Cancer and Metastasis Reviews

, Volume 31, Issue 1–2, pp 89–97 | Cite as

Role of parathymic lymph nodes in metastatic tumor development



Parathymic lymph nodes as potential sites of tumor progression have been neglected in humans. We have established a rat renal capsule–parathymic lymph node model to study in vivo metastasis. Epithelial liver carcinoma (HeDe) and mesenchymal mesoblastic nephroma (NeDe) cell lines have been established after inducing chemical carcinogenesis in newborn Fisher 344 inbred rats by N-nitrosodimethylamine. Implanting the exact number of tumor cells (HeDe, NeDe) under the renal capsule allowed the standardization and timing of metastatic development. Tumor cells released from the primary tumor in the peritoneal cavity were drained to the parathymic lymph nodes (PTNs) as sentinel lymph nodes. Similarly, tumor cells injected i.p. were engulfed by macrophages, drained through the transdiaphragmatic channels, and transported to the thoracal lymphatics, primarily to PTNs. Tumor cells after transdiaphragmic drainage can enter both anterior mammary and parathymic sentinel lymph nodes. The potential common origin can shed new light on the metastatic cell progression of PTNs and mammary tumors.


Carcinogenesis Tumor cell lines Lymph nodes Rat tumor model Metastasis 



This work was supported by the Hungarian Scientific Research Fund (OTKA grant) T 42762 grant to G.B.


