Cancer and Metastasis Reviews

, Volume 2, Issue 1, pp 5–23

Tumor heterogeneity: biological implications and therapeutic consequences

  • Gloria H. Heppner
  • Bonnie E. Miller
Article

Summary

It is now appreciated that cancers can be composed of multiple clonal subpopulations of cancer cells which differ among themselves in many properties, including karyotype, growth rate, ability to metastasize, immunological characteristics, production and expression of markers, and sensitivity to therapeutic modalities. Such tumor heterogeneity has been demonstrated in a wide variety of animal tumors of differing etiology, tissue and cellular origin, and species. It has been shown in autochthonous, as well as transplanted, tumors. Similar results have been reported for human cancers, although much of the evidence that heterogeneity of human cancers, also reflects, at least in part, the existence of clonal subpopulations, is still indirect. Heterogeneity is not a unique property of malignancy. Preneoplastic tumors, as well as normal tissues, are also composed of cellular subpopulations.

Proposed mechanisms for the origin of tumor heterogeneity include coalescence of multiple foci of cancer clones and the generation of diverse subpopulations from a single clone. This latter process could be due to genetic errors arising from classical genetic mechanisms or to the production of cellular variants as in normal tissue differentiation. Indeed, certain tumor subpopulations have been shown to produce variants at high frequency. In some cases this frequency can be modified by environmental circumstances. Nontumor cells may also contribute to production of cancer cell variants, perhaps, in the case of infiltrating phagocytic cells, by producing mutagens or by somatic hybridization with cancer cells. Production of tumor cell variants is a dynamic process which can occur at any time.

Although tumors are mixed populations of cells, knowledge of the characteristics of individual components is not sufficient to predict the behavior of the whole. Individual cancer subpopulations can interact to affect each other's growth, immunogenicity, ability to metastasize, sensitivity to drugs, and clonal stability. The existence of multiple, interactive subpopulations provides a basis for the well-known phenomenon of ‘tumor progression’ in which tumors undergo qualitative changes in characteristics over the course of time. Selection of subpopulations better able to survive changing environmental circumstances allows for such changes as autonomy in regard to endogenous growth regulation, more ‘malignant’ behavior, and loss of response to therapy. Tumor subpopulation interactions may play a regulatory role in this process.

Tumor heterogeneity has obvious consequences to the design of effective therapy. It provides one rationale for combination therapies and suggests that initial treatment should be early and comprehensive. The continuing emergence of new clones suggests that treatment which is unsuccessful at one point might be effective later. Assays to predict effective therapy for individual patients need to address the multiplicity of tumor subpopulations and the ability of these subpopulations to influence each other. Subpopulation interactions may also be useful in therapy design, as may be efforts to control the extent of tumor heterogeneity by agents which effect cellular differentiation. Thus, tumor heterogeneity presents both problems and, perhaps, new solutions for control of cancer.

Keywords

tumor heterogeneity clonal instability tumor progression subpopulation interactions therapy 

