Skip to main content
SpringerLink
Log in

Development of lymph node and pulmonary metastases after local irradiation and hyperthermia of footpad melanomas

  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

C57BL/6 mice with syngeneic B16-F10 melanomas were treated 7 days after tumor inoculation into the footpad with local hyperthermia (HT) of 43.5°C for 90 min. A combination of local 30 Gy X-irradiation (XRT) given 2, 4 or 12 h after HT cured the primary tumor in 34/35 mice, with irreversible damage to normal foot tissues in most of the animals. When 7.5, 10 or 15 Gy XRT were delivered 4, 18 or 24 h after HT, there were only a small number of cures and also a much smaller incidence of irreversible normal tissue damage. HT alone resulted in a significant (P<0.001) increase in metastases to regional lymph nodes (RLN) and the lungs. The ‘curative’ doses of combined XRT and HT resulted in a significant (P<0.001)decrease in metastasis to RLN and to the lungs. Conversely, subcurative doses of combined therapy resulted in anincrease in RLN and lung metastasis (P<0.001). Abdominal lymph node metastasis, not usually seen in control mice, is markedly increased after HT alone or in combination with subcurative XRT (P<0.001). The overall survival of mice treated with HT alone is decreased (P<0.0028). The survival of mice treated with HT followed 4, 18 or 24 h later with 10 Gy XRT is further decreased (P<0.0025). These data show that subcurative HT, or XRT plus HT, increases the incidence of spontaneous metastasis in this syngeneic mouse melanoma model. Curative doses prevent this effect on metastasis, but there is an unacceptable incidence of irreversible damage to the tumor-bearing foot. The cause(s) of this phenomenon are not known.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Arcangeli, G., Barni, E., Civadelli, A., Mauro, F., Merelli, D., Nervi, C., Spano, M., andTabocchini, A., 1980, Effectiveness of microwave hyperthermia combined with ionizing radiation: Clinical results on neck node metastases.International Journal of Radiation, Oncology and Biological Physics,6, 143–148.

    Google Scholar 

  2. Baker, G. D., Sager, H., Constable, W. C., andGoodchild, N. T., 1984, Influence of ultrasound-induced hyperthermia and X-irradiation on the incidence of metastasis from a solid tumor.Invasion and Metastasis,4, 111–124.

    Google Scholar 

  3. Camplejohn, R. S., andPenhaligon, M., 1985, The tumor bed effect: a cell kinetic and histological investigation of tumors growing in irradiated mouse skin.British Journal of Radiology,58, 443–451.

    PubMed  Google Scholar 

  4. Carr, I. andMcGinty, 1974, Lymphatic metastasis and its inhibition: an experimental model.Journal of Pathology,113, 85–95.

    PubMed  Google Scholar 

  5. Corry, P. M., Spanos, W. J., Tilchen, E. J., Barlogie, B., Barkley, H. T., andArmour, E. P., 1982, Combined ultrasound and radiation therapy treatment of human superficial tumors.Radiology,145, 165–169.

    PubMed  Google Scholar 

  6. Cox, B. R., 1982, Regression models and life tables.Journal of the Royal Statisticians Society, Series B,34, 187–202.

    Google Scholar 

  7. Dao, T. L., andKovaric, J., 1962, Incidence of pulmonary and skin metastases in women with breast cancer who received postoperative irradiation.Surgery,52, 203–212.

    Google Scholar 

  8. Dewhirst, M. W., Connor, W. G., andSim, D. A., 1982, Preliminary results of a phase III trial of spontaneous animal tumors to heat and/or radiation: Early normal tissue response and tumor volume influence on initial response.International Journal of Radiation, Oncology and Biological Physics,8, 1951–1961.

    Google Scholar 

  9. Dewhirst, M. W., Sim, D. A., Wilson, S., DeYoung, D., andParsells, J., 1983, Correlation between initial and long term responses of spontaneous pet animal tumors to heat and radiation or radiation alone.Cancer Research,43, 5735–5741.

    PubMed  Google Scholar 

  10. Dewhirst, M. W., Sim, D. A., Forsyth, K., Grochowski, K. J., Wilson, S., andBicknell, E., 1985, Local control and distant metastases in primary canine malignant melanomas treated with hyperthermia and/or radiotherapy.International Journal of Hyperthermia,1, 219–234.

    PubMed  Google Scholar 

  11. Dickson, J. A., andEllis, H. A., 1974, Stimulation of tumor-cell dissemination by raised temperature (42°C) in rats with transplanted Yoshida tumors.Nature,248, 354–358.

