS  Google Scholar 

  58. Hung, S. C., Pochampally, R. R., Hsu, S. C., Sanchez, C., Chen, S. C., Spees, J., and Prockop, D. J. (2007) Short-term exposure of multipotent stromal cells to low oxygen increases their expression of CX3CR1 and CXCR4 and their engraftment in vivo PLoS ONE 2, e416.

    PubMed  Google Scholar 

  59. Ruster, B., Gottig, S., Ludwig, R. J., Bistrian, R., Muller, S., Seifried, E., Gille, J., and Henschler, R. (2006) Mesenchymal stem cells display coordinated rolling and adhesion behavior on endothelial cells Blood 108, 3938–44.

    Google Scholar 

  60. Sordi, V., Malosio, M. L., Marchesi, F., Mercalli, A., Melzi, R., Giordano, T., Belmonte, N., Ferrari, G., Leone, B. E., Bertuzzi, F., Zerbini, G., Allavena, P., Bonifacio, E., and Piemonti, L. (2005) Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets Blood 106, 419–27.

    CAS  Google Scholar 

  61. Son, B. R., Marquez-Curtis, L. A., Kucia, M., Wysoczynski, M., Turner, A. R., Ratajczak, J., Ratajczak, M. Z., and Janowska-Wieczorek, A. (2006) Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases Stem Cells 24, 1254–64.

    PubMed  CAS  Google Scholar 

  62. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J., and Clarke, M. F. (2003) Prospective identification of tumorigenic breast cancer cells Proc Natl Acad Sci USA 100, 3983–8.

    CAS  Google Scholar 

  63. Bonnet, D. and Dick, J. E. (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell Nat Med 3, 730–7.

    CAS  Google Scholar 

  64. Collins, A. T., Berry, P. A., Hyde, C., Stower, M. J., and Maitland, N. J. (2005) Prospective identification of tumorigenic prostate cancer stem cells Cancer Res 65, 10946–51.

    CAS  Google Scholar 

  65. Dalerba, P., Dylla, S. J., Park, I. K., Liu, R., Wang, X., Cho, R. W., Hoey, T., Gurney, A., Huang, E. H., Simeone, D. M., Shelton, A. A., Parmiani, G., Castelli, C., and Clarke, M. F. (2007) Phenotypic characterization of human colorectal cancer stem cells Proc Natl Acad Sci USA 104, 10158–63.

    CAS  Google Scholar 

  66. Ginestier, C., Hur, M. H., Charafe-Jauffret, E., Monville, F., Dutcher, J., Brown, M. J. J., Viens, P., Kleer, C. G., Liu, S., Schott, A., Hayes, D., Birnbaum, D., Wicha, M. S., and Dontu, G. (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome Cell Stem Cell 1, 555–567.

    PubMed  CAS  Google Scholar 

  67. Hermann, P. C., Huber, S. L., Herrler, T., Aicher, A., Ellwart, J. W., Guba, M., Bruns, C. J., and Heeschen, C. (2007) Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer Cell Stem Cell 1, 313–323.

    CAS  Google Scholar 

  68. Hope, K. J., Jin, L., and Dick, J. E. (2004) Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity Nat Immunol 5, 738–43.

    CAS  Google Scholar 

  69. O’Brien, C. A., Pollett, A., Gallinger, S., and Dick, J. E. (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice Nature 445, 106–10.

    Google Scholar 

  70. Prince, M. E., Sivanandan, R., Kaczorowski, A., Wolf, G. T., Kaplan, M. J., Dalerba, P., Weissman, I. L., Clarke, M. F., and Ailles, L. E. (2007) Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma Proc Natl Acad Sci USA 104, 973–8.

    CAS  Google Scholar 

  71. Ricci-Vitiani, L., Lombardi, D. G., Pilozzi, E., Biffoni, M., Todaro, M., Peschle, C., and De Maria, R. (2007) Identification and expansion of human colon-cancer-initiating cells Nature 445, 111–5.

    CAS  Google Scholar 

  72. Schatton, T., Murphy, G. F., Frank, N. Y., Yamaura, K., Waaga-Gasser, A. M., Gasser, M., Zhan, Q., Jordan, S., Duncan, L. M., Weishaupt, C., Fuhlbrigge, R. C., Kupper, T. S., Sayegh, M. H., and Frank, M. H. (2008) Identification of cells initiating human melanomas Nature 451, 345–9.

