Biochemistry (Moscow)

, Volume 77, Issue 1, pp 111–118 | Cite as

Preniche as missing link of the metastatic niche concept explaining organ-preferential metastasis of malignant tumors and the type of metastatic disease

  • V. M. Perelmuter
  • V. N. ManskikhEmail author


Here we attempt to supplement the metastatic niche concept with a stage of “preniche” that determines the site of development of a premetastatic niche and of a subsequent metastasis. The “preniche” includes all cellular and molecular events in the site of a prospective metastasis preceding the entrance of myeloid progenitor cells. The “preniche” integrates an activation of vascular endothelium of the microcirculatory vessels of target organs in the site of a future metastasis under conditions of chronic persistent productive inflammation that can be induced by cytokines from the primary tumor and independently of it. The endothelium activation is responsible for adhesion and clustering of the recruited myeloid progenitor cells and also for the retention of cells of malignant tumors. The preniche easily arises in organs enriched with organspecific macrophages (lungs, liver, brain, etc.) where the endothelium is predisposed for intensive recruiting of myeloid progenitor cells of macrophages, especially under conditions of inflammation. Introduction of the “preniche” concept allows us to avoid difficulties associated with the development of the metastatic niche concept, especially concerning the problem of organ-preferential localization of metastases, and to make some predictions for experimental verification and potential approaches for preventing metastasizing in some oncologic patients.

Key words

preniche organ-preferential metastasizing metastatic niches 



hematopoietic progenitor cells


intercellular adhesion molecule 1


lysyl oxidase


macrophage migration inhibitory factor


macrophage inflammatory protein 2


matrix metalloproteinase 9


serum amyloid A3


stroma cell factor 1


transforming growth factor β


tumor producing a powerful pool of proinflammatory cytokines


hybrid cell clone resulting of fusion of macrophage and tumor cell


tumor necrosis factor α


vascular adhesive protein 1


vascular cell adhesion molecule 1


vascular endothelium growth factor A


vascular endothelium growth factor receptor 1


integrin receptor “very late antigen 4”


