Cancer and Metastasis Reviews

, Volume 2, Issue 1, pp 25–40

The selective nature of metastasis

  • James E. Talmadge


The issue of whether metastases result from the random survival of cells released from a primary tumor or from the selective growth of specialized tumor subpopulations endowed with metastatic properties is important to our understanding of the metastatic process and to the development of therapeutic modalities against metastatic disease. We have found that the tumor cells populating spontaneous metastases are more metastatic than the cells populating the parent neoplasm, clearly indicating that metastasis is selective and not random. The selective nature of metastasis is a consistent observation, however, only when tumor cells are obtained from spontaneous metastases from mice bearing heterogenous, poorly metastatic tumors. Tumor cells from spontaneous metastases from mice bearing tumors that have been selected for metastatic potential or that are homogeneous (cloned) do not differ significantly in metastatic potential from tumor cells populating the parent tumor. Thus, under some conditions the process of metastasis can appear random. Although tumor cells from different individual metastases may be homogeneous with regard to a metastatic phenotype, they may be heterogeneous with regard to their sensitivity to chemotherapeutic agents. Thus, although metastasis selects for metastatic variants, resulting in the population of metastatic foci with tumor cells endowed with metastatic properties, it does not appear to select for phenotypes irrelevant to the process of metastasis such as sensitivity to therapeutic agents.


metastasis selection heterogeneity 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Dunn TB: Morphology of mammary tumors in mice. In: Homburger F, Fisheman NH (eds) Physiopathology of cancer. New York, Karger, 1959, pp 38–84.Google Scholar
  2. 2.
    Foulds L: The histologic analysis of mammary tumors of mice. I. Scope of investigations and general principles of analysis. J Natl Cancer Inst (7): 701–712, 1956.Google Scholar
  3. 3.
    Foulds L: The histologic analysis of mammary tumors in mice. II. The histology of responsiveness and progression. The origins of tumors. J Natl Cancer Inst (17): 713–754, 1956.Google Scholar
  4. 4.
    Foulds L: The histologic analysis of mammary tumors of mice. III. Organoid tumors. J Natl Cancer Inst (17): 755–782, 1956.Google Scholar
  5. 5.
    Foulds L: The histologic analysis of mammary tumors of mice. IV. Secretion. J Natl Cancer Inst (17): 783–802, 1956.Google Scholar
  6. 6.
    Henderson JS, Rous P: The plating of tumor components on the subcutaneous expanses of young mice. J Exp Med (115): 1211–1230, 1962.Google Scholar
  7. 7.
    Prehn RT: Analysis of antigenic heterogeneity within individual 3-methylcholanthrene-induced mouse sarcomas. J Natl Cancer Inst (45): 1039–1044, 1970.Google Scholar
  8. 8.
    Byers WS, Johnston JO: Antigenic differences among osteogenic sarcoma tumor cells taken from different locations in human tumors. Cancer Res (37): 3173–3183, 1977.Google Scholar
  9. 9.
    Pimm MV, Baldwin RW: Antigenic heterogeneity of primary and metastatic tumors and its implications for immunotherapy. In: Grundmann E (ed) Metastatic tumor growth. Stuttgart, Gustav Fischer Verlag, 1980, pp 305.Google Scholar
  10. 10.
    Pimm MV, Embleton MJ, Baldwin RW: Multiple antigenic specificities within primary 3-methylcholanthrene-induced rat sarcomas and metastases. Int J Cancer (25): 621–629, 1980.Google Scholar
  11. 11.
    Kerbel RS: Implications of immunological heterogeneity of tumors. Nature (280): 358–360, 1979.Google Scholar
  12. 12.
    Albino AP, Lloyd KO, Houghton AN, Oettgen HF, Old LJ: Heterogeneity in surface antigen and glycoprotein expression of cell lines derived from different melanoma metastases of the same patient. J Exp Med (154): 1764–1778, 1981.Google Scholar
  13. 13.