    CAS  Google Scholar 

  73. Clarke, M. F., Dick, J. E., Dirks, P. B., Eaves, C. J., Jamieson, C. H., Jones, D. L., Visvader, J., Weissman, I. L., and Wahl, G. M. (2006) Cancer Stem Cells--Perspectives on Current Status and Future Directions: AACR Workshop on Cancer Stem Cells Cancer Res 66, 9339–44.

    PubMed  CAS  Google Scholar 

  74. Pardal, R., Clarke, M. F., and Morrison, S. J. (2003) Applying the principles of stem-cell biology to cancer Nat Rev Cancer 3, 895–902.

    CAS  Google Scholar 

  75. Bjerkvig, R., Tysnes, B. B., Aboody, K. S., Najbauer, J., and Terzis, A. J. (2005) Opinion: the origin of the cancer stem cell: current controversies and new insights Nat Rev Cancer 5, 899–904.

    CAS  Google Scholar 

  76. Al-Hajj, M. and Clarke, M. F. (2004) Self-renewal and solid tumor stem cells Oncogene 23, 7274–82.

    CAS  Google Scholar 

  77. Reya, T., Morrison, S. J., Clarke, M. F., and Weissman, I. L. (2001) Stem cells, cancer, and cancer stem cells Nature 414, 105–11.

    PubMed  CAS  Google Scholar 

  78. Croker, A. K. and Allan, A. L. (2008) Cancer stem cells: implications for the progression and treatment of metastatic disease J Cell Mol Med 12, 374–90.

    CAS  Google Scholar 

  79. Hanahan, D. and Weinberg, R. A. (2000) The hallmarks of cancer Cell 100, 57–70.

    CAS  Google Scholar 

  80. Marx, J. (2003) Cancer research. Mutant stem cells may seed cancer Science 301, 1308–10.

    PubMed  CAS  Google Scholar 

  81. Pereira, D. S., Dorrell, C., Ito, C. Y., Gan, O. I., Murdoch, B., Rao, V. N., Zou, J. P., Reddy, E. S., and Dick, J. E. (1998) Retroviral transduction of TLS-ERG initiates a leukemogenic program in normal human hematopoietic cells Proc Natl Acad Sci USA 95, 8239–44.

    CAS  Google Scholar 

  82. Kelly, L. M. and Gilliland, D. G. (2002) Genetics of myeloid leukemias Annu Rev Genomics Hum Genet 3, 179–98.

    CAS  Google Scholar 

  83. Charafe-Jauffret, E., Ginestier, C., Iovino, F., Wicinski, J., Cervera, N., Finetti, P., Hur, M. H., Diebel, M. E., Monville, F., Dutcher, J., Brown, M., Viens, P., Xerri, L., Bertucci, F., Stassi, G., Dontu, G., Birnbaum, D., and Wicha, M. S. (2009) Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature Cancer Res 69, 1302–13.

    CAS  Google Scholar 

  84. Croker, A. K., Goodale, D., Chu, J., Postenka, C., Hedley, B. D., Hess, D. A., and Allan, A. L. (2008) 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.

    Google Scholar 

  85. Yu, F., Yao, H., Zhu, P., Zhang, X., Pan, Q., Gong, C., Huang, Y., Hu, X., Su, F., Lieberman, J., and Song, E. (2007) let-7 regulates self renewal and tumorigenicity of breast cancer cells Cell 131, 1109–23.

    Google Scholar 

  86. Abraham, B. K., Fritz, P., McClellan, M., Hauptvogel, P., Athelogou, M., and Brauch, H. (2005) Prevalence of CD44+/CD24-/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis Clin Cancer Res 11, 1154–9.

    PubMed  CAS  Google Scholar 

  87. Balic, M., Lin, H., Young, L., Hawes, D., Giuliano, A., McNamara, G., Datar, R. H., and Cote, R. J. (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 12, 5615–21.

    CAS  Google Scholar 

  88. Chambers, A. F., Groom, A. C., and MacDonald, I. C. (2002) Dissemination and growth of cancer cells in metastatic sites Nat Rev Cancer 2, 563–72.

    CAS  Google Scholar 

  89. Chambers, A. F., Naumov, G. N., Varghese, H. J., Nadkarni, K. V., MacDonald, I. C., and Groom, A. C. (2001) Critical steps in hematogenous metastasis: an overview Surg Oncol Clin N Am 10, 243–55, vii.