  1. 1.
    Macchiarini, P., & Ostertag, H. (2004). Uncommon primary mediastinal tumours. The Lancet Oncology, 5, 107–118.PubMedCrossRefGoogle Scholar
  2. 2.
    Davis, R. D., Oldham, H. N., & Sabiston, D. C. (1987). Primary cysts and neoplasms of the mediastinum: Recent changes in clinical presentation, methods of diagnosis, management, and results. The Annals of Thoracic Surgery, 44, 229–237.PubMedCrossRefGoogle Scholar
  3. 3.
    Den Bakker, M. A., & Oosterhuis, J. W. (2009). Tumours and tumour-like conditions of the thymus other than thymoma: A practical approach. Histopathology, 54, 69–89.CrossRefGoogle Scholar
  4. 4.
    Sachithanandan, A., Badmanaban, B., Graham, A., & O’Kane, H. (2002). Malignant internal mammary lymph nodes during mobilization of the internal mammary artery. The European Journal of Cardio-thoracic Surgery, 22, 5847–5848.Google Scholar
  5. 5.
    Chambers, A. A., Cado, D., Truong, T., & Allison, J. P. (1997). Thymocyte development is normal in CTLA-4-deficient mice. Proceedings of the National Academy of Sciences USA, 94, 296–9301.CrossRefGoogle Scholar
  6. 6.
    Mishell, B. B., & Shiigii, S. M. (1980). Selected methods in cellular immunology (pp. 8–9). San Francisco: Freeman.Google Scholar
  7. 7.
    Blau, J. N., & Gaugas, J. M. (1968). Parathymic lymph nodes in rats and mice. Immunology, 14, 763–765.PubMedGoogle Scholar
  8. 8.
    Takahashi, S., & Patrick, G. (1987). Pattern of lymphatic drainage to individual thoracic and cervical lymph nodes in the rat. Laboratory Animals, 21, 31–34.PubMedCrossRefGoogle Scholar
  9. 9.
    Tilney, N. L. (1971). Patterns of lymphatic drainage in the adult laboratory rat. Journal of Anatomy, 109, 369–383.PubMedGoogle Scholar
  10. 10.
    Dunn, T. B. (1954). Normal and pathologic anatomy of the reticular tissue in laboratory mice, with a classification and discussion of neoplasms. Journal of the National Cancer Institute, 14, 1281–1433.PubMedGoogle Scholar
  11. 11.
    Waterhouse, P., Penninger, J. M., Timms, E., Wakeham, A., Shahinian, A., Lee, K. P., et al. (1995). Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science, 270, 985–988.PubMedCrossRefGoogle Scholar
  12. 12.
    Tivol, E. A., Borriello, F., Schweitzer, A. N., Lynch, W. P., Bluestone, J. A., & Sharpe, A. H. (1995). Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity, 3, 541–546.PubMedCrossRefGoogle Scholar
  13. 13.
    Yamashita, A., Miyasaka, M., & Trnka, Z. (1985). Early post- thymic T cells: Studies on lymphocytes in the lymph coming from thymus of the sheep. In B. Morris & M. Miyasaka (Eds.), Immunology of the sheep (p. 162). Basel: Editions Roche.Google Scholar
  14. 14.
    Harris, P. F., & Templeton, W. R. (1966). Preliminary studies on the lymphatic drainage of the guinea-pig thymus with special reference to extrinsic vessels. Journal of Anatomy London, 100, 694.Google Scholar
  15. 15.
    Severeanu, G. Die Lymphgefäße der Thymus. Arch Anat Entw Gesch 1909, 93.Google Scholar
  16. 16.
    Tanegashima, A., Yamashita, A., Yamamoto, H., & Fukunaga, T. (1999). Human parathymic lymph node: Morphological and functional significance. Immunology, 97, 301–308.PubMedCrossRefGoogle Scholar
  17. 17.
    Finger, H., Heymer, B., Emmerling, P., & Hof, H. (1977). Antibody-forming potential of lymph nodes in aged mice, with special reference to the influence of adjuvant. Gerontology, 23, 185–204.PubMedCrossRefGoogle Scholar
  18. 18.
    Pitt, M. L. M., & Anderson, A. O. (1988). Direct transdiaphragmatic traffic of peritoneal macrophages to the lung. In S. Sigbjorn & B. Rolstad (Eds.), Histopathology of the immune system (pp. 627–632). New York: Plenum.Google Scholar
  19. 19.
    Marco, A. J., Domingo, M., Ruberte, J., Carretero, A., Briones, V., & Dominguez, L. (1992). Lymphatic drainage of Listeria inonocytogenes and Indian ink inoculated in the peritoneal cavity of the mouse. Laboratory Animals, 26, 200–205.PubMedCrossRefGoogle Scholar
  20. 20.
    Steer, H. W., & Lewis, D. A. (1983). Cell responses to acute gastrointestinal inflammation. The Journal of Pathology, 140, 237–253.PubMedCrossRefGoogle Scholar
  21. 21.
    Roca, M., Balasch, M., Segalés, J., Calsamiglia, M., Viaplana, E., Urniza, A., et al. (2004). In vitro and in vivo characterization of an infectious clone of a European strain of porcine circovirus type 2. Journal of General Virology, 85, 1259–1266.PubMedCrossRefGoogle Scholar
  22. 22.
    Esato, K., Kaku, R., & Yamaki, R. (1975). Reevaluation of parasternal lymph node dissection in the treatment of mammary cancer. The Japanese Journal of Surgery, 5, 139–144.PubMedCrossRefGoogle Scholar