    PubMed  Google Scholar 

  12. Dickson, J. A., andEllis, H. A., 1976, The influence of tumor volume and the degree of heating on the response of the solid Yoshida sarcoma to hyperthermia (40–42°C).Cancer Research,36, 1188–1195.

    PubMed  Google Scholar 

  13. Ehrhart, J. C., Duthu, A., Ullrich, S., Appella, E., andMay, P., 1988, Specific interaction between a subset of the p53 protein family and heat shock proteins hsp72/hsc 73 in a human osteosarcoma cell line.Oncogene,3 595–603.

    PubMed  Google Scholar 

  14. Fajardol, L. F., 1984, Pathological effects of hyperthermia in normal tissues.Cancer Research,44 (Suppl.), 4826–4835.

    Google Scholar 

  15. Fisher, E. R., andFisher, B., 1969, Effects of X-irradiation on parameters of tumor growth, histology and ultrastructure.Cancer,24, 39–55.

    PubMed  Google Scholar 

  16. Folkman, J., 1985, Angiogenesis and its inhibitors.Important Advances in Oncology, edited by V. T. DeVita, S. Hellman and S. A. Rosenberg (New York: J. B. Lippincott), p. 42.

    Google Scholar 

  17. Hahn, E. W., Alfieri, A. A., andHo, K. J., 1979, The significance of local tumor hyperthermia/radiation on the production of disseminated disease.International Journal of Radiation, Oncology and Biological Physics,5, 819–823.

    Google Scholar 

  18. Heisel, M. A., Laug, W. E., Stowe, S. M. et al., 1984, Effects of X-irradiation on artificial blood vessel wall degradation by invasive tumor cells.Cancer Research,44, 2441–2445.

    PubMed  Google Scholar 

  19. Hetzel, F. W., andDunn, J. A., 1985, Hyperthermia and radiation in cancer therapy: a review.Radiation and Physical Chemistry,24, 337–345.

    Google Scholar 

  20. Hewitt, H. B., andBlake, E. R., 1977, Facilitation of nodal metastasis from a non-immunogenic murine carcinoma by previous whole body irradiation of tumor recipients.British Journal of Cancer,36, 23–34.

    PubMed  Google Scholar 

  21. Hill, S. A., andDenekamp, J., 1982, Does local tumor heating in mice influence metastatic spread?British Journal of Radiology,55, 441–451.

    Google Scholar 

  22. Kaae, S., 1953, Metastatic frequency of spontaneous mammary carcinoma in mice following biopsy and following local roentgen irradiation.Cancer Research,13, 744–747.

    PubMed  Google Scholar 

  23. Kaplan, H. S., andMurphy, E. D., 1949, The effect of local irradiation on the biological behaviour of a transplanted mouse carcinoma I. Increased frequency of pulmonary metastases.Journal of the National Cancer Institute,9, 407–413.

    Google Scholar 

  24. Kim, J. H., Hahn, E. W., andAhmed, S. A., 1982, Combination hyperthermia and radiation therapy for malignant melanoma.Cancer,50, 478–482.

    PubMed  Google Scholar 

  25. Kito, S., 1988, Intralobular lymphatic vessels and their relationship to blood vessels in the mouse thymus. Light and electron microscopic study.Cell and Tissue Research,253, 181–187.

    PubMed  Google Scholar 

  26. ]Krebs, C., 1929, The effects of roentgen irradiation on the interrelation between malignant tumors and their hosts.Acta Radiologica, Suppl. VII, 9–133.

    Google Scholar 

  27. Kripke, M. L., andMcClendon, E., 1986, Studies on the role of antigen presenting cells in the systemic suppression of contact hypersensitivity by UVB radiation.Journal of Immunology,137, 443–447.

    Google Scholar 

  28. Liotta, L. A., 1985, Mechanisms of cancer invasion and metastasis.Important Advances in Oncology, edited by V. T. De Vita, S. Hellman and S. A. Rosenberg (New York: J. B. Lippincott), pp. 28–41.

    Google Scholar 

  29. Liotta, L. A. andSteeg, P. S., 1990, Clues to the function of NM23 and AWD proteins in development, signal transduction and tumor metastasis provided by studies ofDictyostelium discoideum.Journal of the National Cancer Institute,82, 1170–1172.