    Google Scholar 

  90. Pantel, K. and Brakenhoff, R. H. (2004) Dissecting the metastatic cascade Nat Rev Cancer 4, 448–56.

    CAS  Google Scholar 

  91. Cameron, M. D., Schmidt, E. E., Kerkvliet, N., Nadkarni, K. V., Morris, V. L., Groom, A. C., Chambers, A. F., and MacDonald, I. C. (2000) Temporal progression of metastasis in lung: cell survival, dormancy, and location dependence of metastatic inefficiency Cancer Res 60, 2541–6.

    PubMed  CAS  Google Scholar 

  92. Luzzi, K. J., MacDonald, I. C., Schmidt, E. E., Kerkvliet, N., Morris, V. L., Chambers, A. F., and Groom, A. C. (1998) Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases Am J Pathol 153, 865–73.

    CAS  Google Scholar 

  93. Weiss, L. (1990) Metastatic inefficiency Adv Cancer Res 54, 159–211.

    CAS  Google Scholar 

  94. Allan, A. L., Vantyghem, S. A., Tuck, A. B., and Chambers, A. F. (2006) Tumor dormancy and cancer stem cells: implications for the biology and treatment of breast cancer metastasis Breast Dis 26, 87–98.

    CAS  Google Scholar 

  95. Scadden, D. T. (2007) The stem cell niche in health and leukemic disease Best Pract Res Clin Haematol 20, 19–27.

    CAS  Google Scholar 

  96. Hendrix, M. J., Seftor, E. A., Seftor, R. E., Kasemeier-Kulesa, J., Kulesa, P. M., and Postovit, L. M. (2007) Reprogramming metastatic tumour cells with embryonic microenvironments Nat Rev Cancer 7, 246–55.

    CAS  Google Scholar 

  97. Chepko, G. and Dickson, R. B. (2003) Ultrastructure of the putative stem cell niche in rat mammary epithelium Tissue Cell 35, 83–93.

    CAS  Google Scholar 

  98. Burger, J. A. and Peled, A. (2009) CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers Leukemia 23, 43–52.

    PubMed  CAS  Google Scholar 

  99. Kaplan, R. N., Riba, R. D., Zacharoulis, S., Bramley, A. H., Vincent, L., Costa, C., MacDonald, D. D., Jin, D. K., Shido, K., Kerns, S. A., Zhu, Z., Hicklin, D., Wu, Y., Port, J. L., Altorki, N., Port, E. R., Ruggero, D., Shmelkov, S. V., Jensen, K. K., Rafii, S., and Lyden, D. (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche Nature 438, 820–7.

    PubMed  CAS  Google Scholar 

  100. Psaila, B., Kaplan, R. N., Port, E. R., and Lyden, D. (2006) Priming the ‘soil’ for breast cancer metastasis: the pre-metastatic niche Breast Dis 26, 65–74.

    CAS  Google Scholar 

  101. Hiratsuka, S., Nakamura, K., Iwai, S., Murakami, M., Itoh, T., Kijima, H., Shipley, J. M., Senior, R. M., and Shibuya, M. (2002) MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis Cancer Cell 2, 289–300.

    PubMed  CAS  Google Scholar 

  102. Hiratsuka, S., Watanabe, A., Sakurai, Y., Akashi-Takamura, S., Ishibashi, S., Miyake, K., Shibuya, M., Akira, S., Aburatani, H., and Maru, Y. (2008) The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase Nat Cell Biol 10, 1349–55.

    PubMed  CAS  Google Scholar 

  103. Wicha, M. S., Liu, S., and Dontu, G. (2006) Cancer stem cells: an old idea--a paradigm shift Cancer Res 66, 1883–90; discussion 1895–6.

    Google Scholar 

  104. Li, L. and Neaves, W. B. (2006) Normal stem cells and cancer stem cells: the niche matters Cancer Res 66, 4553–7.

    CAS  Google Scholar 

  105. Kucia, M., Reca, R., Miekus, K., Wanzeck, J., Wojakowski, W., Janowska-Wieczorek, A., Ratajczak, J., and Ratajczak, M. Z. (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, 879–94.

    PubMed  CAS  Google Scholar 

  106. Ratajczak, M. Z., Zuba-Surma, E., Kucia, M., Reca, R., Wojakowski, W., and Ratajczak, J. (2006) The pleiotropic effects of the SDF-1-CXCR4 axis in organogenesis, regeneration and tumorigenesis Leukemia 20, 1915–24.

    PubMed  CAS  Google Scholar 

  107. Orimo, A., Gupta, P. B., Sgroi, D. C., Arenzana-Seisdedos, F., Delaunay, T., Naeem, R., Carey, V. J., Richardson, A. L., and Weinberg, R. A. (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion Cell 121, 335–48.