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References

  1. 1.
    Foulds L: Neoplastic development, 2 vols. Academic Press, New York, 1969, 1975.Google Scholar
  2. 2.
    Vaupel PW, Frinak S, Bicher HI: Heterogeneous oxygen partial pressure and pH distribution in C3H mouse mammary adenocarcinoma. Cancer Res (41): 2008–2013, 1981.Google Scholar
  3. 3.
    Dethlefsen L: The growth dynamics of murine mammary tumor cells in situ. In: McGrath CM, Brennan MJ, Rich MA (eds) Cell biology of breast cancer. New York, Academic Press 1980, pp 145–160.Google Scholar
  4. 4.
    Bosman HB, Winston RA: Synthesis of glycoprotein, glycolipid, protein, and lipid in synchronized L5178Y cells. J Cell Biol (45): 23–33, 1970.Google Scholar
  5. 5.
    Pasternak CA, Warmsley AMH, Thomas DB: Structured alterations in the surface membrane during the cell cycle. J Cell Biol (50): 562–564, 1971.Google Scholar
  6. 6.
    Cikes M, Klein G: Quantitative studies of antigen expression in cultured mirine lymphoma cells. I. Cell-surface antigens in ‘Asynchronous’ cultures. J Natl Cancer Inst (49): 1599–1606, 1972.Google Scholar
  7. 7.
    Panem S, Schauf V: Cell-cycle dependent appearance of murine leukemia—sarcoma virus antigens. J Virol (13): 1169–1175, 1974.Google Scholar
  8. 8.
    Everson LK, Plocinik BA, Rogentine GN: HL-A expression on the G1, S, and G2 cell-cycle stages of human lymphoid cells. J Natl Cancer Inst (53): 913–920, 1974.Google Scholar
  9. 9.
    Shipley WU. Immune cytolysis in relation to the growth cycle of chinese hamster cells. Cancer Res (31): 925–929, 1971.Google Scholar
  10. 10.
    Lerner RA, Oldstone MBA, Cooper NR: Cell cycle-dependent immune lysis of Moloney virus-transformed lymphocytes: presence of viral antigen, accessibility to antibody, and complement activation. Proc Nat Acad Sci USA (68): 2584–2588, 1971.Google Scholar
  11. 11.
    Valeriote F, van Putten L. Proliferation dependent cytotoxicity of anticancer agents: a review. Cancer Res (35): 2619–2630, 1975.Google Scholar
  12. 12.
    Suzuki N, Withers HR, Koehler MW: Heterogeneity and variability of artificial lung colony forming ability among clones from mouse fibrosarcoma. Cancer Res (38): 3349–3351, 1978.Google Scholar
  13. 13.
    Weiss L: Cancer cells in primary tumors and their metastases. In: McGrath CM, Brennan MJ, Rich MA (eds) Cell biology of breast cancer. New York, Academic Press, 1980, pp 189–205.Google Scholar
  14. 14.
    Prehn RT: Analysis of antigenic heterogeneity within individual 3-methylcholanthrene-induced mouse sarcomas. J Natl Cancer Inst (45): 1039–1045, 1970.Google Scholar
  15. 15.
    Hakansson L, Tropé C: On the presence within tumors of clones that differ in sensitivity to cytostatic drugs. Acta Pathol Microbiol Scand Suppl Section A (82): 35–40, 1974.Google Scholar
  16. 16.
    Fidler IJ, Hart IR: Biological and experimental consequences of the zonal composition of solid tumors. Cancer Res (41): 3266–3267, 1981.Google Scholar
  17. 17.
    Gray JM, Pierce GB: Relationship between growth rate and differentiation of melanoma in vivo. J Natl Cancer Inst (32): 1201–1211, 1964.Google Scholar
  18. 18.
    Fidler IJ, Kripke ML: Metastasis results from preexisting variant cells within a malignant tumor. Science (197): 893–895, 1977.Google Scholar
  19. 19.
    Fidler IJ, Gruys E, Cifone MA, Barnes Z, Bucana C: Demonstration of multiple phenotypic diversity in a murine melanoma of recent origin. J Natl Cancer Inst (67): 947–956, 1981.Google Scholar
  20. 20.
    Olsson L, Ebbesen P: Natural polyclonality of spontaneous AKR leukemia and its consequences for so-called specific immunotherapy. J Natl Cancer Inst (62): 623–627, 1979.Google Scholar
  21. 21.
    Mathieson BJ, Zatz MM, Sharrow SO, Asofsky R, Logan W, Kanellopoulos-Langevin C. Separation and characterization of two component tumor lines within the AKR lymphoma, AKTB-1, by fluorescence-activated cell sorting and flow microfluorometry analysis. J Immunol (128): 1832–1838, 1982.Google Scholar
  22. 22.
    Mitelman F: The chromosomes of fifty primary Rous rat sarcomas. Heriditas (69): 155–186, 1971.Google Scholar
  23. 23.
    Nicolson GL, Brunson KW, Fidler IJ: Specificity of arrest, suvival, and growth of selected metastatic variant cell lines. Cancer Res (38): 4105–4111, 1978.Google Scholar
  24. 24.
    Varani J, Orr W, Ward PA. A comparison of the migration patterns of normal and malignant cells in two assay systems. Am J Pathol (90): 159–172, 1978.Google Scholar
  25. 25.
    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
  26. 26.
    Raz A, Hanna N, Fidler IJ: In vivo isolation of a metastatic tumor cell variant involving selective and nonadaptive processes. J Natl Cancer Inst (66): 183–189, 1981.Google Scholar
  27. 27.
    Henderson JS, Rous P: The plating of tumor components on the subcutaneous expanses of young mice. J Exp Med (115): 1211–1229, 1962.Google Scholar
  28. 28.
    Dominguez OV, Huseby RA: Heterogeneity of induced testicular interstitial cell tumors of mice as evidenced by steroid biosynthetic enzyme activities. Cancer Res (28): 348–353, 1968.Google Scholar
  29. 29.
    Pierce GB: Cellular heterogeneity of cancers. In: T'so POP, DiPaolo JA (eds) World symposium on model studies in chemical carcinogenesis. New York, Dekker, 1974, pp 463–472.Google Scholar
  30. 30.
    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
  31. 31.
    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
  32. 32.
    Tseng MT: Ultrastructure of the hormone-dependent N-Nitrosomethylurea-induced mammary carcinoma of the rat. Cancer Res (40): 3112–3115, 1980.Google Scholar
  33. 33.
    Macinnes JI, Chan ECM, Percy DH, Morris VL: Mammary tumors from GR mice contain more than one population of mouse mammary tumor virus-infected cells. Virol (113): 119–129, 1981.Google Scholar
  34. 34.
    Colcher D, Hand PH, Teramoto YA, Wunderlich D, Schlom J. Use of monoclonal antibodies to define the diversity of mammary tumor viral gene products in virions and mammary tumors of the genus Mus. Cancer Res (41): 1451–1459, 1981.Google Scholar
  35. 35.
    Michalides R, Wagenaar E, Sluyser M: Mammary tumor virus DNA as a marker for genotypic variance within hormone-responsive GR mouse mammary tumors. Cancer Res (42): 1154–1158, 1982.Google Scholar
  36. 36.
    Kobori O, Oota K: Neuroendocrine cells in serially passaged rat stomach cancers induced by MNNG. Int J Cancer (23): 536–541, 1979.Google Scholar
  37. 37.
    Hager J, Fligiel S, Stanley W, Richardson AM, Heppner GH: Characterization of a variant producing tumor cell line from a heterogeneous strain BALB/cfC3H mouse mammary tumor. Cancer Res (41): 1293–1300, 1981.Google Scholar
  38. 38.
    Sluyser M, Evers SG, DeGoeij CCJ: Sex hormone receptors in mammary tumors of GR mice. Nature (263): 386–389, 1976.Google Scholar
  39. 39.
    Pimm MV, Baldwin RW: Antigenic differences between primary methylcholanthrene-induced rat sarcomas and post-surgical recurrences. Int J Cancer (20): 37–43, 1977.Google Scholar
  40. 40.
    Fuji H, Mihich E, Pressman D: Differential tumor immunogenicity of L1210 and its sublines. J Immunol (119): 983–986, 1977.Google Scholar
  41. 41.
    Killion JJ: Immunotherapy with tumor cell subpopulations. Cancer Immunol Immunother (4): 115–119, 1978.Google Scholar
  42. 42.
    Schirrmacher V, Bosslet K, Shantz G, Claver 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
  43. 43.
    Miller FR, Heppner GH: Immunologic heterogeneity of tumor cell subpopulations from a single mouse mammary tumor. J Natl Cancer Inst (63): 1457–1464, 1979.Google Scholar
  44. 44.
    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
  45. 45.
    Miller FR: Intratumor immunologic heterogeneity. Cancer Metastasis Rev (1): 319–334, 1982.Google Scholar
  46. 46.
    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
  47. 47.
    Miller FR, Miller BE, Heppner GH: Metastatic heterogeneity of a single mouse mammary tumor: frequency, stability, and site dependency. Invasion Metastasis (in press).Google Scholar
  48. 48.
    Varani J, Orr W, Ward PA: Adhesive characteristics of tumor cell variants of high and low tumorigenic potential J Natl Cancer Inst (64): 1173–1178, 1980.Google Scholar
  49. 49.
    Soule HD, 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
  50. 50.
    Rios A, Laux D, Heppner GH: Patterns of lymphocyte infiltration in tumor sublines of a single mammary adenocarcinoma. Proc AACR (23): 1021 (abstract), 1982.Google Scholar
  51. 51.
    Levan A, Hauschka TS: Endomitotic reduplication mechanisms in ascites tumors of the mouse. J Natl Cancer Inst (14): 1–21, 1953.Google Scholar
  52. 52.
    Makino S: Further evidence favoring the concept of the stem cell in ascites tumors of rats. Ann N Y Acad Sci (63): 818–830, 1956.Google Scholar
  53. 53.
    Becker FF, Klein KM, Wolman SR, Asofsky R, Sell S: Characterization of primary hepatocellular carcinomas and initial transplant generations. Cancer Res (33): 3330–3338, 1973.Google Scholar
  54. 54.
    Ishidate M, Aoshima M, Sakurai Y: Population changes of a rat leukemia by different routes of transplantation. J Natl Cancer Inst (53): 773–781, 1974.Google Scholar
  55. 55.
    Nowell PC: The clonal evolution of tumor cell populations. Science (194): 23–28, 1976.Google Scholar
  56. 56.
    Wang N, Yu SH, Liener IE, Hebbel RP, Eaton JW, McKhann CF: Characterization of high and low metastatic clones derived from a methylcholanthrene-induced murine fibrosarcoma. Cancer Res (42): 1046–1051, 1982.Google Scholar
  57. 57.
    Hager JC, Heppner GH: Heterogeneity of expression and induction of mouse mammary tumor virus antigens in mouse mammary tumors. Cancer Res (42): 4325–4329, 1982.Google Scholar
  58. 58.
    Geier GR, Schwarz JA, Schlag P: Cytologic uniformity of breast cancer from different locations: a pattern analyses study. Expl Cell Biol (47): 241–249, 1979.Google Scholar
  59. 59.
    Parbhoo SP: Heterogeneity in human mammary cancer. In: Stoll BA (ed) Systemic control of breast cancer. London, William Heinemann Medical Books, 1981, pp 55–77.Google Scholar
  60. 60.
    Ewing SL, Sumner HW, Ophoven JJ, Mayer JE, Humphrey EW: Small cell anaplastic carcinoma with differentiation: a report of 14 cases (abstract). Lab Invest (42): 115, 1980.Google Scholar
  61. 61.
    McDowell EM, Sorokin SP, Hoyt RF, Trump BF: An unusual bronchial carcinoid tumor: light and electron microscopy. Human Pathol (12): 338–348, 1981.Google Scholar
  62. 62.
    Stich HF, Florian SF, Emson HE: The DNA content of tumor cells. I. Polyps and adenocarcinoma of the large intestine of man. J Natl Cancer Inst (24): 471–482, 1960.Google Scholar
  63. 63.
    Vindelv LL, Hansen HH, Christensen HJ, 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
  64. 64.
    Byers VS, Johnston JO: Antigenic differences among osteogenic sarcoma tumor cells taken from different locations in human tumors. Cancer Res (37): 3173–3183, 1977.Google Scholar
  65. 65.
    Tan MN, Shimano T, Chu TM: Differential localization of human pancreas cancer-associated antigen and carcinoembryonic antigen in homologous pancreatic tumoral xenograft. J Natl Cancer Inst (67): 563–569, 1981.Google Scholar
  66. 66.
    Horan Hand P, Nuti M, Colcher D, Schlom J: Monoclonal antibodies to tumor associated antigens define antigenic heterogeneity among human mammary cancer cell populations (submitted for publication).Google Scholar
  67. 67.
    Weiss MA, Michael JG, Pesce AJ, DiPersio L: Heterogeneity of B2-microglobulin in human breast carcinoma. Lab Invest (45): 46–57, 1981.Google Scholar
  68. 68.
    Lee SH: Cytochemical study of estrogen receptor in human mammary cancer. Am J Clin Pathol (70): 197–203, 1978.Google Scholar
  69. 69.
    Pertschuk LP, Tobin EH, Brigati DJ, Kim DS, Bloom ND, Gaetjens E, Berman PJ, Carter AC, Degenstein GA: Immunofluorescent detection of estrogen receptors in breast cancer. Cancer (41): 907–911, 1978.Google Scholar
  70. 70.
    Brennan MJ, Donegan WL, Appleby DE: The variability of estrogen receptors in metastatic breast cancer. Am J Surg (137): 260–262, 1979.Google Scholar
  71. 71.
    Lippman SM, Mendelsohn G, Trump DL, Wells SA, Baylin SB: The prognostic and biological significance of cellular heterogeneity in medullary thyroid carcinoma: a study of calcitonin, L-Dopa decarboxylase, and histaminase. J Clin Endo Met (54): 233–240, 1982.Google Scholar
  72. 72.
    Baylin SB, Weisburger WR, Eggleston JC, Mendelsohn G, Beaven MA, Abeloff MD, Ettinger DS: Variable content of histaminase, L-Dopa decarboxylase and calcitonin in small-cell carcinoma of the lung. New Engl J Med (299): 105–110, 1978.Google Scholar
  73. 73.
    Siracký J: An approach to the problem of heterogeneity of human tumor-cell populations. Br J Cancer (39): 570–577, 1979.Google Scholar
  74. 74.
    Barranco SC, Ho DHW, Drewinko B, Romsdahl MM, Humphrey RM: Differential sensitivity of human melanoma cells grown in vitro to arabinosylcytosine. Cancer Res (32): 2733–2736, 1972.Google Scholar
  75. 75.
    Barranco SC, Drewinko B, Humphrey RM: Differential response by human melanoma cells to 1,3-bis-(2-chloroethyl)-1-nitrosourea and bleomycin. Mutation Res (19): 277–280, 1973.Google Scholar
  76. 76.
    Sorg C, Bruggen J, Seibert E, Macher E: Membrane-associated antigens of human malignant melanoma IV: changes in expression of antigens on cultured melanoma cells. Cancer Immunol Immunother (3): 259–271, 1978.Google Scholar
  77. 77.
    Albino AP, Lloyd KO, Houghton AN, Oettgen H, 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
  78. 78.
    Aubert C, Rougé F, Galindo JR: Tumorigenicity of human malignant melanocytes in nude mice in relation to their differentiation in vitro. J Natl Cancer Inst (64): 1029–1040, 1980.Google Scholar
  79. 79.
    Brattain MG, Fine WD, Khaled FM, Thompson J, Brattain DE: Heterogeneity of malignant cells from a human colonic carcinoma. Cancer Res (41): 1751–1756, 1981.Google Scholar
  80. 80.
    Dexter DL, Spremulli EN, Fligiel Z, Barbosa JA, Vogel R, VanVoorhees A, Calabresi P: Heterogeneity of cancer cells from a single human colon carcinoma. Am J Med (71): 949–956, 1981.Google Scholar
  81. 81.
    Chu MY: Tumor cell heterogeneity in human lung carcinoma. Proc AACR (20): 151 (abstract), 1979.Google Scholar
  82. 82.
    Mackintosh FA, Louie AC, Evans TL, Amylon MD, Sikic BI: Clonal heterogeneity in a human ovarian adenocarcinoma. Proc AACR (22): 184 (abstract), 1981.Google Scholar
  83. 83.
    Kajiji SM, Meitner PA, Bogaars HA, Dexter DL, Cummings FJ, Calabresi P, Turner MD: Establishment of a fast growing variant of human pancreatic cancer (HPC). Proc AACR (23): 119 (abstract), 1982.Google Scholar
  84. 84.
    Shapiro JR, Yung WA, Shapiro WR: Isolation, karyotype, and clonal growth of heterogeneous subpopulations of human malignant gliomas. Cancer Res (41): 2349–2359, 1981.Google Scholar
  85. 85.
    Wikstrand CJ, Bigner SP, Bigner DD: Antigenic heterogeneity of an established human glioma cell line (HGCL) and eight single cell derived clones as defined by specific anti-glioma monoclonal antibodies (MCA). Proc AACR (23): 1070 (abstract), 1982.Google Scholar
  86. 86.
    Kimball PM, Brattain MG: Isolation of a cellular subpopulation from a human colonic carcinoma cell line. Cancer Res (40): 1574–1579, 1980.Google Scholar
  87. 87.
    Okamura S, Chechik BE, Lee C, Gelfand EW, Mak TW: Heterogeneity of human thymocytes and a malignant T-lymphoblast cell line, MOLT-3. Cancer Res (41): 1664–1668, 1981.Google Scholar
  88. 88.
    Butler WB, Berlinski PJ, Kelsey WH, Toehniges MM: Heterogeneity of the human breast cancer cell line MCF-7. Proc AACR (23): 931 (abstract), 1982.Google Scholar
  89. 89.
    Fialkow PJ: Clonal origin of human tumors. Ann Rev Med (30): 135–143, 1979.Google Scholar
  90. 90.
    Friedman JM, Fialkow PJ: Viral ‘tumorigenesis’ in man: cell markers in condylomata acuminata. Int J Cancer (17): 57–61, 1976.Google Scholar
  91. 91.
    Tanooka 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
  92. 92.
    Reddy AL, Fialkow PJ: Multicellular origin of fibrosarcomas in mice induced by the chemical carcinogen 3-methylcholanthrene. J Exp Med (150): 878–887, 1979.Google Scholar
  93. 93.
    Till JE, McColloch EA: Hemopoietic stem cell differentiation. Biochim Biophys Acta (605): 431–459, 1980.Google Scholar
  94. 94.
    Good RA: Structure — function relations in the lymphoid system. In: Bach FH, Good RA (eds) Clinical immunobiology, vol 1, New York, Academic Press, 1972, pp 1–28.Google Scholar
  95. 95.
    St. George JA, Cardiff RD, Young LJT, Faulkin LJ: Immunocytochemical distribution of mouse mammary tumor virus antigens in BALB/cfC3H mammary epithelium. J Natl Cancer Inst (63): 813–820, 1979.Google Scholar
  96. 96.
    Griffen JE, Allman DR, Durrant JL, Wilson JD: Variation in steroid 5α-reductase activity in cloned human skin fibroblasts. J Bio Chem (256): 3662–3666, 1981.Google Scholar
  97. 97.
    Ogawa K, Solt DB, Farber E: Phenotype diversity as an early property of putative preneoplastic hepatocyte populations in liver carcinogenesis. Cancer Res (40): 725–733, 1980.Google Scholar
  98. 98.
    Ashley RL, Cardiff RD, Mitchel DJ, Faulkin LJ, Lund JK: Development and characterization of mouse hyperplastic mammary outgrowth lines from BALB/cfC3H hyperplastic alveolar nodules. Cancer Res (40): 4232–4242, 1980.Google Scholar
  99. 99.
    Boone CW, Vembu D, White BJ, Takeichi N, Paranjpe M: Karyotypic, antigenic, and kidney-invasive properties of cell lines from fibrosarcomas arising in C3H/10T1/2 cells implanted subcutaneously attached to plastic plates. Cancer Res (39): 2172–2178, 1979.Google Scholar
  100. 100.
    Kakunaga T, Crow JD: Cell variants showing differential susceptibility to ultraviolet light-induced transformation. Science (209): 505–507, 1980.Google Scholar
  101. 101.
    Cifone M, Fidler IJ: Increasing metastatic potential is associated with increasing genetic instability of clones isolated from murine neoplasms. Proc Natl Acad Sci USA (78): 6249–6252, 1981.Google Scholar
  102. 102.
    Jansson B, Révész L. A deductive approach to the analysis of the growth of ascites tumor cell populations. In: Busch H (ed) Methods in cancer research, Vol XIII. New York, Academic Press, 1976, pp 227–290.Google Scholar
  103. 103.
    Smith BL, Sager R: Multistep origin of tumor-forming ability in chinese hamster embryo fibroblast cells. Cancer Res (42): 389–396, 1982.Google Scholar
  104. 104.
    Canaani E, Aaronson SA: Restriction enzyme analysis of mouse cellular type C viral DNA: emergence of new viral sequences in spontaneous AKR/J lymphomas. Proc Natl Acad Sci USA (76): 1677–1681, 1979.Google Scholar
  105. 105.
    Bennett DC, Peachey LA, Durbin H, Rudland PS: A possible mammary stem cell line. Cell (15): 283–298, 1978.Google Scholar
  106. 106.
    Dulbecco R, Henahan M, Bowman M, Okada S, Battifora H, Unger M: Generation of fibroblast-like cells from cloned epithelial mammary cells in vitro: a possible new cell type. Proc Natl Acad Sci USA (78): 2345–2349, 1981.Google Scholar
  107. 107.
    Imada M, Sueoka N: Clonal sublines of rat neurotumor RT4 and cell differentiation. I. Isolation and characterization of cell lines and cell type conversion. Devel Biol (66): 97–108, 1978.Google Scholar
  108. 108.
    Daley MJ: Intratumor maturational heterogeneity within the murine myeloma MOPC-315. Cancer Res (41): 187–191, 1981.Google Scholar
  109. 109.
    Chow DA, Greenberg AH: The generation of tumor heterogeneity in vivo. Int J Cancer (25): 261–265, 1980.Google Scholar
  110. 110.
    Loveless SE, Wang CY, Heppner GH: Mutagenic activity of tumor-associated macrophages (submitted for publication).Google Scholar
  111. 111.
    Weitzman SA, Stossel TP: Mutation caused by human phagocytes. Science (212): 546–547, 1981.Google Scholar
  112. 112.
    Weitzman SA, Stossel TP: Effects of oxygen radical scavengers and anti-oxidants on phagocyte-induced mutagenesis. J Immunol (128): 2770–2772, 1982.Google Scholar
  113. 113.
    Talmadge JE, Starkey JR, Davis WC, Cohen AL: Introduction of metastatic heterogeneity by short-term in vivo passage of a cloned transformed cell line. J Supramol Struct (12): 227–243, 1979.Google Scholar
  114. 114.
    DeBaetselier P, Gorelik E, Eshhar Z, Ron Y, Katzav S, Feldman M, Segal S: Metastatic properties conferred on nonmetastatic tumors by hybridization of spleen B-lymphocytes with plasmacytoma cells. J Natl Cancer Inst (67): 1079–1087, 1981.Google Scholar
  115. 115.
    Goldenberg DM, Pavia RA, Tsao MC: In vivo hybridization of human tumour and normal hamster cells. Nature (250): 649–651, 1974.Google Scholar
  116. 116.
    Hu F, Pasztor LM: In vivo hybridization of cultured melanoma cells and isogeneic normal mouse cells. Differentiation (4): 92–97, 1975.Google Scholar
  117. 117.
    Lala PK, Santer V, Rahl KS: Spontaneous fusion between Ehrlich ascites tumor cells and host cells in vivo: kinetics of hybridization, and concurrent changes in the histocompatibility profile of the tumor after propagation in different host strains. Eur J Cancer (16): 487–510, 1980.Google Scholar
  118. 118.
    Goldenberg DM, Pavia RA: Malignant potential of murine stromal cells after transplantation of human tumors into nude mice. Science (212): 65–67, 1981.Google Scholar
  119. 119.
    Kerbel RS, Florian M, Man MS, Dennis J, McKenzie IFC: Carcinogenicity of tumor cell populations: origin of a putative H-2 isoantigenic loss variant tumor. J Natl Cancer Inst (64): 1221–1230, 1980.Google Scholar
  120. 120.
    Frost P, Kerbel RS, Tartamella-Biondo R: Generation of highly metastatic tumors in DBA/2 mice. Invasion Metastasis (1): 22–33, 1981.Google Scholar
  121. 121.
    Mantovani A, Giavazzi R, Alessandri G, Spreafico F, Garattini S: Characterization of tumor lines derived from spontaneous metastases of a transplanted murine sarcoma. Eur J Cancer (17): 71–76, 1981.Google Scholar
  122. 122.
    Talmadge JE: Evidence that the process of metastasis is selective and not random. Proc AACR (23): 173 (abstract), 1982.Google Scholar
  123. 123.
    Chambers AF, Hill RP, Ling V: Tumor heterogeneity and stability of the metastatic phenotype of mouse KHT sarcoma cells. Cancer Res (41): 1368–1372, 1981.Google Scholar
  124. 124.
    Neri A, Nicolson GL: Phenotypic drift of metastatic and cell-surface properties of mammary adenocarcinoma cell clones during growth in vitro. Int J Cancer (28): 731–738, 1981.Google Scholar
  125. 125.
    Dennis J, Donaghue T, Florian M, Kerbel RS: Apparent reversion of stable in vitro genetic markers detected in tumour cells from spontaneous metastases. Nature (292): 242–245, 1981.Google Scholar
  126. 126.
    Poste G, Doll J, Fidler IJ: Interactions among clonal subpopulations affect stability of the metastatic phenotype in polyclonal populations of B16 melanoma cells. Proc Natl Acad Sci USA (78): 6626–6630, 1981.Google Scholar
  127. 127.
    Rubin H: Is somatic mutation the major mechanism of malignant transformation? J Natl Cancer Inst (64): 995–1000, 1980.Google Scholar
  128. 128.
    Ludford RJ, Barlow H: The influence of malignant cells upon the growth of fibroblasts in vitro. Cancer Res (4): 694–703, 1944.Google Scholar
  129. 129.
    Ranadive KJ, Bhide SV: Tissue interactions between normal and malignant cells. In: Brennan MJ, Simpson WL (eds) Biological interactions in normal and neoplastic growth. Boston, Little, Brown, and Co, 1962, pp 337–354.Google Scholar
  130. 130.
    Stoker M: Regulation of growth and orientation in hamster cells transformed by polyoma virus. Virol (24): 165–174, 1964.Google Scholar
  131. 131.
    Slemmer G: Interactions of separate types of cells during normal and neoplastic mammary gland growth. J Invest Derm (63): 27–47, 1974.Google Scholar
  132. 132.
    Nandi S: Hormonal carcinogenesis: a novel hypothesis for the role of hormones. J Environ Pathol Tox (2): 13–20, 1978.Google Scholar
  133. 133.
    DeOme KB, Miyamoto MJ, Osborn RC, Guzman RC, Lum K: Detection of inapparent nodule-transformed cells in the mammary gland tissues of virgin female BALB/cfC3H mice. Cancer Res (38): 2103–2111, 1974.Google Scholar
  134. 134.
    Medina D, Shepherd F, Gropp T. Enhancement of the tumorigenicity of preneoplastic mammary nodule lines by enzymatic dissociation. J Natl Cancer Inst (60): 1121–1126, 1978.Google Scholar
  135. 135.
    Simnett JD: Regulation of growth and cell division in the whole organism. In: Sherbet GV (ed) Regulation of growth in neoplasia. Basel, Karger, 1981, pp 1–51.Google Scholar
  136. 136.
    Hauschka TS: Methods of conditioning the graft in tumor transplantation. J Natl Cancer Inst (14): 723–736, 1953.Google Scholar
  137. 137.
    Heppner GH: The challenge of tumor heterogeneity. In: Bulbrook RD, Taylor DJ (eds) Commentaries on research in breast disease. New York, Alan R. Liss, Inc. 1979, pp 177–191.Google Scholar
  138. 138.
    Makino S: Further evidence favoring the concept of the stem cell in ascites tumors of rats. Ann N Y Acad Sci (63): 818–830, 1956.Google Scholar
  139. 139.
    Chesire PJ: The effect of multiple tumors on mammary tumor growth rates in the C3H mouse. Br J Cancer (24): 542–547, 1970.Google Scholar
  140. 140.
    Heppner G, Miller B, Cooper DN, Miller FR: Growth interactions between mammary tumor cells. In: McGrath CM, Brennan MJ, Rich MA (eds) Cell biology of breast cancer. New York, Academic Press, 1980, pp 161–172.Google Scholar
  141. 141.
    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
  142. 142.
    Heppner GH: Tumor subpopulation interactions. In: Owens A (ed) Tumor cell heterogeneity: origins and implications. New York, Academic Press, 1982.Google Scholar
  143. 143.
    Riley PA: Control of proliferation of normal and neoplastic cells in culture. In: Sherbet GV (ed) Regulation of growth neoplasia. Basel, Karger, 1981, pp 131–198.Google Scholar
  144. 144.
    DeLarco JE, Todaro GJ: Growth factors from murine sarcoma virus-transformed cells. Proc Natl Acad Sci USA (75): 4001–4005, 1978.Google Scholar
  145. 145.
    Horoszewicz JS, Leong SS, Carter WA: Noncycling tumor cells are sensitive targets for the antiproliferative activity of human interferon. Science (206): 1091–1093, 1979.Google Scholar
  146. 146.
    Moody TW, Pert CB, Gazder AF, Carney DN, Minna JD: High levels of intracellular bombasin characterize human small-cell lung carcinoma. Science (214): 1246–1248, 1981.Google Scholar
  147. 147.
    Nowotny A, Grodsman J: Mixed tumor challenge of strain specific and nonspecific TA3 mouse ascites mammary adenocarcinoma. Int Arch Allergy (44): 434–440, 1973.Google Scholar
  148. 148.
    Miller FR, Heppner GH: Intratumor immunologic heterogeneity. Proc AACR (21): 201 (abstract), 1979.Google Scholar
  149. 149.
    Browning HC: Heterologous and homologous growth of transplants during the course of development of spontaneous mammary tumors in C3H mice. J Natl Cancer Inst (8): 173–189, 1948.Google Scholar
  150. 150.
    Klein G, Klein E: Conversion of solid neoplasms into ascites tumors. Ann N Y Acad Sci (63): 640–661, 1956.Google Scholar
  151. 151.
    DeWys WD: Studies correlating the growth rate of a tumor and its metastasis and providing evidence for tumor-related systemic growth-retarding factors. Cancer Res (32): 374–379, 1972.Google Scholar
  152. 152.
    Greene HSN, Harvey EK: The inhibitory influence of a transplanted hamster lymphoma on metastasis. Cancer Res (20): 1094–1100, 1960.Google Scholar
  153. 153.
    Milas L, Hunter N. Mason K, Withers HR: Immunological resistance to pulmonary metastasis in C3Hf/Bu mice bearing syngeneic fibrosarcomas of different sizes. Cancer Res (34): 61–71, 1974.Google Scholar
  154. 154.
    Yuhas JM, Pazmiño NH: Inhibition of subcutaneously growing line 1 carcinomas due to metastatic spread. Cancer Res (34): 2005–2010, 1974.Google Scholar
  155. 155.
    Goldie H, Walker M, Kelley L, Gaines J: Free tumor cell growth in the peritoneal cavity (ascites tumor) of mice bearing subcutaneous tumors. Cancer Res (16): 553–558, 1956.Google Scholar
  156. 156.
    Gorelik E, Segal S, Feldman M: Growth of a local tumor exerts a specific inhibitory effect on progression of lung metastases. Int J Cancer (21): 617–625, 1978.Google Scholar
  157. 157.
    Gorelik E, Segal S, Feldman M: On the mechanism of tumor ‘concomitant immunity’. Int J Cancer (27): 847–856, 1981.Google Scholar
  158. 158.
    Miller F: Subpopulation interactions in metastasis. Invasion Metastasis (in press).Google Scholar
  159. 159.
    Poste G, Doll J, Brown AE, Tzeng J, Zeidman I: Comparison of the metastatic properties of B16 melanoma clones isolated from cultured cell lines, subcutaneous tumors, and individual lung metastases. Cancer Res (42): 2770–2778, 1982.Google Scholar
  160. 160.
    Biswas C, Morgan WP, Bloch KJ, Gross J: Collagenolytic activity of rabbit V2-carcinoma growing at multiple sites. Biochem Biophys Res Comm (80): 33–38, 1980.Google Scholar
  161. 161.
    Poste G, Nicolson G: Arrest and metastasis of bloodborne tumor cells are modified by fusion of plasma membrane vesicles from highly metastatic cells. Proc Natl Acad Sci USA (77): 399–403, 1980.Google Scholar
  162. 162.
    Dvorak HF, Quay SC, Orenstein NS, Dvorak AM, Hahn P, Bitzer AM, Carvallo AC: Tumor shedding and coagulation. Science (212): 923–924, 1981.Google Scholar
  163. 163.
    Sinha AA: Hormone sensitivity and autonomy of tumours. In: Stoll BA (ed) Hormonal management of endocrine-related cancer. London, Lloyd-Luke Medical Books, 1981, pp 13–19.Google Scholar
  164. 164.
    Sluyser M: The emergence of hormone-independent cells in hormone-dependent breast cancer. In: McGrath CM, Brennan MJ, Rich MA (eds) Cell biology of breast cancer. New York, Academic Press, 1980, pp 173–187.Google Scholar
  165. 165.
    Lee C, Lapin V, Oyasu R, Battifora H: Effect of ovariectomy on serially transplanted rat mammary tumors induced by 7,12-dimethylbenz[a]anthracene. Eur J Cancer Clin Oncol (17): 801–808, 1981.Google Scholar
  166. 166.
    Sinha AA, Blackard CE, Seal US: A critical analyses of tumor morphology and hormone treatments in the untreated and estrogen-treated responsive and refractory human prostatic carcinoma. Cancer (4): 2836–2850, 1977.Google Scholar
  167. 167.
    Isaacs JT, Coffey DS: Adaptation versus selection as the mechanism responsible for the relapse of prostatic cancer to androgen ablation therapy as studies in the Dunning B-3327-H adenocarcinoma. Cancer Res (41): 5070–5075, 1981.Google Scholar
  168. 168.
    Hart IR, Fidler IJ: Cancer invasion and metastasis. Quart Rev Biol (55): 121–142, 1980.Google Scholar
  169. 169.
    Sluyser M, DeGoeij KCJ, Evers SG: Outgrowth of grafts containing different ratios of hormone-dependent and independent mouse mammary tumor cells. Cancer Lett (13): 71–77, 1981.Google Scholar
  170. 170.
    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, 1982.Google Scholar
  171. 171.
    Hager JC, Miller FR, Heppner GH: Influence of serial transplantation on the immunological clinical correlates of BALB/cfC3H mouse mammary tumors. Cancer Res (38): 2492–2500, 1978.Google Scholar
  172. 172.
    Kiang DT, King M, Zhang HJ, Kennedy BJ, Wang N: Cyclic biological expression in mouse mammary tumors. Science (216): 68–70, 1982.Google Scholar
  173. 173.
    Vaage J: Inherent changes in the in vivo growth characteristics of C3H/Hc mammary carcinomas. Cancer Res (40): 3495–3501, 1980.Google Scholar
  174. 174.
    Law LW: Origin of the resistance of leukemic cells to folic acid antagonists. Nature (169): 628–629, 1952.Google Scholar
  175. 175.
    Hakansson L and Tropé C: Cell clones with differed sensitivity to cytostatic drugs in methylcholanthrene-induced mouse sarcomas. Acta Pathol Microbiol Scand Section A (82): 41–47, 1974.Google Scholar
  176. 176.
    Tropé C, Aspegun K, Kullander S, Astedt B: Heterogeneous response of disseminated human ovarian cancer to cytostates in vitro. Acta Obstet Gyncol Scand (58): 543–546, 1979.Google Scholar
  177. 177.
    Biörkland A, Hakansson L, Stenstam B, Tropé C, Akerman M: On heterogeneity of non-Hodgkin's lymphomas as regards sensitivity to cytostatic drugs. Eur J Cancer (16): 647–654, 1980.Google Scholar
  178. 178.
    Dexter DL, Spremulli EN, Fligiel Z, Barbosa JA, Vogel R, VanVoorhees A, Calabresi P: Heterogeneity of cancer cells from a single human colon carcinoma. Am J Med (71): 949–956, 1981.Google Scholar
  179. 179.
    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
  180. 180.
    Sacchi A, Calabresi F, Greco C, Zupi G: Different metastatic potential of in vitro and in vivo lines selected from Lewis lung carcinoma: correlation with response to different bleomycin schedulings. Invasion Metastasis (1): 227–238, 1981.Google Scholar
  181. 181.
    Yung WA, Shapiro JR, Shapiro WR: Heterogeneous chemosensitivities of subpopulations of human glioma cells in culture. Cancer Res (42): 992–998, 1982.Google Scholar
  182. 182.
    Smith HS, Staupfer MR, Hackett AJ: Adriamycin sensitivity of cultured malignant and nonmalignant human mammary epithelial cells (abstract). J Cell Biol (suppl 6), 367, 1982.Google Scholar
  183. 183.
    Lotan R, Nicolson GL: Heterogeneity in growth inhibition by B-trans-retinoic acid of metastatic B-16 melanoma clones and in vivo-selected cell variant lines. Cancer Res (39): 4767–4771, 1979.Google Scholar
  184. 184.
    Hill HZ, Hill GJ, Miller CF, Kwong F, Purdy J: Radiation and melanoma response of B16 mouse tumor cells and clonal lines to in vitro irradiation. Rad Res (80): 259–276, 1979.Google Scholar
  185. 185.
    Leith JT, Brenner HJ, DeWyngaert JK, Dexter DL, Calabresi P, Glicksman AS: Selective modification of the X-ray response of two mouse mammary adenocarcinoma sublines by N,N-dimethylformamide. Int J Rad Oncol Biol Phys (7): 943–947, 1981.Google Scholar
  186. 186.
    Leith JT, Gaskins LA, Dexter DL, Calabresi P, Glicksman AS: Alteration of the survival response of two human colon carcinoma subpopulations to X-irradiation by N,N-dimethylformamide. Cancer Res (42): 30–34, 1982.Google Scholar
  187. 187.
    Leith JT, Dexter DL, DeWyngaert JK, Zeman EM, Chu MY, Calabresi P, Glicksman AS: Differential responses to X-irradiation of subpopulations of two heterogeneous human carcinomas in vitro. Cancer Res (42): 2556–2561, 1982.Google Scholar
  188. 188.
    Berd D, Mastrangelo MJ: Differential sensitivity of two murine leukemia sublines to cytolysis by Corynebacterium parvum-activated macrophages. Br J Cancer (44): 819–827, 1981.Google Scholar
  189. 189.
    Dennis JW, Donaghue TP, Kerbel RS: An examination of tumor antigen loss in spontaneous metastases. Invasion Metastases (1): 111–125, 1981.Google Scholar
  190. 190.
    Strzadala L, Opolski A, Radzikowski C, Mihich E: Differential expression of murine leukemia antigen on L1210 parental and drug-resistant sublines. Cancer Res (41): 4934–4937, 1981.Google Scholar
  191. 191.
    Young WWJr, Hakomori S: Therapy of mouse lymphoma with monoclonal antibodies to glycolipid: selection of low antigenic variants in vivo. Science (211): 487–489, 1981.Google Scholar
  192. 192.
    Miller BE, Miller FR, Heppner GH: Interactions between tumor subpopulations affecting their sensitivity to the antineoplastic agents cyclophosphamide and methotrexate. Cancer Res (41): 4378–4381, 1981.Google Scholar
  193. 193.
    Subak-Sharpe H, Burk RR, Pitts JD: Metabolic cooperation between biochemically marked mammalian cells in tissue culture. J Cell Sci (4): 353–367, 1969.Google Scholar
  194. 194.
    Loewenstein WR: Junctional intercellular communication and the control of growth. Biochim Biophys Acta (560): 1–65. 1979.Google Scholar
  195. 195.
    Salmon SE, Hamburger AW, Soehnlen B, Durie BG, Alberts DS, Moon TE: Quantitation of differential sensitivity of human tumor stem cells to anticancer drugs. N Engl J Med (298): 1321–1327, 1978.Google Scholar
  196. 196.
    Giovanella BC: Experimental chemotherapy of human tumors heterotransplanted in nude mice. Antibiot Chemother (28): 21–27, 1980.Google Scholar
  197. 197.
    Miller BE, Miller FR, Heppner GH: Development of a drug-sensitivity assay for heterogeneous tumors based on growth in 3-dimensional collagen gels. In: Chabner BA (ed) Rational basis for chemotherapy. New York, Alan R Liss, Inc (in press).Google Scholar
  198. 198.
    Goldie JH, Coldman AJ: A mathematical model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep (63): 1727–1733, 1979.Google Scholar
  199. 199.
    Luria JE, Delbruck M: Mutations of bacteria from virus sensitivity to virus resistance. Genetics (28): 491–511, 1943.Google Scholar
  200. 200.
    Mulder JH, Smink T, VanPutten LM: 5-Fluorouracil and methotrexate combination chemotherapy: the effect of drug scheduling. Eur J Chem Oncol (17): 831–837, 1981.Google Scholar
  201. 201.
    Gewirtz AM, Cadman E: Preliminary report on the efficacy of sequential methrotrexate and 5-fluorouracil in advanced breast cancer. Cancer (47): 2552–2555, 1981.Google Scholar
  202. 202.
    Cadman EC, Benz C, Voigt J, Heimer R: Enhanced 5-fluorouracil (5FU) nucleotide formation following methotrexate (MTX) is the consequence of increased intercellular phosphoribosylpyrophosphate (PRPP). Proc AACR (20): 258 (abstract), 1979.Google Scholar
  203. 203.
    Roberts D, Peck C: Effect of methotrexate and 1-β-D-arabinofuranosylcytosine on pools of deoxyribonucleoside triphosphates in L1210 ascites cells. Cancer Res (40): 505–510, 1981.Google Scholar
  204. 204.
    Fried J, Perez AG, Doblin JM, Clarkson BD: Cytotoxic and cytokinetic effects of thymidine, 5-fluorouracil, and deoxycytidine on HeLa cells in culture. Cancer Res (41): 2627–2632, 1981.Google Scholar
  205. 205.
    Ritch PS, Occhipinti SJ, Cunningham RE, Shackney SW: Schedule-dependent synergism of combinations of hydroxyurea with adriamycin and 1-β-D-arabinofuranocylcytosine with adriamycin. Cancer Res (41): 3881–3884, 1981.Google Scholar
  206. 206.
    Fodstad Ø, Pihl A: Synergistic effect of ricin in combination with daunorubicin, cis-dichlorodiammine-platinum (II) and vincristine in systemic L1210 leukemia. Cancer Res (42): 2152–2158, 1982.Google Scholar

Copyright information

© Martinus Nijhoff Publishers 1983

Authors and Affiliations

  • Gloria H. Heppner
    • 1
  • Bonnie E. Miller
    • 1
  1. 1.Michigan Cancer FoundationDetroitUSA
  2. 2.Department of ImmunologyMichigan Cancer FoundationDetroitUSA

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