  23. 23.
    Kamperdijk, E. W. A., van den Berg, M., & Hoefsmit, E. C. M. (1984). Lymph node accessory cells in the immune response. The primary response to paratyphoid vaccine in rat parathymic lymph nodes. Cell and Tissue Research, 237, 39–42.PubMedCrossRefGoogle Scholar
  24. 24.
    James, T. N. (1983). Thrombi in antrum atrii dextri of human heart as clinically important source for microembolisation to lungs. British Heart Journal, 49, 122–132.PubMedCrossRefGoogle Scholar
  25. 25.
    Banfalvi, G., & Cernay, L. (1975). Factors influencing the formation of 113mIn–Fe(OH)3 macroaggregates. Acta Pharmaceutica Hungarica, 45, 215–221.PubMedGoogle Scholar
  26. 26.
    Arras, M., Strasser, R., Mohri, M., Doll, R., Eckert, P., Schaper, W., et al. (1998). Tumor necrosis factor-alpha is expressed by monocytes/macrophages following cardiac microembolization and is antagonized by cyclosporine. Basic Research in Cardiology, 93, 97–107.PubMedCrossRefGoogle Scholar
  27. 27.
    Banfalvi, G., Pal, I., & Csernay, L. (1972). Production of 113mIn-colloid suitable for liver-scintigraphy. Acta Pharmaceutica Hungarica, 42, 25–32.PubMedGoogle Scholar
  28. 28.
    Parragh, G., Foris, G., Paragh, G., Jr., Seres, I., Karanyi, Z., Fulop, P., et al. (2005). Different anticancer effects of fluvastatin on primary hepatocellular tumors and metastases in rats. Cancer Letters, 222, 17–22.CrossRefGoogle Scholar
  29. 29.
    Trencsenyi, G., Kertai, P., Somogyi, C., Nagy, G., Dombradi, Z., Gacsi, M., et al. (2007). Chemically induced carcinogenesis affecting chromatin structure in rat hepatocarcinoma cells. DNA and Cell Biology, 26, 649–655.PubMedCrossRefGoogle Scholar
  30. 30.
    Trencsenyi, G., Kertai, P., Bako, F., Hunyadi, J., Marian, T., Hargitai, Z., et al. (2009). Renal capsule. Parathymic lymph node complex: A new in vivo metastatic model in rats. Anticancer Research, 29, 2121–2126.PubMedGoogle Scholar
  31. 31.
    Trencsenyi, G., Juhasz, T., Bako, F., Marian, T., Pocsi, I., Kertai, P., et al. (2010). Comparison of the tumorigenic potential of liver and kidney tumors induced by N-nitrosodimethylamine. Histology and Histopathology, 25, 309–320.PubMedGoogle Scholar
  32. 32.
    Rozsa, D., Trencsenyi, G., Kertai, P., Marian, T., Nagy, G., & Banfalvi, G. (2009). Lymphatic spread of mesenchymal renal tumor to metastatic parathymic lymph nodes. Histology and Histopathology, 24, 1367–1379.PubMedGoogle Scholar
  33. 33.
    Steer, H. W., & Foot, R. A. (1987). Changes in the medulla of the parathymic lymph nodes of the rat during acute gastro-intestinal inflammation. Journal of Anatomy, 152, 23–36.PubMedGoogle Scholar
  34. 34.
    Manville, L. J., & Ane, J. N. (1932). A Roentgen-ray study in absorption of thorium dioxide from peritoneal cavity of albino rat. Proceedings of the Society for Experimental Biology and Medicine, 30, 28–30.Google Scholar
  35. 35.
    Zhdanov, D. A. (1952). General anatomy and physiology of the lymphatic system. Leningrad: Medgiz.Google Scholar
  36. 36.
    Olin, T., & Saldeen, T. (1964). The lymphatic pathways from the peritoneal cavity: A lymphangiographic study in the rat. Cancer Research, 24, 1700–1711.PubMedGoogle Scholar
  37. 37.
    Williams, L., & Warwick, R. (Eds.). (1980). Gray’s anatomy (36th ed., p. 377). London: Churchill-Livingstone.Google Scholar
  38. 38.
    Sapin, M. R., & Shvedavchenko, A. I. (1981). Anatomy and topography of the parasternal lymph nodes in the adult. Voprosy Onkologii, 27, 66–70 (in Russian).PubMedGoogle Scholar
  39. 39.
    Drinker, C. K., Field, M. E., & Ward, H. K. (1934). The filtering capacity of lymph nodes. The Journal of Experimental Medicine, 59, 393–405.PubMedCrossRefGoogle Scholar
  40. 40.
    Widdicombe, J. G., Hughes, R., & May, A. J. (1955). The efficiency of filtration by the popliteal lymph node of the rabbit. British Journal of Experimental Pathology, 36, 473–478.PubMedGoogle Scholar
  41. 41.
    Durham, H. E. (1986). The mechanism of reactions to peritoneal infection. Journal of Pathology and Bacteriology, 4, 338–382.CrossRefGoogle Scholar
  42. 42.
    Fisher, B., Wolmark, N., Redmond, C., Deutsch, M., & Fisher, E. R. (1981). Findings from NSABP protocol no. B-04: Comparison of radical mastectomy with alternative treatments. II. The clinical and biologic significance of medial-central breast cancers. Cancer, 48, 1863–1872.PubMedCrossRefGoogle Scholar
  43. 43.
    Menard, S., Bufalino, R., Rilke, F., Cascinelli, N., Veronesi, U., & Colnaghi, M. I. (1994). Prognosis based on primary breast carcinoma instead of pathological nodal status. British Journal of Cancer, 70, 709–712.PubMedCrossRefGoogle Scholar
  44. 44.
    Braun, S., Pantel, K., Muller, P., Janni, W., Hepp, F., & Kentenich, C. R. M. (2000). Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. The New England Journal of Medicine, 342, 525–533.PubMedCrossRefGoogle Scholar
  45. 45.
    Kato, T., Kameoka, S., Kimura, T., Nishikawa, T., & Kobayashi, M. (2003). The combination of angiogenesis and blood vessel invasion as a prognostic indicator in primary breast cancer. British Journal of Cancer, 88, 1900–1908.PubMedCrossRefGoogle Scholar
  46. 46.
    Thor, A. D., Moore, D. H., II, Edgerton, S. M., Kawasaki, E. S., Reihsaus, E., Lynch, H. T., et al. (1992). Accumulation of p53 tumour suppressor gene protein: An independent marker of prognosis in breast cancers. Journal of the National Cancer Institute, 84, 1845–1855.Google Scholar
  47. 47.
    Gilchrist, K. W., Gray, R., Fowble, B., Tormey, D. C., & Taylor, S. G., 4th. (1993). Tumor necrosis is a prognostic predictor for early recurrence and death in lymph node-positive breast cancer: A 10-year follow-up study of 728 Eastern Cooperative Oncology Group patients. Journal of Clinical Oncology, 11, 1929–1935.PubMedGoogle Scholar
  48. 48.
    Zhang, G. J., Kimijima, I., Abe, R., Watanabe, T., Kanno, M., Hara, K., et al. (1998). Apoptotic index correlates to bcl-2 and p53 protein expression, histological grade and prognosis in invasive breast cancers. Anticancer Research, 18, 1989–1998.PubMedGoogle Scholar
  49. 49.
    Kato, T., Kimura, T., Miyakawa, R., Nobue, I., Fujii, A., Yamamoto, K., et al. (1999). The methodology of quantitation of microvessel density and prognostic value of neovascularization associated with long-term survival in Japanese patients with breast cancer. Breast Cancer Research and Treatment, 53, 19–31.PubMedCrossRefGoogle Scholar
  50. 50.
    Beenken, S. W., Grizzle, W. E., & Crowe, D. R. (2001). Molecular biomarkers for breast cancer prognosis: Coexpression of c-erbB-2 and p53. Annals of Surgery, 233, 630–638.PubMedCrossRefGoogle Scholar
  51. 51.
    Sirvent, J. J., Fortuno-Mar, A., Olona, M., & Orti, A. (2001). Prognostic value of p53 protein expression and clinicopathological factors in infiltrating ductal carcinoma of the breast. A study of 192 patients. Histology and Histopathology, 16, 99–106.PubMedGoogle Scholar
  52. 52.
    Liu, T. J., Wang, S. J., & Tsai, S. C. (2000). Lymphoscintigraphy using larger colloid particles may enhance visualization of the sentinel node in breast cancer: A case report. Clinical Nuclear Medicine, 25, 191–192.PubMedCrossRefGoogle Scholar
  53. 53.
    De Cicco, C., Cremonesi, M., Luini, A., Bartolomei, M., Grana, C., Prisco, G., et al. (1998). Lymphoscintigraphy and radioguided biopsy of the sentinel axillary node in breast cancer. Journal of Nuclear Medicine, 39, 2080–2084.PubMedGoogle Scholar
  54. 54.
    Mirzaei, S., Knoll, P., Hoffmann, B., Kreuzer, W., & Kohn, H. (2001). Optimized mammary lymphoscintigraphy using larger colloid particles. Journal of Nuclear Medicine, 42, 826.PubMedGoogle Scholar
  55. 55.
    Wilhem, A. J., Mijnhout, S., & Franssen, E. J. F. (1999). Radiopharmaceuticals in sentinel lymph-node detection: An overview. European Journal of Nuclear Medicine, 26(Suppl), S36–S42.Google Scholar
  56. 56.
    Olmos, R. V., Hoefnagel, C., & Nieweg, O. (2001). Optimized mammary lymphoscintigraphy using larger colloid particles. Journal Nuclear Medicine, 42, 826.Google Scholar
  57. 57.
    Raharison, F., & Sautet, J. (2006). Lymph drainage of the mammary glands in female cats. Journal of Morphology, 267, 292–299.PubMedCrossRefGoogle Scholar
  58. 58.
    Weinberg, J. A. (1972). The intrathoracic lymphatics. In C. D. Haagensen (Ed.), The lymphatics in cancer (pp. 231–299). Philadelphia: Saunders.Google Scholar
  59. 59.
    Sun, Q.-L., Charyulu, V., Lobo, D., & Lopez, D. M. (2002). Role of thymic stromal cell dysfunction in the thymic involution of mammary tumor-bearing mice. Anticancer Research, 22, 91–96.PubMedGoogle Scholar
  60. 60.
    Ben-Hur, H., Kossoy, G., Lifschitz, O., & Zusman, I. (2002). Splenectomy, chemically-induced mammary tumors and parathymic lymph nodes in rats: Experimental and morphological studies. In Vivo, 16, 275–280.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Microbial Biotechnology and Cell BiologyUniversity of DebrecenDebrecenHungary

Personalised recommendations