    PubMed  Google Scholar 

  30. Lord, P. F., Kapp, D. S., andMorrow, D., 1981, Increased skeletal metastasis of spontaneous canine osteosarcoma after fractionated systemic hyperthermia and local X-irradiation.Cancer Research,41, 4331–4334.

    PubMed  Google Scholar 

  31. Marmor, J. B., Pounos, D., andHahn, G. M., 1982, Clinical studies with ultrasound-induced hyperthermia.National Cancer Institute Monographs,6, 333–337.

    Google Scholar 

  32. Mead, M. J., Nathanson, S. D., Lee, M., andPeterson, E., 1985, Prophylactic lymphadenectomy for B16 melanoma in C57BL/6 mice: survival based on size and heterogeneous variant of the primary.Journal of Surgical Research,38, 319–327.

    PubMed  Google Scholar 

  33. Milas, L., Hunter, N., andPeters, L. J., 1987, The tumor effect: dependence of tumor take, growth rate and metastases on the time interval between irradiation and tumor cell transplantation.International Journal of Radiation, Oncology and Biological Physics,13, 379–383.

    Google Scholar 

  34. Morimoto, R. I.,Tissieres, A., andGeorgopoulos, C., 1990, The stress response, function of the proteins, and perspectives.Stress Proteins in Biology and Medicine, edited by R. I. Morimoto, A. Tissieres and C. Georgopoulos (Cold Spring Harbor Laboratory Press), pp. 1–36.

  35. Moses, L., Emerson, J., andHosein, H., 1984, Analyzing data for order categories.New England Journal of Medicine,311, 442–448.

    PubMed  Google Scholar 

  36. Nathanson, S. D., Haas, G. P., Mead, M. J., andLee, M., 1986, Spontaneous regional lymph node metastases of three primary variants of the B16 melanoma: relationship to primary tumor size and pulmonary metastases.Journal of Surgical Oncology,33, 41–45.

    PubMed  Google Scholar 

  37. Nathanson, S. D., Haas, G., Bobrowski, R., Lee, M., Tilley, B., Schultz, andHetzel, F. W., 1987, Regional lymph node and pulmonary metastases after local hyperthermia of melanomas in C57BL/6 mice.International Journal of Radiation, Oncology and Biological Physics,13, 243–249.

    Google Scholar 

  38. Nathanson, S. D., Westrick, P., Anaya, P., Hetzel, F. W., andJacobsen, G., 1989, Relationship of spontaneous regional lymph node metastases to dose of local irradiation of primary B16 melanomas.Cancer Research,49, 4412–4416.

    PubMed  Google Scholar 

  39. Nathanson, S. D., Cerra, R. F., Hetzel, F. W., Zarbo, R. J., Crissman, J. D., Page, R., Anaya, P., andWestrick, P., 1990, Changes associated with metastasis in B16-F1 melanoma cells surviving heat.Archives of Surgery,125, 216–219.

    PubMed  Google Scholar 

  40. Nathanson, S. D., andPutnam, M., 1990, Metastasis to regional lymph nodes: the influence of lymphatic flow rates.Clinical and Experimental Metastasis,8 (Suppl), 71–72.

    Google Scholar 

  41. Nicolson, G. L., 1988, Orgain specificity of tumor metastasis: role of preferential adhesion, invasion and growth of malignant cells at specific secondary sites.Cancer and Metastasis Reviews,7, 143–188.

    PubMed  Google Scholar 

  42. O'Hara, M. D., Hetzel, F. W., andFrinak, S., 1985, Thermal distribution in a water bath heated mouse tumor.International Journal of Radiation, Oncology and Biological Physics,11, 817–822.

    Google Scholar 

  43. Olch, P. D., Eck, R. V., andSmith, R. R. 1959, An experimental study of the effect of external irradiation on a primary tumor and its distant metastases.Cancer,12, 23–26.

    PubMed  Google Scholar 

  44. Overgaard, J., 1980, Simultaneous and sequential hyperthermia and radiation treatment of an experimental tumor and its surrounding normal tissuein vivo.International Journal of Radiation, Oncology and Biological Physics,6, 1507–1517.

    Google Scholar 

  45. Schechter, M., Stowe, S. M., andMorosan, H., 1978, Effects of hyperthermia on primary and metastatic tumor growth and host immune response in rats.Cancer Research,38, 498–502.

    PubMed  Google Scholar 

  46. Scott, R. S., Johnson, R. J. R., Kowal, H., Krishnamsetty, R. M., Story, K., andClay, L., 1983, Hyperthermia in combination with radiotherapy: a review of 5 years experience in the treatment of superficial tumors.International Journal of Radiation, Oncology and Biological Physics,9, 1327–1333.

    Google Scholar 

  47. Sheldon, P. W., andFowler, J. F., 1973, The effect of irradiating a transplanted murine lymphosarcoma on the subsequent development of metastases.British Journal of Cancer,28, 508–514.

    PubMed  Google Scholar 

  48. Sikov, M. R., Cook, B. B., andLofstrom, J. E., 1960, Metastastic spread of lymphosarcoma as influenced by radiation.Federation Proceedings,19, 399.

    Google Scholar 

  49. Sugarbaker, E. V., 1979, Cancer metastasis: a product of tumor-host interactions.Current Problems in Cancer,3, 3–39.

    Google Scholar 

  50. Talmadge, J. E., Wolman, S. R., andFidler, I. J., 1982, Evidence for the clonal origin of spontaneous metastasis.Science,217, 361–363.

    PubMed  Google Scholar 

  51. Tandon, A. K., Clark, G. M., Chamness, G. C., Fuqua, S. A. W., Welch, W. J., Riehl, R. M., andMcGuire, W. L., 1990, Heat shock/stress response proteins: biological and clinical significance in breast cancer.Proceedings of the American Society of Clinical Oncology,9, A84.

    Google Scholar 

  52. Tomasovic, S. P., andWelch, D. R., 1986, Heat stress proteins and experimental cancer metastasis.International Journal of Hyperthermia,2, 253–266.

    PubMed  Google Scholar 

  53. Urano, M., Rice, L., Kahn, J., andSedlacek, R. S., 1990, Studies on fractionated hyperthermia in experimental animal systems. I. The foot reaction after equal doses: heat resistance and repopulation.International Journal of Radiation, Oncology and Biological Physics,6, 1519–1523.

    Google Scholar 

  54. Van den Brenk, H. A. S., andSharpington, C., 1971, Effect of local X-irradiation of a primary sarcoma in the rat on dissemination and growth of metastases: dose response characteristics.British Journal of Cancer,25, 812–830.

    PubMed  Google Scholar 

  55. Vogelstein, B., Fearon, E. R., Kern, S. E., Hamilton, S. R., Preisinger, A. C., Nakamura, Y., andWhite, R., 1989, Allelotype of colorectal carcinomas.Science,244, 207–211.

    PubMed  Google Scholar 

  56. Von Essen, C. F., andKaplan, H. S., 1952, Further studies on metastasis of a transplantable mouse mammary carcinoma after roentgen irradiation.Journal of the National Cancer Institute,12, 883–892.

    PubMed  Google Scholar 

  57. Wahl, A., Brustad, T., andMossigi, J., 1979, Effect of hyperthermia alone and in combination with60Co radiation on the growth of B16 melanoma in mice.Acta Radiologica et Oncological 18, 343–356.

    Google Scholar 

  58. Walker, A., McCallum, H. M., Wheldon, T. E., Nias, A. H. W., andAbdelaal, A. S., 1978, Promotion of metastasis of C3H mouse mammary carcinoma by local hyperthermia.British Journal of Cancer,38, 561–563.

    PubMed  Google Scholar 

  59. Yamamoto, T., 1936, Experimental study on the effect of X-ray on metastasis of malignant tumor, especially on bones.Japanese Journal of Obstetrics and Gynecology,19, 559–569.

    Google Scholar 

  60. Yerushalmi, A., 1976, Influence on metastatic spread of whole body or local tumor hyperthermia.European Journal of Cancer,12, 455–463.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, Henry Ford Hospital, 48202, Detroit, MI, USA

    S. D. Nathanson, L. Nelson & P. Anaya

  2. Department of Biostatistics, Henry Ford Hospital, 48202, Detroit, MI, USA

    S. Havstad

  3. Department of Radiation Oncology, Henry Ford Hospital, 48202, Detroit, MI, USA

    F. W. Hetzel

Authors
  1. S. D. Nathanson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. Anaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Havstad
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F. W. Hetzel
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nathanson, S.D., Nelson, L., Anaya, P. et al. Development of lymph node and pulmonary metastases after local irradiation and hyperthermia of footpad melanomas. Clin Exp Metast 9, 377–392 (1991). https://doi.org/10.1007/BF01769357

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01769357

Keywords

Search

Navigation