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  1. 1.
    Psaila, B., and Lyden, D. (2009) Nat. Rev. Cancer, 9, 285–293.PubMedCrossRefGoogle Scholar
  2. 2.
    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) Nature, 438, 820–827.PubMedCrossRefGoogle Scholar
  3. 3.
    Hiratsuka, S., Watanabe, A., Aburatani, H., and Maru, Y. (2006) Nat. Cell Biol., 8, 1369–1375.PubMedCrossRefGoogle Scholar
  4. 4.
    Hiratsuka, S., Watanabe, A., Sakurai, Y., Akashi-Takamura, S., Ishibashi, S., Miyake, K., Shibuya, M., Akira, S., Aburatani, H., and Maru, Y (2008) Nat. Cell Biol., 10, 1349–1355.PubMedCrossRefGoogle Scholar
  5. 5.
    Peinado, H., Lavotshkin, S., and Lyden, D. (2011) Sem. Cancer Biol., 21, 139–146.CrossRefGoogle Scholar
  6. 6.
    Kaplan, R. N., Psaila, B., and Lyden, D. (2006) Cancer Metastasis Rev., 25, 521–529.PubMedCrossRefGoogle Scholar
  7. 7.
    Berge, T. (1974) Acta Pathol. Microbiol. Scand., 82, 499–506.Google Scholar
  8. 8.
    Fidler, I. J., Yano, S., Zhang, R. D., Fujimaki, T., and Bucana, C. D. (2002) Lancet Oncol., 3, 53–57.PubMedCrossRefGoogle Scholar
  9. 9.
    Fidler, I. J. (2001) Surg. Oncol. Clin. Am., 10, 257–269.Google Scholar
  10. 10.
    Lalor, P. F., Edwards, S., McNab, G., Salmi, M., Jalkanen, S., and Adams, D. H. (2002) J. Immunol., 169, 983–992.PubMedGoogle Scholar
  11. 11.
    Alix-Panabieres, C., Riethdorf, S., and Pantel, K. (2008) Clin. Cancer Res., 14, 5013–5021.PubMedCrossRefGoogle Scholar
  12. 12.
    Weiss, L. (1996) Cancer Treat. Res., 82, 1–11.PubMedCrossRefGoogle Scholar
  13. 13.
    Bidard, F. C., Pierga, J. Y., Vincent-Salomon, A., and Poupon, M. F. (2008) Cancer Metastasis Rev., 27, 5–10.PubMedCrossRefGoogle Scholar
  14. 14.
    Poste, G., and Fidler, I. J. (1980) Nature, 283, 139–146.PubMedCrossRefGoogle Scholar
  15. 15.
    Wong, J., Johnston, B., Lee, S. S., Bullard, D. C., Smith, C. W., Beaudet, A. L., and Kubes, P. (1997) J. Clin. Invest., 99, 2782–2790.PubMedCrossRefGoogle Scholar
  16. 16.
    Hu, M., and Polyak, K. (2008) Eur. J. Cancer, 44, 2760–2765.PubMedCrossRefGoogle Scholar
  17. 17.
    Lyden, D., Hattori, K., Dias, S., Costa, C., Blaikie, P., Butros, L., Chadburn, A., Heissig, B., Marks, W., Witte, L., Wu, Y., Hicklin, D., Zhu, Z., Hackett, N. R., Crystal, R. G., Moore, M. A., Hajjar, K. A., Manova, K., Benezra, R., and Rafii, S. (2001) Nat. Med., 7, 1194–1201.PubMedCrossRefGoogle Scholar
  18. 18.
    Langley, R. R., and Fidler, I. J. (2011) Int. J. Cancer, 128, 2527–2535.PubMedCrossRefGoogle Scholar
  19. 19.
    Peinado, H., Rafii, S., and Lyden, D. (2008) Cancer Cell, 14, 347–349.PubMedCrossRefGoogle Scholar
  20. 20.
    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) Nature, 438, 820–827.PubMedCrossRefGoogle Scholar
  21. 21.
    Kaplan, R. N., Rafii, S., and Lyden, D. (2006) Cancer Res., 66, 11089–11093.PubMedCrossRefGoogle Scholar
  22. 22.
    Wilson, A., and Trumpp, A. (2006) Nat. Rev. Immunol., 6, 93–106.PubMedCrossRefGoogle Scholar
  23. 23.
    Schofield, R. (1978) Blood Cells, 4, 7–25.PubMedGoogle Scholar
  24. 24.
    Wels, J., Kaplan, R. N., Rafii, S., and Lyden, D. (2008) Genes Dev., 22, 559–574.PubMedCrossRefGoogle Scholar
  25. 25.
    Burger, J., Spoo, A., Dwenger, A., Burger, M., and Behringer, D. (2003) Br. J. Haematol., 122, 579–589.PubMedCrossRefGoogle Scholar
  26. 26.
    Scott, L., Priestly, G., and Papayannopoulou, T. (2003) Mol. Cell Biol., 23, 9349–9360.PubMedCrossRefGoogle Scholar
  27. 27.
    Neeson, P., Thurlow, P., Jamieson, G., and Bradley, C. (2003) Pathology, 35, 50–55.PubMedGoogle Scholar
  28. 28.
    Jonjic, N., Jilek, P., Bernasconi, S., Peri, G., Martin-Padura, I., Cenzuales, S., Dejana, E., and Mantovani, A. (1992) J. Immunol., 148, 2080–2083.PubMedGoogle Scholar
  29. 29.
    Fogelgren, B., Polgar, N., Szauter, K. M., Ujfaludi, Z., Laczko, R., Fong, K. S., and Csiszar, K. (2005) J. Biol. Chem., 280, 24690–24697.PubMedCrossRefGoogle Scholar
  30. 30.
    Erler, J. T., Bennewith, K. L., Cox, T. R., Lang, G., Bird, D., Koong, A., Le, Q. T., and Giaccia, A. J. (2009) Cancer Cell, 15, 35–44.PubMedCrossRefGoogle Scholar
  31. 31.
    Denko, N. C., Fontana, L. A., Hudson, K. M., Sutphin, P. D., Raychaudhuri, S., Altman, R., and Giaccia, A. J. (2003) Oncogene, 22, 5907–5914.PubMedCrossRefGoogle Scholar
  32. 32.
    Murdoch, C., Giannoudis, A., and Lewis, C. E. (2004) Blood, 104, 2224–2234.PubMedCrossRefGoogle Scholar
  33. 33.
    Ferrara, N. (2009) Arterioscler. Thromb. Vasc. Biol., 29, 789–791.PubMedCrossRefGoogle Scholar
  34. 34.
    Mac Gabhann, F., and Popel, A. S. (2008) Microcirculation, 15, 715–738.PubMedCrossRefGoogle Scholar
  35. 35.
    Carmeliet, P. (2005) Oncology, 69, 4–10.PubMedCrossRefGoogle Scholar
  36. 36.
    Nemeth, E., Baird, A. W., and O’Farrelly, C. (2009) Semin. Immunopathol., 31, 333–343.PubMedCrossRefGoogle Scholar
  37. 37.
    Burke, B., and Lewis, C. E. (2002) The Macrophage, Oxford University Press Inc., N. Y.Google Scholar
  38. 38.
    Mayansky, D. N. (1991) Chronic Inflammation [in Russian], Meditsina, Moscow.Google Scholar
  39. 39.
    Fox, J. M., Chamberlain, G., Ashton, B. A., and Middleton, J. (2007) Br. J. Haematol., 137, 491–502.PubMedCrossRefGoogle Scholar
  40. 40.
    Wang, Y., Johnsen, H. E., Mortensen, S., Bindslev, L., Ripa, R. S., Haack-Sorensen, M., Jorgensen, E., Fang, W., and Kastrup, J. (2006) Heart, 92, 768–774.PubMedCrossRefGoogle Scholar
  41. 41.
    Zvaifler, N. J., Marinova-Mutafchieva, L., Adams, G., Edwards, C. J., Moss, J., Burger, J. A., and Maini, R. N. (2000) Arthritis Res., 2, 477–488.PubMedCrossRefGoogle Scholar
  42. 42.
    Pollard, J. W. (2009) Nat. Rev. Immunol., 9, 259–270.PubMedCrossRefGoogle Scholar
  43. 43.
    Ronzoni, M., Manzoni, M., Mariucci, S., Loupakis, F., Brugnatelli, S., Bencardino, K., Rovati, B., Tinelli, C., Falcone, A., Villa, E., and Danova, M. (2010) Ann. Oncol., 21, 2382–2389.PubMedCrossRefGoogle Scholar
  44. 44.
    Doerschuk, C. M. (2001) Microcirculation, 8, 71–88.PubMedGoogle Scholar
  45. 45.
    Steinhoff, G., Behrend, M., Schrader, B., Duijvestijn, A. M., and Wonigeit, K. (1993) Am. J. Pathol., 142, 481–488.PubMedGoogle Scholar
  46. 46.
    Scoazec, J. Y., and Feldmann, G. (1994) J. Hepatol., 20, 296–300.PubMedCrossRefGoogle Scholar
  47. 47.
    McNab, G., Reeves, J. L., Salmi, M., Hubscher, S., Jalkanen, S., and Adams, D. H. (1996) Gastroenterology, 110, 522–528.PubMedCrossRefGoogle Scholar
  48. 48.
    Hattori, K., Heissig, B., Wu, Y., Dias, S., Tejada, R., Ferris, B., Hicklin, D. J., Zhu, Z., Bohlen, P., Witte, L., Hendrikx, J., Hackett, N. R., Crystal, R. G., Moore, M. A., Werb, Z., Lyden, D., and Rafii, S. (2002) Nat. Med., 8, 841–849.PubMedGoogle Scholar
  49. 49.
    Lalor, P. F., Shields, P., Grant, A. J., and Adams, D. H. (2002) Immunol. Cell Biol., 80, 52–64.PubMedCrossRefGoogle Scholar
  50. 50.
    Male, D., Rahman, J., Pryce, G., Tamatani, T., and Miyasaka, M. (1994) Immunology, 81, 366–372.PubMedGoogle Scholar
  51. 51.
    Vasiliev, J. M. (1958) Br. J. Cancer, 12, 524–536.PubMedCrossRefGoogle Scholar
  52. 52.
    Black, J. W. (1964) Br. J. Cancer, 18, 143–145.PubMedCrossRefGoogle Scholar
  53. 53.
    Crowley, J. D., and Still, W. J. B. (1960) Med. J., 1, 1411–1412.CrossRefGoogle Scholar
  54. 54.
    Das Roy, L., Pathangey, L., Tinder, T., and Mukherjee, P. (2009) Breast Cancer Res., 11, 56.CrossRefGoogle Scholar
  55. 55.
    Mohr, U. (1996) Pathobiology of Aging Mouse, 1/2, ILSI Press.Google Scholar
  56. 56.
    Maronpot, R. (1999) Pathology of the Mouse: Reference and Atlas, Cache River Press, Vienna, IL.Google Scholar
  57. 57.
    Bertini, G., Colavito, V., Tognoli, C., Etet, P. F., and Bentivoglio, M. (2010) Ital. J. Anat. Embryol., 115, 31–38.PubMedGoogle Scholar
  58. 58.
    Willis, R. A. (1952) The Spread of Tumors in the Human Body, 2nd Edn., London (Butterworth), p. 299.Google Scholar
  59. 59.
    Roberson, E. D. O., and Bowcock, A. M. (2010) Trends Genetics, 26, 415–423.CrossRefGoogle Scholar
  60. 60.
    Levin, G., Kariv, N., Khomiak, E., and Raz, A. (2000) Chemotherapy, 46, 429–437.PubMedCrossRefGoogle Scholar
  61. 61.
    De Visser, K. E., Korets, L. V., and Coussens, L. M. (2005) Cancer Cell, 7, 411–423.PubMedCrossRefGoogle Scholar
  62. 62.
    DeNardo, D. G., Barreto, J. B., Andreu P., Vasquez, L., Tawfik, D., Kolhatkar, N., and Coussens, L. M. (2009) Cancer Cell, 16, 91–102.PubMedCrossRefGoogle Scholar
  63. 63.
    Saccani, A., Schioppa, T., Porta, C., Biswas, S. K., Nebuloni, M., Vago, L., Bottazzi, B., Colombo, M. P., Mantovani, A., and Sica, A. (2006) Cancer Res., 66, 11432–11434.PubMedCrossRefGoogle Scholar
  64. 64.
    Mantovani, A., Sozzani, S., Locati, M., Allavena, P., and Sica, A. (2002) Trends Immunol., 23, 549–555.PubMedCrossRefGoogle Scholar
  65. 65.
    Sinha, P., Clements, V. K., Bunt, S. K., Albelda, S. M., and Ostrand-Rosenberg, S. (2007) J. Immunol., 179, 977–983.PubMedGoogle Scholar
  66. 66.
    Mantovani, A., Sica, A., Sozzani, S., Allavena, P., Vecchi, A., and Locati, M. (2004) Trends Immunol., 25, 677–686.PubMedCrossRefGoogle Scholar
  67. 67.
    Mantovani, A., and Sica, A. (2010) Curr. Opin. Immunol., 22, 231–237.PubMedCrossRefGoogle Scholar
  68. 68.
    McEver, R. P. (2002) Curr. Opin. Cell Biol., 14, 581–586.PubMedCrossRefGoogle Scholar
  69. 69.
    Muller, W. A. (2002) Lab. Invest., 82, 521–533.PubMedCrossRefGoogle Scholar
  70. 70.
    Johnson, Z., Proudfoot, A. E., and Handel, T. M. (2005) Cytokine Growth Factor Rev., 16, 625–636.PubMedCrossRefGoogle Scholar
  71. 71.
    Lyden, D., Young, A. Z., Zagzag, D., Yan, W., Gerald, W., O’Reilly, R., Bader, B. L., Hynes, R. O., Zhuang, Y., Manova, K., and Benezra, R. (1999) Nature, 401, 670–677.PubMedCrossRefGoogle Scholar
  72. 72.
    Khatib, A. M., Kontogiannea, M., Fallavollita, L., Jamison, B., Meterissian, S., and Brodt, P. (1999) Cancer Res., 59, 1356–1361.PubMedGoogle Scholar
  73. 73.
    Khatib, A. M., Fallavollita, L., Wancewicz, E. V., Monia, B. P., and Brodt, P. (2002) Cancer Res., 62, 5393–5398.PubMedGoogle Scholar
  74. 74.
    Jones, D. H., Nakashima, T., Sanchez, O. H., Kozieradzki, I., Komarova, S. V., Sarosi, I., Morony, S., Rubin, E., Sarao, R., Hojilla, C. V., Komnenovic, V., Kong, Y. Y., Schreiber, M., Dixon, S. J., Sims, S. M., Khokha, R., Wada, T., and Penninger, J. M. (2006) Nature, 440, 692–696.PubMedCrossRefGoogle Scholar
  75. 75.
    Crumley, A. B., McMillan, D. C., McKernan, M., McDonald, A. C., and Stuart, R. C. (2006) Br. J. Cancer, 94, 637–641.PubMedGoogle Scholar
  76. 76.
    Larizza, L., Schirrmacher, V., Graf, L., Pfluger, E., Peres-Martinez, M., and Stohr, M. (1984) Int. J. Cancer, 34, 699–707.PubMedCrossRefGoogle Scholar
  77. 77.
    Pawelek, J. M., and Chakraborty, A. K. (2008) Nat. Rev. Cancer, 8, 377–386.PubMedCrossRefGoogle Scholar
  78. 78.
    Pawelek, J. M., and Chakraborty, A. K. (2008) Adv. Cancer Res., 101, 397–444.PubMedCrossRefGoogle Scholar

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© Pleiades Publishing, Ltd. 2012

Authors and Affiliations

  1. 1.Cancer Research InstituteSiberian Branch of Russian Academy of Medical SciencesTomskRussia
  2. 2.Siberian State Medical UniversityTomskRussia
  3. 3.Faculty of Bioengineering and BioinformaticsLomonosov Moscow State UniversityMoscowRussia

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