A New Breast Cancer Model for Lymphatic Metastasis

  • Michael M. Lizardo
  • Ian C. MacDonald
  • Alan B. Tuck
  • Ann F. Chambers
Part of the Cancer Treatment and Research book series (CTAR, volume 135)

Lymphatic vessels provide one of the main anatomical routes by which invasive tumor cells can disseminate from the primary tumor. Certain types of cancer, breast cancer in particular, have a propensity to disseminate via the lymphatics.Yet despite the prevalence of lymphatic metastasis, experimental work elucidating the underlying biology, until recently, has been relatively limited. In the past several years, experimental metastasis research has experienced a surge in the number of studies examining the molecular determinants of lymphatic metastasis, as well as in vivo imaging of its progression in animal models.The following review aims to highlight recent preclinical experimental work that contributes to our basic understanding of lymphatic metastasis in breast cancer, and to describe a recently developed human cell model for lymphatic metastasis. Before continuing, however, a brief overview of clinical and pathological studies that detail the natural history of lymphatic metastasis in breast cancer will set the disease model, which experimental models must mimic.


Breast Cancer Lymphatic Vessel Lymphatic Invasion Lymphatic Metastasis Lymphatic Endothelial Cell 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Allan AL, George R, Vantyghem SA, Lee MW, Hodgson NC, Engel CJ, Holliday RL, Girvan DP, Scott LA, Postenka CO, Al-Katib W, Stitt LW, Uede T, Chambers AF, Tuck AB (2006) Role of the integrin-binding protein osteopontin in lymphatic metastasis of breast cancer. Am J Pathol 169:233–246.PubMedCrossRefGoogle Scholar
  2. 2.
    Banerji S, Ni J, Wang SX, Clasper S, Su J, Tammi R, Jones M, DG Jackson (1999) LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 144:789–801.PubMedCrossRefGoogle Scholar
  3. 3.
    Breiteneder-Geleff S, Soleiman A, Kowalski H, Horvat R, Amann G, Kriehuber E, Diem K, Weninger W, Tschachler E, Alitalo K, Kerjaschki D (1999) Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol 154:385–394.PubMedGoogle Scholar
  4. 4.
    Carr J, Carr I, Dreher B, Betts K (1980) Lymphatic metastasis: invasion of lymphatic vessels and efflux of tumour cells in the afferent popliteal lymph as seen in the Walker rat carcinoma. J Pathol 132:287–305.PubMedCrossRefGoogle Scholar
  5. 5.
    Carr I, McGinty F (1976) Neoplastic invasion and metastasis within the lymphoreticular system. Advances in Experimental Medicine and Biology 73(Pt B):319–329.Google Scholar
  6. 6.
    Carr I, Carr J (1982) Tumor Invasion and Metastasis: Experimental models of lymphatic metastasis. In: Liotta LA, and IR Hart (eds) Developments in Oncology 7. Martinus Nijhoff Publishers, Boston, pp 189–206.Google Scholar
  7. 7.
    Contesso G, Rouesse J, Petit JY, Mouriesse H (1977) Les facteurs anatomo-pathologiques du pronostic des cancers du sein. Bulletin du Cancer 64:525–236.PubMedGoogle Scholar
  8. 8.
    Cook AC, Tuck AB, McCarthy S, Turner JG, Irby RB, Bloom GC, Yeatman TJ, Chambers AF (2005) Osteopontin induces multiple changes in gene expression that reflect the six “hallmarks of cancer” in a model of breast cancer progression. Molecular Carcinogenesis 43:225–236.PubMedCrossRefGoogle Scholar
  9. 9.
    Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867.PubMedCrossRefGoogle Scholar
  10. 10.
    Fisher ER, Sass E, Fisher B (1984) Pathological findings from the NSABP Protocol 4: discriminants for tenth year treatment failure. Cancer 53:712–723.PubMedCrossRefGoogle Scholar
  11. 11.
    Folkman J (1992) The role of angiogenesis in tumor growth and metastasis. Seminars in Oncology 6 supplement 6:15–18.Google Scholar
  12. 12.
    Foster RS (1996) The biologic and clinical significance of lymphatic metastasis in breast cancer. Surgical Oncology Clinics of North America 5:79–104.PubMedGoogle Scholar
  13. 13.
    Greene FL, Page DL, Fleming ID, Fritz AG, Balch CM, Haller DG, Morrow M (2002) AJCC Cancer Staging Manual 6th ed. New York: Springer.Google Scholar
  14. 14.