    PubMed  CAS  Google Scholar 

  108. Spoo, A. C., Lubbert, M., Wierda, W. G., and Burger, J. A. (2007) CXCR4 is a prognostic marker in acute myelogenous leukemia Blood 109, 786–91.

    PubMed  CAS  Google Scholar 

  109. Rubin, J. B., Kung, A. L., Klein, R. S., Chan, J. A., Sun, Y., Schmidt, K., Kieran, M. W., Luster, A. D., and Segal, R. A. (2003) A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors Proc Natl Acad Sci USA 100, 13513–8.

    PubMed  CAS  Google Scholar 

  110. Dewan, M. Z., Ahmed, S., Iwasaki, Y., Ohba, K., Toi, M., and Yamamoto, N. (2006) Stromal cell-derived factor-1 and CXCR4 receptor interaction in tumor growth and metastasis of breast cancer Biomed Pharmacother 60, 273–6.

    PubMed  CAS  Google Scholar 

  111. Muller, A., Homey, B., Soto, H., Ge, N., Catron, D., Buchanan, M. E., McClanahan, T., Murphy, E., Yuan, W., Wagner, S. N., Barrera, J. L., Mohar, A., Verastegui, E., and Zlotnik, A. (2001) Involvement of chemokine receptors in breast cancer metastasis Nature 410, 50–6.

    CAS  Google Scholar 

  112. Liang, Z., Wu, T., Lou, H., Yu, X., Taichman, R. S., Lau, S. K., Nie, S., Umbreit, J., and Shim, H. (2004) Inhibition of breast cancer metastasis by selective synthetic polypeptide against CXCR4 Cancer Res 64, 4302–8.

    Google Scholar 

  113. Shipitsin, M., Campbell, L. L., Argani, P., Weremowicz, S., Bloushtain-Qimron, N., Yao, J., Nikolskaya, T., Serebryiskaya, T., Beroukhim, R., Hu, M., Halushka, M. K., Sukumar, S., Parker, L. M., Anderson, K. S., Harris, L. N., Garber, J. E., Richardson, A. L., Schnitt, S. J., Nikolsky, Y., Gelman, R. S., and Polyak, K. (2007) Molecular definition of breast tumor heterogeneity Cancer Cell 11, 259–73.

    CAS  Google Scholar 

  114. Tuck, A. B., Chambers, A. F., and Allan, A. L. (2007) Osteopontin overexpression in breast cancer: knowledge gained and possible implications for clinical management J Cell Biochem 102, 859–68.

    CAS  Google Scholar 

  115. Marhaba, R. and Zoller, M. (2004) CD44 in cancer progression: adhesion, migration and growth regulation J Mol Histol 35, 211–31.

    PubMed  CAS  Google Scholar 

  116. Ponta, H., Sherman, L., and Herrlich, P. A. (2003) CD44: from adhesion molecules to signalling regulators Nat Rev Mol Cell Biol 4, 33–45.

    PubMed  CAS  Google Scholar 

  117. Zen, K., Liu, D. Q., Guo, Y. L., Wang, C., Shan, J., Fang, M., Zhang, C. Y., and Liu, Y. (2008) CD44v4 is a major E-selectin ligand that mediates breast cancer cell transendothelial migration PLoS ONE 3, e1826.

    PubMed  Google Scholar 

  118. Mani, S. A., Guo, W., Liao, M. J., Eaton, E. N., Ayyanan, A., Zhou, A. Y., Brooks, M., Reinhard, F., Zhang, C. C., Shipitsin, M., Campbell, L. L., Polyak, K., Brisken, C., Yang, J., and Weinberg, R. A. (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells Cell 133, 704–15.

    CAS  Google Scholar 

  119. Fillmore, C. M. and Kuperwasser, C. (2008) Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy Breast Cancer Res 10, R25.

    PubMed  Google Scholar 

  120. Ponti, D., Costa, A., Zaffaroni, N., Pratesi, G., Petrangolini, G., Coradini, D., Pilotti, S., Pierotti, M. A., and Daidone, M. G. (2005) Isolation and in vitro propagation of ­tumorigenic breast cancer cells with stem/progenitor cell properties Cancer Res 65, 5506–11.

    CAS  Google Scholar 

  121. Sheridan, C., Kishimoto, H., Fuchs, R. K., Mehrotra, S., Bhat-Nakshatri, P., Turner, C. H., Goulet, R., Jr., Badve, S., and Nakshatri, H. (2006) CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis Breast Cancer Res 8, R59.