    Miller FR, Heppner GH: Immunologic heterogeneity of tumor cell subpopulations from a single mouse mammary tumor. JNCI (63): 1457–1463, 1979.Google Scholar
  14. 14.
    Killion JJ, Kollmorgen GM: Isolation of immunogenic tumor cells by cell-affinity chromatography. Nature (259): 674–676, 1976.Google Scholar
  15. 15.
    Killion JJ: Immunotherapy with tumor subpopulations. I. Active, specific immunotherapy of L1210 leukemia. Cancer Immunol Immunother (4): 115–119, 1978.Google Scholar
  16. 16.
    Fogel M, Gorelik E, Segal S, Feldman M: Differences in cell surface antigens of tumor metastases and those of the local tumor. JNCI (62): 585–588, 1979.Google Scholar
  17. 17.
    Fuji H, Mihich E: Selection for high immunogenicity in drug resistant sublines of murine lymphomas demonstrated by plaque assay. Cancer Res (35): 946–952, 1975.Google Scholar
  18. 18.
    Schirrmacher V, Bosslet K, Shantz G, Clauer K, Hubsch D: Tumor metastases and cell-mediated immunity in a model system in DBA/2 mice. IV. Antigenic differences between a metastasizing variant, and the parental tumor line revealed by cytotoxic T lymphocytes. Int J Cancer (23): 245–252, 1979.Google Scholar
  19. 19.
    Fuji H, Mihich E, Pressman D: Differential tumor immunogenicity of L1210 and its sublines. J Immunol (119): 983–986, 1977.Google Scholar
  20. 20.
    Gorelick E, Fogel M, Segal S, Feldman M: Tumorassociated antigenic differences between the primary and distant metastatic tumor populations J Supramol Struct (12): 385–402, 1979.Google Scholar
  21. 21.
    Olsson L, Kiger N, Kronstrom H: Sensitivity of cloned high and low-metastatic murine Lewis lung tumor cells to lysis by cytotoxic autoreactive cells. Cancer Res (41): 4706–4709, 1981.Google Scholar
  22. 22.
    Nicolin A, Canti G, Marelli O, Veronese F, Goldin A: Chemotherapy and immunotherapy of L1210 leukemic mice with antigenic tumor sublines. Cancer Res (41): 1358–1362, 1981.Google Scholar
  23. 23.
    Bosslet K, Schirrmacher V: Escape of metastasizing clonal tumor cell variants from tumor-specific cytolytic T lymphocytes. J Exp Med (154): 557–562, 1981.Google Scholar
  24. 24.
    Bosslet K, Schirrmacher V: High-frequency generation of new immunoresistant tumor variants during metastasis of a cloned murine tumor line. Int J Cancer (29): 195–202, 1982.Google Scholar
  25. 25.
    Olsson L, Ebbesen P: Natural polyclonality of spontaneous AKR leukemia and its consequence for so-called specific immunotherapy. JNCI (62): 623–627, 1979.Google Scholar
  26. 26.
    McCune CS, Schapira DV, Henshaw EC: Specific immunotherapy of advanced renal carcinoma: evidence for the polyclonality of metastases. Cancer (47): 1984–1987, 1981.Google Scholar
  27. 27.
    Barranco SC, Haenelt BR, Gee EL: Differential sensitivities of five rat hepatoma cell lines to anticancer drugs. Cancer Res (38): 656–660, 1978.Google Scholar
  28. 28.
    Hakansson L, Trope C: On the presence within tumors of clones that differ in sensitivity to cytostatic drugs. Acta Pathol Microbiol Scand [A] (82): 35–40, 1974.Google Scholar
  29. 29.
    Hakansson L, Trope C: Cell clones with different sensitivity to cytostatic drugs in methylcholanthrene-induced mouse sarcomas. Acta Pathol Microbiol Scand [A] (82): 41–47, 1974.Google Scholar
  30. 30.
    Trope C: Different sensitivity to cytostatic drugs of primary tumor and metastasis of the Lewis lung carcinoma. Neoplasma (22): 171–180, 1975.Google Scholar
  31. 31.
    Lotan R, Nicolson GL: Heterogeneity in growth inhibition by β-trans-retinoic acid of metastatic B16 melanoma clones and in vivo selected cell variant lines. Cancer Res (39): 4767–4771, 1979.Google Scholar
  32. 32.
    Heppner GH, Dexter DL, DeNucci T, Miller FR, Calabresi P: Heterogeneity in drug sensitivity among tumor cell subpopulations of a single mammary tumor. Cancer Res (38): 3758–3763, 1978.Google Scholar
  33. 33.
    Barranco SC, Ho D, Derwinko B, Romsdahl MM, Humphrey RM: Differential sensitivities of human melanoma cells grown in vitro to arabinosylcytosine. Cancer Res (32): 2733–2736, 1972.Google Scholar
  34. 34.
    Barranco SC, Derwinko B, Humphrey RM: Differential response by human melanoma cells to 1,2-bis-(2-chloroethyl)-1-nitrosourea and bleomycin. Mutat Res (19): 277–280, 1973.Google Scholar
  35. 35.
    Lotan R: Different susceptibilites of human melanoma and breast carcinoma cell lines to retinoic acid-induced growth inhibition. Cancer Res (39): 1014–1019, 1979.Google Scholar
  36. 36.
    Trope C, Hakansson L, Dencker H: Heterogeneity of human adenocarcinomas of the colon and the stomach as regards sensitivity to cytostatic drugs. Neoplasma (22): 423–430, 1975.Google Scholar
  37. 37.
    Trope C: Different susceptibilities of tumor cell subpopulations to cytotoxic agents. In: Fidler IJ, White RJ (eds) Design of models for testing cancer chemotherapeutic agents. New York, D. Van Nostrand Co., 1982, pp 64–79.Google Scholar
  38. 38.
    Trope C, Aspergen K, Kullander S, Astredt B: Heterogeneous response of disseminated human ovarian cancers to cytostasis in vitro. Acta Obstet Gynecol Scand (58): 543–546, 1979.Google Scholar
  39. 39.
    Siracky J: An approach to the problem of heterogeneity of human tumor-cell populations. Br J Cancer (39): 570–577, 1979.Google Scholar
  40. 40.
    Baylin SB: Clonal selection and heterogeneity of human solid neoplasms. In: Fidler IJ, White RJ (eds) Design of models for testing cancer therapeutic agents. New York, D Van Nostrand Co, 1982, pp 50–63.Google Scholar
  41. 41.
    Biorklund A, Hakansson L, Stenstarn B, Trope C: Heterogeneity of non-Hodgkin's lymphomas as regards sensitivity to cytostatic drugs. Eur J Cancer (16): 654–657, 1980.Google Scholar
  42. 42.
    Baylin SB, Weisburger WR, Eggleston JC, Mendelshon G, Bearnen MA, Abeloff MD, Ettinger DS: Variable content of histaminase, L-dopa decarboxylase and calcitonin in small-cell carcinoma of the lung. Biologic and clinical implications. N Engl J Med (299): 105–110, 1978.Google Scholar
  43. 43.
    Tsuruo T, Fidler IJ: Differences in drug sensitivity among tumor cells from parental tumors, selected variants, and spontaneous metastases. Cancer Res (41): 3058–3064, 1981.Google Scholar
  44. 44.
    DeWys WD: Studies correlating the growth rate of a tumor and its metastases and providing evidence for tumor-related systemic growth-retarding factors. Cancer Res (32): 374–379, 1972.Google Scholar
  45. 45.
    Cifone MA, Kripke ML, Fidler IJ: Growth rate and chromosome number of tumor cell lines with different metastatic potential. J Supramol Struct (11): 467–476, 1979.Google Scholar
  46. 46.
    Cifone MA, Fidler IJ: Correlation of patterns of anchorage-independent growth with in vivo behavior of cells from a murine fibrosarcoma. Proc Natl Acad Sci USA (77): 1039–1043, 1980.Google Scholar
  47. 47.
    Miller BE, Miller FR, Leith J, Heppner GH: Growth interaction in vivo between tumor subpopulations derived from a single mouse mammary tumor. Cancer Res (40): 3977–3981, 1980.Google Scholar
  48. 48.
    Soule HB, Maloney T, McGrath CM: Phenotypic variance among cells isolated from spontaneous mouse mammary tumors in primary suspension culture. Cancer Res (41): 1154–1164, 1981.Google Scholar
  49. 49.
    Zupi G, Mauro F, Sacchi A: Cloning in vitro and in vivo of Lewis lung carcinoma: properties and characteristics. Br J Cancer (41): 309–310, 1981.Google Scholar
  50. 50.
    Talmadge JE, Starkey JR, Stanford DR: In vitro characteristics of metastatic variant subclones of restricted genetic origin. J Supramol Struct (15): 139–152, 1981.Google Scholar
  51. 51.
    Danielson KG, Anderson LW, Hosick HL: Selection and characterization in culture of mammary tumor cells with distinctive growth properties in vivo. Cancer Res (40): 1812–1819, 1980.Google Scholar
  52. 52.
    Rabotti G: Ploidy of primary and metastatic human tumours. Nature (183): 1276–1277, 1959.Google Scholar
  53. 53.
    Ito E, Moore GE: Characteristic differences in clones isolated from an S37 ascites tumor in vitro. Exp Cell Res (48): 440–447, 1967.Google Scholar
  54. 54.
    Mittleman F: The chromosomes of fifty primary Rous rat sarcomas. Hereditas (69): 155–186, 1971.Google Scholar
  55. 55.
    Ohno S: Genetic implication of karyological instability of malignant somatic cells. Physiol Rev (51): 496–526, 1971.Google Scholar
  56. 56.
    Bohm N, Sondritter W: DNA in human tumors: a cytophotometric study. Curr Top Pathol (60): 152–219, 1975.Google Scholar
  57. 57.
    Straus MJ: In: Straus MJ (ed) Lung cancer. New York, Grune and Stratton, 1977, pp 19–32.Google Scholar
  58. 58.
    Vindelov LV: Flow microfluorometric analysis of nuclear DNA in cells from solid tumors and cell suspensions. Cell Pathol (24): 227–242, 1977.Google Scholar
  59. 59.
    Shapiro JR, Yung W, Shapiro WR: Isolation, karyotype and clonal growth of heterogeneous subpopulations of human malignant gliomas. Cancer Res (41): 2349–2359, 1981.Google Scholar
  60. 60.
    Vindelov LV, Hansen HH, Christensen IJ, Spang-Thomsen M, Hirsch FR, Hansen M, Nissen NI: Clonal heterogeneity of small-cell anaplastic carcinoma of the lung demonstrated by flow cytometric DNA analysis. Cancer Res (40): 4295–4300, 1980.Google Scholar
  61. 61.
    Tilley WD, Keightley DD, Cant ELM: Intersite variation of α estrogen receptors in human breast cancer. Br J Cancer (38): 544–546, 1978.Google Scholar
  62. 62.
    Dexter DL, Kowalski HM, Blazer BA, Fligiel Z, Vogel R, Heppner GH: Heterogeneity of tumor cells from a single mouse mammary tumor. Cancer Res (38): 3174–3181, 1978.Google Scholar
  63. 63.
    Kusyk CJ, Seski JC, Medlin WV, Edwards CL: Progressive chromosome changes associated with different sites of one ovarian carcinoma. INCI (66): 1021–1025, 1981.Google Scholar
  64. 64.
    Fidler IJ, Gruys E, Cifone MA, Barnes Z, Bucana C: Demonstration of multiple phenotypic diversity in a murine melanoma of recent origin. JNCI (67): 947–956, 1981.Google Scholar
  65. 65.
    Niles RM, Makarski JS: Hormonal activation of adenylate cyclase in mouse melanoma metastatic variants. J Cell Physiol (96): 355–359, 1978.Google Scholar
  66. 66.
    Tao TW, Burger MM: Nonmetastasizing variants selected from metastasizing melanoma cells. Nature (270): 437–438, 1977.Google Scholar
  67. 67.
    Brunson KW, Nicolson GL: Selection and biologic properties of malignant variants of a murine lymphosarcoma. JNCI (61): 1499–1503, 1978.Google Scholar
  68. 68.
    Raz A, McLellan WE, Hart IR, Bucana CD, Hoyer LC, Sela BA, Dragsten P, Fidler IJ: Cell surface properties of B16 melanoma variants with differing metastatic potential. Cancer Res (40): 1645–1651, 1980.Google Scholar
  69. 69.
    Reading CL, Belloni DN, Nicolson GL: Selection and in vivo properties of lectin-attachment variants of malignant murine lymphosarcoma cell lines. JNCI (64): 1241–1249, 1980.Google Scholar
  70. 70.
    Franks LM, Estrogen-treated prostatic cancer. Cancer (13): 490–501, 1960.Google Scholar
  71. 71.
    Sluyser M, Evers SG, DeGoey CC: Sex hormone receptors in mammary tumours of GR mice. Nature (263): 386–389, 1976.Google Scholar
  72. 72.
    Sluyser M, Van Nie R: Estrogen receptor content and hormone-responsive growth of mouse mammary tumors. Cancer Res (34): 3252–3257, 1974.Google Scholar
  73. 73.
    Brennan MJ, Donegan WL, Appleby DE: The variability of estrogen receptors in metastatic breast cancer. Am J Surg (137): 260–262, 1979.Google Scholar
  74. 74.
    Isaacs JT, Wake N, Coffey DS, Sandberg AA: Genetic instability coupled to clonal selection as a mechanism for tumor progression in the Dunning R-3327 rat prostatic adenocarcinoma system. Cancer Res (42): 2353–2361, 1981.Google Scholar
  75. 75.
    Isaacs JR, Coffey DS: Adaptation versus selection as the mechanism responsible for the relapse of prostatic cancer to androgen ablation therapy as studied in the Dunning R-3327H adenocarcinoma. Cancer Res (41): 5070–5075, 1981.Google Scholar
  76. 76.
    Semple TV, Moore GE, Morgan RT, Woods LK, Quinn LA: Multiple cell lines from patients with malignant melanoma: morphology, karyology and biochemical analysis. JNCI (68): 365–371, 1982.Google Scholar
  77. 77.
    Kiricuta I, Mustea I, Rogozaw I, Simu G: Relations between tumor and metastases. I. Aspects of the crabtree effect. Cancer (68): 365–371, 1982.Google Scholar
  78. 78.
    Baylin SB, Abeloff MD, Wieman KC, Tomford JW, Ettinger DS: Elevated histaminase (diamine oxidase) activity in small-cell carcinoma of the lung. N Engl J Med (293): 1286–1290, 1975.Google Scholar
  79. 79.
    Lavner EH, Rutherford CL: Implementation of micromethods to resolve problems of human breast tumor heterogeneity in analysis of cyclic 3′: 5′ nucleotide phosphodieiterase. Cancer Res (42): 1661–1668, 1982.Google Scholar
  80. 80.
    Angello JC, Danielson KG, Anderson LW, Hosick HL: Glycosaminoglycan synthesis by subpopulations of epithelial cells from a mammary adenocarcinoma. Cancer Res (42): 2207–2210, 1982.Google Scholar
  81. 81.
    Willis RA: The mode of origin of tumours (fields of origin of epithelial tumours). In: Willis RA (ed) Pathology of tumors. London, Butterworth, 1960, p 108.Google Scholar
  82. 82.
    Foulds L: The experimental study of tumor progression: a review. Cancer Res (14): 327–339, 1954.Google Scholar
  83. 83.
    Reddy AL, Fialkow PJ: Multicellular origin of fibrosarcomas in mice induced by the chemical carcinogen 3-methylcholanthrene. J Exp Med (150): 878–886, 1980.Google Scholar
  84. 84.
    Tanouka H, Tanaka K: Evidence for single cell origin of 3-methylcholanthrene-induced fibrosarcomas in mice with cellular mosaicism. Cancer Res (42): 1856–1858, 1982.Google Scholar
  85. 85.
    Fialkow PJ: Use of genetic markers to study cellular origin and development of tumors in human females. Adv Cancer Res (15): 191–226, 1972.Google Scholar
  86. 86.
    Fialkow PJ: Clonal origin of human tumors. Biochim Biophys Acta (458): 283–310, 1976.Google Scholar
  87. 87.
    Nowell PS: The clonal evolution of tumor cell subpopulations. Science (194): 23–28, 1976.Google Scholar
  88. 88.
    Barrett CJ, Ts'o POP: Evidence for the progressive nature of neoplastic transformation in vitro. Proc Natl Acad Sci USA (75): 3761–3765, 1978.Google Scholar
  89. 89.
    Iannaccone PM, Gardner RL, Harris H: The cellular origin of chemically induced tumors. J Cell Sci (29): 249–255, 1978.Google Scholar
  90. 90.
    Rubin H: Is somatic mutation the major mechanism of malignant transformation? JNCI (64): 995–1000, 1980.Google Scholar
  91. 91.
    Klein E: Gradual transformation of solid into ascites tumors. Permanent difference between the original and the transformed sublines. Cancer Res (14): 482–485, 1954.Google Scholar
  92. 92.
    Klein E: Gradual transformation of solid into ascites tumors. Evidence favoring the mutation-selection theory. Exp Cell Res (8): 188–212, 1955.Google Scholar
  93. 93.
    Potter VR: Phenotypic diversity in experimental hepatomas: the concept of partially blocked ontogeny. Br J Cancer (1): 23–29, 1978.Google Scholar
  94. 94.
    Hager C, Miller FR, Heppner GH: Influence of serial transplantation on the immunological-clinical correlates of BALB/cf C3H mouse mammary tumors. Cancer Res (38): 2492–2498, 1978.Google Scholar
  95. 95.
    Hager JC, Russo J, Ceriani RL, Peterson JA, Fligiel S, Jolly G, Heppner GH: Epithelial characteristics of five subpopulations of a heterogeneous strain BALB/cf C3H mouse mammary tumor. Cancer Res (41): 1720–1730, 1981.Google Scholar
  96. 96.
    Loeb LA, Springate CG, Battula N: Errors in DNA replication as a basis of malignant changes. Cancer Res (34): 2311–2321, 1974.Google Scholar
  97. 97.
    Waren ST, Schultz RA, Chang C, Wade HJ, Trosko JE: Elevated spontaneous mutation rate in Bloom syndrome fibroblasts. Proc Natl Acad Sci USA (78): 3133–3137, 1981.Google Scholar
  98. 98.
    Cifone MA, Fidler IJ: Increasing metastatic potential is associated with increasing genetic instability of clones isolated from murine neoplasms. Proc Natl Acad Sci USA (78): 6949–6952, 1981.Google Scholar
  99. 99.
    Fidler IJ, Hart IR: Biological and experimental consequences of the zonal composition of solid tumors. Cancer Res (41): 3266–3267, 1981.Google Scholar
  100. 100.
    Koch FE: Zur frage der metastazenbildung bei Limpftumoren. Z Krebsforsch (48): 495–499, 1939.Google Scholar
  101. 101.
    Fidler IJ: Selection of successive tumor lines for metastasis. Nature (242): 148–149, 1973.Google Scholar
  102. 102.
    Fidler IJ, Kripke ML: Metastasis results from preexisting variant cells within a malignant tumor. Science (197): 893–895, 1977.Google Scholar
  103. 103.
    Kripke ML, Fidler IJ: Enhanced experimental metastasis of ultraviolet light-induced fibrosarcomas in ultraviolet light-irradiated syngeneic mice. Cancer Res (40): 625–629, 1980.Google Scholar
  104. 104.
    Kripke ML, Gruys E, Fidler IJ: Metastatic heterogeneity of cells from an ultraviolet light-induced murine fibrosarcoma of recent origin. Cancer Res (38): 2962–2967, 1978.Google Scholar
  105. 105.
    Fidler IJ, Hart IR: The origin of metastatic heterogeneity in tumors. Eur J Cancer (17): 487–494, 1981.Google Scholar
  106. 106.
    Tarin D, Price JE: Metastatic colonization potential of primary tumour cells in mice. Br J Cancer (39): 740–754, 1979.Google Scholar
  107. 107.
    Schmitt M, Daynes RA: Heterogeneity of tumorigenicity phenotype in murine tumors. I. Characterization of regressor and progressor clones isolated from a nonmutagenized ultraviolet regressor tumor. J Exp Med (153): 1344–1359, 1981.Google Scholar
  108. 108.
    Dexter DL, Kowalski HM, Blazar BA, Fligiel Z, Vogel R, Heppner GH: Heterogeneity of tumor cells from a single mouse mammary tumor. Cancer Res (38): 3174–3181, 1978.Google Scholar
  109. 109.
    Brattain MG, Fine WD, Khaled FM, Thompson J, Brattain DE: Heterogeneity of malignant cells from a human colonic carcinoma. Cancer Res (41): 1751–1758, 1981.Google Scholar
  110. 110.
    Stackpole CW: Distinct lung-colonizing and lung-metastasizing cell populations in B16 mouse melanoma. Nature (289): 798–800, 1981.Google Scholar
  111. 111.
    Suzuki N, Withers R, Koehler MW: Heterogeneity and variability of artificial lung colony-forming ability among clones from mouse fibrosarcoma. Cancer Res (38): 3349–3351, 1978.Google Scholar
  112. 112.
    Poste G, Fidler IJ: The pathogenesis of cancer metastasis. Nature (283): 139–146, 1980.Google Scholar
  113. 113.
    Briles EB, Kornfeld S: Isolation and metastatic properties of detachment variants of B16 melanoma cells. JNCI (60): 1217–1222, 1978.Google Scholar
  114. 114.
    Poste GH, Doll J, Hart IR, Fidler IJ: Selection of variant lines with increased invasive capacities. Cancer Res (40): 1636–1644, 1980.Google Scholar
  115. 115.
    Hart IR: Selection and characterization of an invasive variant of the B16 melanoma. Am J Pathol (97): 587–600, 1979.Google Scholar
  116. 116.
    Fidler IJ, Bucana C: Mechanism of tumor cell resistance to lysis by syngeneic lymphocytes. Cancer Res (37): 3945–3956, 1977.Google Scholar
  117. 117.
    Schirrmacher V, Bosslet K: Tumor metastases and cell-mediated immunity in a model system in DBA/2 mice. X. Immunoselection of tumor variants differing in tumor antigen expression and metastatic capacity. Int J Cancer (25): 781–788, 1980.Google Scholar
  118. 118.
    Frost PH, Kerbel RS: Immunoselection in vitro of a nonmetastatic variant from a highly metastatic tumor. In J Cancer (27): 381–385, 1981.Google Scholar
  119. 119.
    Talmadge JE, Meyers KM, Prieur DJ, Starkey JR: Role of NK cells in tumour growth and metastasis in beige mice. Nature (284): 622–624, 1980.Google Scholar
  120. 120.
    Hanna N, Fidler IJ: Relationship between metastatic potential and resistance to NK cell-mediated cytotoxicity in three murine tumor systems. JNCI (66): 1183–1190, 1981.Google Scholar
  121. 121.
    Gorelik E, Feldman M, Segal S: Selection of 3LL tumor subline resistant to natural effector cells concomitantly selected for increased metastatic potency. Cancer Immunol Immunother (12): 105–109, 1982.Google Scholar
  122. 122.
    Talmadge JE, Starkey JR, Davis WC, Cohen A: Introduction of metastatic heterogeneity by short term in vivo passage of a cloned transformation cell line. J Supramol Struct (120): 227, 1979.Google Scholar
  123. 123.
    Shearman PJ, Longenecker BM: Selection for virulence and organ-specific metastasis of Herpes virus-transformed lymphoma cells. Int J Cancer (25): 363–369, 1980.Google Scholar
  124. 124.
    Enders JF, Diamondopoulos FT: A study of variation and progression in oncongenicity in an SV 40-transformed hamster heart cell line and its clones. Proc Soc Biol (171): 431–443, 1969.Google Scholar
  125. 125.
    Talmadge JE, Fidler IJ: Cancer metastasis is either selective or random depending on the parent tumour population. Nature (289): 301–303, 1981.Google Scholar
  126. 126.
    Talmadge JE, Fidler IJ: Enhanced metastatic potential of tumor cells harvested from spontaneous metastases of heterogeneous murine tumors. JNCI (69): 975–980, 1982.Google Scholar
  127. 127.
    Talmadge JE, Key ME, Hart IR: Characterization of a murine ovarian reticulum cell sarcoma of histiocytic origin. Cancer Res (41): 1271–1280, 1981.Google Scholar
  128. 128.
    Hart IR, Talmadge JE, Fidler IJ: Metastatic behavior of murine reticulum cell sarcoma exhibiting organ-specific growth. Cancer Res (41): 1281–1287, 1981.Google Scholar
  129. 129.
    Neri A, Welch D, Kawaguchi T, Nicolson GL: Development and biologic properties of malignant cell sublines and clones of a spontaneously metastasizing rat mammary adenocarcinoma. JNCI (68): 507–517, 1982.Google Scholar
  130. 130.
    Raz A, Hanna N, Fidler IJ: In vivo isolation of a metastatic tumor cell variant involving selective and nonadaptive processes. JNCI (66): 183–189, 1981.Google Scholar
  131. 131.
    Nicolson GL, Custead SE: Tumor metastasis is not due to adaptation of cells to a new organ environment. Science (215): 176–178, 1982.Google Scholar
  132. 132.
    Mantovani A, Giavazzi R, Alessandri G, Spreafico F, Garattini S: Characterization of tumor lines derived from spontaneous metastases of a transplantable murine sarcoma. Eur J Cancer (17): 71–76, 1981.Google Scholar
  133. 133.
    Giavazzi R, Alessandri G, Spreafico F, Garattini S, Mantovani A: Metastasizing capacity of tumour cells from spontaneous metastases of transplanted murine tumours. Br J Cancer (42): 432–442, 1980.Google Scholar
  134. 134.
    Talmadge JE, Wolman S, Fidler IJ: Evidence for the clonal origin of spontaneous metastases. Science (217): 361–363, 1982.Google Scholar

Copyright information

© Martinus Nijhoff Publishers 1983

Authors and Affiliations

  • James E. Talmadge
    • 1
  1. 1.Cancer Metastasis and Treatment LaboratoryNCI-Frederick Cancer Research FacilityFrederickUSA
  2. 2.Cancer Metastasis and Treatment LaboratoryNCI-Frederick Cancer Research FacilityFrederickUSA

Personalised recommendations