    Heyn C, Ronald JA, Ramadan SS, Snir JA, Barry AM, MacKenzie LT, Mikulis DJ, Palmieri D, Bronder JL, Steeg PS, Yoneda T, MacDonald IC, Chambers AF, Rutt BK, Foster PJ (2006) In vivo MRI of cancer cell fate at the single-cell level in a mouse model of breast cancer metastasis to the brain. Magnetic Resonance in Medicine 56:1001–1010.PubMedCrossRefGoogle Scholar
  15. 15.
    Huvos AG, Hutter RV, Berg JW (1971) Significance of axillary macrometastases and micrometastases in mammary cancer. Annals of Surgery 173:44–46.PubMedCrossRefGoogle Scholar
  16. 16.
    Jain RK (2002) Angiogenesis and lymphangiogenesis in tumors: insights from intravital microscopy. Cold Spring Harb Symp Quant Biol 67:239–248.PubMedCrossRefGoogle Scholar
  17. 17.
    Kahn HJ, Bailey D, Marks A (2002) Monoclonal antibody D2–40, a new marker of lymphatic endothelium, reacts with Kaposi’s sarcoma and a subset of angiosarcomas. Modern Pathology 15:434–440.PubMedCrossRefGoogle Scholar
  18. 18.
    Karpanen T, Egeblad M, Karkkainen MJ, Kubo H, Yla-Herttuala S, Jaattela M, Alitalo K (2001) Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 61:1786–1790.PubMedGoogle Scholar
  19. 19.
    Koscielny S, Le MG, Tubiana M (1989) The natural history of human breast cancer: The relationship between involvement of axillary lymph nodes and the initiation of distant metastases. Br J Cancer 59:775–782.PubMedGoogle Scholar
  20. 20.
    Lauria R, Perrone F, Carlomagno C, De Laurentiis M, Morabito A, Gallo C, Varriale E, Pettinato G, Panico L, Petrella G, et al (1995) The prognostic value of lymphatic and blood vessel invasion in operable breast cancer. Cancer 76:1772–1778.PubMedCrossRefGoogle Scholar
  21. 21.
    Luzzi KJ, MacDonald IC, Schmidt EE, Kerkvliet N, Morris VL, Chambers AF, Groom AC (1998) Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 153:865–873.PubMedGoogle Scholar
  22. 22.
    MacDonald IC, Groom AC, Chambers AF (2002) Cancer spread and micrometastasis development: quantitative approaches for in vivo models. Bioessays 24:885–893.PubMedCrossRefGoogle Scholar
  23. 23.
    Maibenco DC, Dombi GW, Kau TY, Severson RK (2006) Significance of micrometastases on the survival of women with T1 breast cancer. Cancer 107:1234–1239.PubMedCrossRefGoogle Scholar
  24. 24.
    Mattila MM, Ruohola JK, Karpanen T, Jackson DG, Alitalo K, Harkonen PL (2002) VEGF-C induced lymphangiogenesis is associated with lymph node metastasis in orthotopic MCF-7 tumors. Int J Cancer 98:946–951.PubMedCrossRefGoogle Scholar
  25. 25.
    Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E, Zlotnik Z (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410:50–56.PubMedCrossRefGoogle Scholar
  26. 26.
    Nakamura Y, Yasuoka H, Tsujimoto M, Imabun S, Nakahara M, Nakao K, Nakamura M, Mori I, Kakudo K (2005) Lymph vessel density correlates with nodal status, VEGF-C expression, and prognosis in breast cancer. Breast Cancer Research and Treatment 91:125–132.PubMedCrossRefGoogle Scholar
  27. 27.
    Nathanson SD, Anaya P, Avery M, Hetzel FW, Sarantou T, Havstad S (1997) Sentinal lymph node metastasis in experimental melanoma: relationships among primary tumor size, lymphatic vessel diameter, and 99mTc-labeled human albumin clearance. Annals of Surgical Oncology 4:161–168.PubMedCrossRefGoogle Scholar
  28. 28.
    Naumov GN, Wilson SM, MacDonald IC, Schmidt EE, Morris VL, Groom AC, Hoffman RM, Chambers AF (1999) Cellular expression of green fluorescent protein, coupled with high-resolution in vivo videomicroscopy, to monitor steps in tumor metastasis. J Cell Science 112:1833–1842.Google Scholar
  29. 29.
    Naumov GN, MacDonald IC, Weinmeister PM, Kerkvliet N, Nadkarni KV, Wilson SM, Morris VL, Groom AC, Chambers AF (2002) Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy. Cancer Res 62:2162–2168.PubMedGoogle Scholar
  30. 30.
    Nemoto T, Vana J, Bedwani RN, Baker HW, McGregor FH, Murphy GP (1980) Management and survival of female breast cancer: results of a national survey by the American College of Surgeons. Cancer 45:2917–2924.PubMedCrossRefGoogle Scholar
  31. 31.
    Peloquin A, Poljicak M, Falardeau M, Gravel D, Moisescu R, Peloquin L (1991) Cancer of the breast: a study of 1520 consecutive patients operated on between 1960 and 1980. Canadian Journal of Surgery 34:151–156.Google Scholar
  32. 32.
    Price JE, Zhang RD (1990) Studies of human breast cancer metastasis using nude mice. Cancer Metastasis Reviews 8:285–297.PubMedCrossRefGoogle Scholar
  33. 33.
    Querzoli P, Pedriali M, Rinaldi R, Lombardi AR, Biganzoli E, Boracchi P, Ferretti S, Frasson C, Zanella C, Ghisellini S, Ambrogi F, Antolini L, Piantelli M, Iacobelli S, Marubini E, Alberti S, Nenci I (2006) Axillary lymph node nanometastases are prognostic factors for disease-free survival and metastatic relapse in breast cancer patients. Clin Cancer Res 12:6696–6701.PubMedCrossRefGoogle Scholar
  34. 34.
    Rittling SR, Chambers AF (2004) Role of osteopontin in tumour progression. Br J Cancer 90:1877–1881.PubMedCrossRefGoogle Scholar
  35. 35.
    Schoppmann, SF, Bayer G, Aumayr K, Taucher S, Geleff S, Rudas M, Kubista E, Hausmaninger H, Samonigg H, Gnant M, Jakesz R, Horvat R, and Austrian Breast and Colorectal Cancer Study Group (2004) Prognostic value of lymphangiogenesis and lymphovascular invasion in invasive breast cancer. Annals of Surgery 240:306–312.Google Scholar
  36. 36.
    Schoppmann SF, Fenzl A, Nagy K, Unger S, Bayer G, Geleff S, Gnant M, Horvat R, Jakesz R, Birner P (2006) VEGF-C expressing tumor-associated macrophages in lymph node positive breast cancer: impact on lymphangiogenesis and survival. Surgery 139:839–846.PubMedCrossRefGoogle Scholar
  37. 37.
    Singletary SE, Greene FL (2003) Revision of breast cancer staging: the 6th edition of the TNM Classification. Seminars in Surgical Oncology 21:53–59.PubMedCrossRefGoogle Scholar
  38. 38.
    Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, Riccardi L, Alitalo K, Claffey K, Detmar M (2001) Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nature Medicine 7:192–198.PubMedCrossRefGoogle Scholar
  39. 39.
    Tuck AB, Chambers AF (2001) The role of osteopontin in breast cancer: clinical and experimental studies. Journal of Mammary Gland Biology and Neoplasia 6:419–429.PubMedCrossRefGoogle Scholar
  40. 40.
    Vantyghem SA, Allan AL, Postenka CO, Al-Katib W, Keeney M, Tuck AB, Chambers AF (2005) A new model for lymphatic metastasis: development of a variant of the MDA-MB-468 human breast cancer cell line that aggressively metastasizes to lymph nodes. Clinical and Experimental Metastasis 22:351–61.PubMedCrossRefGoogle Scholar
  41. 41.
    Weiss L (2000) Metastasis of cancer: A conceptual history from antiquity to the 1990s. Cancer and Metastasis Reviews 19:219–234.CrossRefGoogle Scholar
  42. 42.
    Wigle JT, Oliver G (1999) Prox1 function is required for the development of the murine lymphatic system. Cell 98:769–78.PubMedCrossRefGoogle Scholar
  43. 43.
    Wilting J, Papoutsi M, Christ B, Nicolaides KH, von Kaisenberg CS, Borges J, Stark GB, Alitalo K, Tomarev SI, Niemeyer C, Rossler J (2002) The transcription factor Prox1 is a marker for lymphatic endothelial cells in normal and diseased human tissues. FASEB Journal 16:1271–1273.PubMedGoogle Scholar
  44. 44.
    Zhang RD, Fidler IJ, Price JE (1991) Relative malignant potential of human breast carcinoma cell lines established from pleural effusions and a brain metastasis. Invasion Metastasis 11:204–215.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Michael M. Lizardo
    • 1
  • Ian C. MacDonald
    • 1
  • Alan B. Tuck
    • 2
  • Ann F. Chambers
    • 3
  1. 1.Department of Medical BiophysicsUniversity of Western OntarioLondonCanada
  2. 2.Department of PathologyLondon Health Sciences CenterLondonCanada
  3. 3.London Regional Cancer ProgramLondonCanada

Personalised recommendations