    PubMed  Google Scholar 

  122. Liu, R., Wang, X., Chen, G. Y., Dalerba, P., Gurney, A., Hoey, T., Sherlock, G., Lewicki, J., Shedden, K., and Clarke, M. F. (2007) The prognostic role of a gene signature from tumorigenic breast-cancer cells N Engl J Med 356, 217–26.

    CAS  Google Scholar 

  123. Honeth, G., Bendahl, P. O., Ringner, M., Saal, L. H., Gruvberger-Saal, S. K., Lovgren, K., Grabau, D., Ferno, M., Borg, A., and Hegardt, C. (2008) The CD44+/CD24- phenotype is enriched in basal-like breast tumors Breast Cancer Res 10, R53.

    PubMed  Google Scholar 

  124. Li, C., Heidt, D. G., Dalerba, P., Burant, C. F., Zhang, L., Adsay, V., Wicha, M., Clarke, M. F., and Simeone, D. M. (2007) Identification of pancreatic cancer stem cells Cancer Res 67, 1030–7.

    CAS  Google Scholar 

  125. Zhang, S., Balch, C., Chan, M. W., Lai, H. C., Matei, D., Schilder, J. M., Yan, P. S., Huang, T. H., and Nephew, K. P. (2008) Identification and characterization of ovarian cancer-initiating cells from primary human tumors Cancer Res 68, 4311–20.

    CAS  Google Scholar 

  126. Polyak, K. and Weinberg, R. A. (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits Nat Rev Cancer.

    Google Scholar 

  127. Thiery, J. P. and Sleeman, J. P. (2006) Complex networks orchestrate epithelial-mesenchymal transitions Nat Rev Mol Cell Biol 7, 131–42.

    CAS  Google Scholar 

  128. Yang, J. and Weinberg, R. A. (2008) Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis Dev Cell 14, 818–29.

    CAS  Google Scholar 

  129. Hugo, H., Ackland, M. L., Blick, T., Lawrence, M. G., Clements, J. A., Williams, E. D., and Thompson, E. W. (2007) Epithelial--mesenchymal and mesenchymal--epithelial transitions in carcinoma progression J Cell Physiol 213, 374–83.

    PubMed  CAS  Google Scholar 

  130. Eccles, S. A. and Welch, D. R. (2007) Metastasis: recent discoveries and novel treatment strategies Lancet 369, 1742–57.

    CAS  Google Scholar 

  131. Kang, Y. and Massague, J. (2004) Epithelial-mesenchymal transitions: twist in development and metastasis Cell 118, 277–9.

    CAS  Google Scholar 

  132. Stover, D. G., Bierie, B., and Moses, H. L. (2007) A delicate balance: TGF-beta and the tumor microenvironment J Cell Biochem 101, 851–61.

    CAS  Google Scholar 

  133. Moreno-Bueno, G., Portillo, F., and Cano, A. (2008) Transcriptional regulation of cell polarity in EMT and cancer Oncogene 27, 6958–69.

    CAS  Google Scholar 

  134. Peinado, H., Olmeda, D., and Cano, A. (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7, 415–28.

    PubMed  CAS  Google Scholar 

  135. Morel, A. P., Lievre, M., Thomas, C., Hinkal, G., Ansieau, S., and Puisieux, A. (2008) Generation of breast cancer stem cells through epithelial-mesenchymal transition PLoS ONE 3, e2888.

    Google Scholar 

Download references

Acknowledgments

We thank members of our laboratory and our collaborators for their research work and helpful discussions. The authors’ research on adult and malignant stem cells is supported by grants from the Canadian Institutes of Health Research (CIHR) (#MOP86759, MOP86702 to D.A.H.), The Krembil Foundation (to D.A.H), Canada Foundation for Innovation (#13199 to A.L.A.), and the Ontario Institute for Cancer Research (#08NOV-230 to A.L.A. and D.A.H). A.L.A. is supported by a CIHR New Investigator Award and an Early Researcher Award from the Ontario Ministry of Research and Innovation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alison L. Allan .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Hess, D.A., Allan, A.L. (2011). Migratory Strategies of Normal and Malignant Stem Cells. In: Filippi, MD., Geiger, H. (eds) Stem Cell Migration. Methods in Molecular Biology, vol 750. Humana Press. https://doi.org/10.1007/978-1-61779-145-1_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-61779-145-1_2

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-61779-144-4

  • Online ISBN: 978-1-61779-145-1

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics