Summary
Somatic cell hybridization between nonmetastatic tumor cells and normal cells of the lymphoreticular system results in hybrid cells manifesting metastatic properties of defined target organ specificity. Thus, fusion of the nonmetastatic BALB/c originated NSI plasmacytoma with C57BL B lymphocytes resulted in hybridomas, each of which were metastatic. Of 10 hybridomas, 7 generated metastases in the spleen and liver, whereas 3 generated liver metastases. The generation of liver metastases by hybridomas which homed to both spleen and liver, but not by those which homed to the liver only, was controlled by the spleen. The acquisition of metastatic properties via somatic cell fusion seems to represent a general principle, in which the normal partner determines the target organ specificity for the metastatic growth. Thus, fusion of SP2/O myeloma cells with syngeneic B lymphocytes also resulted in a hybrid cell metastasizing to the spleen and liver, yet a somatic hybrid between NSI and a macrophage or dendritic-like cell metastasized to the lung. Cell surface molecules encoded by the genome of the normal partner was demonstrated to control the target organ specificity: antibodies against MHC-encoded antigens of the normal B cell partner prevented the generation of metastases by hybridomas metastasizing to the spleen and liver, but not by those metastasizing to the liver only. This is in accordance with the function of MHC molecules on lymphocytes in controlling their homing to lymphoid organs. Hybridomas of T cell lymphomas also manifested metastatic properties. Analysis of the cell surface Thy-1 antigens of a hybridoma (DCH10), produced via somatic fusion between BW5145 lymphoma and a putative macrophage cell indicated that cells of liver metastases (DCH10-Li) generated by the hybrid cells might have undergone further somatic cell fusion in vivo with host (T?) cells. These cells have acquired new metastatic properties, generating metastases in spleen, liver and kidneys. In fact, even the inoculation of the parental BW lymphoma cells resulted in a case of liver metastasis (BW-Li). Such BW-Li cells, upon reinoculation, also generated metastases in the spleen, liver and kidneys. Analysis of the Thyl phenotype indicated that BW-Li cells may also have undergone somatic cell fusion in vivo with host (T?) cells, resulting in the acquisition of metastatic properties. The pattern of cell-cell interactions (adhesion, infiltration) with liver cell monolayers of BW-Li cells and of DCH10-Li (T-cell lymphomas) was identical, and differed from cells of liver metastases of the myeloma-B cell hybridomas which might be based on responses to liver growth signals. Accordingly, the morphology of liver metastases generated by the two categories of hybridomas was different. It appears therefore, that (a) the acquisition of metastatic properties following somatic cell fusion with normal lymphoreticular cells is of a general significance; (b) somatic cell fusion provides an experimental system for the analysis of molecular properties determining the acquisition of metastatic capability; and (c) it may also represent a mechanism for tumor progression in vivo.
Similar content being viewed by others
References
Barski G, Sorieul S, Cornefert F: ‘Hybrid’-type cells in combined cultures of two different mammalian cell strains. J Natl Cancer Inst 26: 1269–1291, 1961.
Barski G, Cornefert F: Characteristics of ‘hybrid’-type cell lines obtained from mixed cultures in vitro. J Natl Cancer Inst 28: 801–821, 1962.
Harris H, Mimmer OJ, Klein G, Worst P, Tachibana T: Suppression of malignancy by cell fusion. Nature 223: 363–368, 1969.
Klein G, Bregula U, Wiener F, Harris H: The analyses of malignancy by cell fusion. I. Hybrids between tumor cells and L cell derivatives. J Cell Sci 8: 659–672, 1971.
Wiener F, Fenyö EM, Klein G: Fusion of tumor cells with host cells. Nature New Biol 238: 155–159, 1972.
Wiener F, Fenyö EM, Klein G: Tumor-host cell hybrids in radiochimeras. Proc Natl Scad Sci USA 71: 147–152, 1974.
Fenyö EM, Wiener F, Klein G, Harris H: Selection of tumor-host cell hybrids from polyoma virus- and methylcholanthrene-induced sarcomas. J Natl Cancer Inst 51: 1865–1875, 1973.
Ber R, Wiener F, Fenyö EM: Proof of in vivo fusion of murine tumor cells with host cells by universal fusers. J Natl Cancer Inst 60: 931–933, 1978.
Lala PK, Santer V, Rahil 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, 1979.
Marshall MJ, Shone DG, Windle JM, Worsfold M: Spontaneous fusion of malignant and host mouse cells in culture detected by phosphoglucose isomerase isoenzymes (GPI). Br J Cancer 46: 811–816, 1982.
Goldenberg DM, Pavia RA, Tsao MC: In vivo hybridization of human tumor and normal hamster cells. Nature 250: 649–651, 1974.
Katzav S, De Baetselier P, Tartakovsky B, Segal S, Feldman M: Immunogenetic properties of tumor metastases. In: Vitetta ES (ed) B and T cell Tumors. Academic Press, New York, 1982, pp 233–245.
Katzav S, De Baetselier P, Tartakovsky B, Gorelik E, Segal S, Feldman M: Immunogenetic determinants controlling the metastatic properties of tumor cells. In: Fabris N (ed) Immunoregulation. Plenum Press, New York, 1983, pp 453–463.
De Baetselier P, Katzav S, Gorelik E, Feldman M, Segal S: Differential expression of H-2 gene products in tumor cells is associated with their metastatic properties. Nature 288: 179–181, 1980.
Katzav S, De Baetselier P, Gorelik E, Feldman M, Segal S: Immunologic control of metastasis formation by a methylcholanthrene-induced tumor (T10) in mice: Differential expression of H-2 gene products. Transpl Proc XIII: 742–746, 1981.
De Baetselier 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.
Witte PL, Ber R: Improved efficiency of hybridoma ascites production by intrasplenic inoculation in mice. J Natl Cancer Inst 70: 575–577, 1983.
Slavin S, Morecki S, Weiss L: The role of the spleen in tumor growth: Kinetics of the murine B cell leukemia (BCL1). J Immunol 124: 586–589, 1980.
Ron Y, De Baetselier P, Segal S: Involvement of the spleen in murine B cell differentiation. Eur J Immunol 11: 94–99, 1981.
Ron Y, De Baetselier P, Feldman M, Segal S: Involvement of the spleen in the control of the immunogenic and phagocytic function of thioglycollate-induced macrophages. Eur J Immunol 11: 608–611, 1981.
De Baetselier P, Gorelik E, Eshhar Z, Ron Y, Katzav S, Feldman M, Segal S: Organ-specific homing of B cell hybridomas. In: Nieuwenhuis P, van den Broek AA, Hanna MG (eds) In vivo immunology. Plenum, New York, 1982, pp 179–185.
Degos L, Pla M, Colombani JM: H-2 restriction for lymphocyte homing into lymph nodes. Eur J Immunol 9: 808–814, 1979.
Woodruff JJ, Gesner BM: The effect of neuraminidase on the fate of transfused lymphocytes. J Exp Med 129: 551–567, 1969.
Schirrmacher V, Cheingsong-Popv R, Arnheiter H: Hepatocyte tumor cell interaction in vitro. I. Conditions for rosette formation and inhibition by anti H-2 antibodies. J Exp Med 151: 984–988, 1980.
Fogel M, Altevogt P, Schirrmacher V: Metastatic potential severely altered by changes in tumor cell adhesiveness and cell-surface sialylation. J Exp Med 157: 371–376, 1983.
Eshhar Z, Mandler R: Changes in tumorigenic and metastatic pattern of thymoma cells induced by their hybridization to normal lymphocytes. In: Vitetta ES (ed) B and T cell tumors. Academic Press, New York, 1982, pp 313–318.
Williams AF, Barclay AN, Letarte-Muirhead M, Morris RJ: Rat Thy-1 antigens from thymus and brain: Their tissue distribution, purification and chemical composition. Cold Spring Harbor Symp Quant Biol 41: 51–61, 1976.
Peters JH: Hybridomas of mouse dendritic cells (DC) expressing phenotypic markers of DC including growth-stimulating action on T-lymphocytes. In: Pusch K, Kirchner H (eds) Mechanisms of lymphocyte activation. Elsevier North Holland, 1981, pp 537–540.
Britz JS, Askenase PW, Ptak W, Steinman RM, Gershon RK: Specialized antigen-presenting cells. Splenic dendritic cells and peritoneal exudate cells induced by mycobacteria activate effector T cells that are resistant to suppresion. J Exp Med 155: 1344–1356, 1982.
Claman HN, Miller SD, Conlov PJ, Moorhedd JW: Control of experimental contact sensitivity. Adv in Immunol 30: 121–158, 1980.
Roos E, van de Pavert I, Middelhoop OP: Infiltration of tumor cells into cultures of isolated hepatocytes. J Cell Sci 47: 385–397, 1981.
Schirrmacher V: Shifts in tumor cell phenotypes induced by signals from the microenvironment. Relevance for the immunobiology of cancer metastasis. Immunobiology 157: 89–98, 1980.
Schirrmacher V, Fogel M, Russmann E, Bosslet K, Altevogt P, Beck L: Antigenic variation in cancer metastasis: Immune escape versus immune control. Cancer Metastasis Rev 1: 241–274, 1982.
Altevogt P, Kurnick JT, Kimura AK, Bosslet K, Schirrmacker V: Different expression of Lyt differentiation antigens and cell surface glycoproteins by a murine T lymphoma line and its high metastatic variant. Eur J Immunol 12: 300–307, 1982.
Dennis J, Donaghue TP, Florian M, Kerbel RS: Apparent reversion of stable in vitro genetic markers detected in tumor cells from spontaneous metastases. Nature 292: 242–245, 1981.
Kerbel RS, Dennis JW, Lagarde AE, Frost P: Tumor progression in metastasis: An experimental approach using lectin resistant tumor variants. Cancer Metastasis Rev 1: 93–140, 1982.
Kerbel RS, Lagarde AE, Dennis JW, Donaghue TP: Spontaneous host cell x tumor cell hybridization in vivo: Contribution to the emergence of metastatic cell variants. Mol Cell Biol 3: 523–538, 1983.
Rios A, Laux D, Heppner GH: Patterns of lymphocyte infiltration in tumor sublines of a single mammary adenocarcinoma (Abstract). Proc AACR 28: 1021, 1982.
Roos E, Van de Pavert IV: Antigen-activated T lymphocytes infiltrate hepatocyte cultures in a manner comparable to liver-colonizing lymphosarcoma cells. Clin Exp Metast 1: 173–180, 1983.
Vlodavsky I, Ariav Y, Fuks Z, Altevogt P, Schirrmacher V: Lymphoma cell-mediated degradation of sulfated proteoglycans in the subendothelial basa lamina: Relation to tumor cell metastasis. Cancer Res (in press).
De Baetselier P, Kapon A, Feldman M, Segal S: Activated macrophages modulate the tumorigenicity of 3LL tumor cells. In: Levy E (ed) Advances in pathology, Vol 1. Pergamon Press, Oxford & New York, 1982, pp 305–308.
De Baetselier P, Kapon A, Katzav S, Feldman M, Segal S: Selection of an immunogenic 3LL tumor subline following serial growth in vivo in the local presence of peritoneal macrophages. In: Norman SJ, Sorkin E (eds) Macrophages and natural killer cells. Plenum Publ Corp, New York, 1982, pp 281–288.
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, 1981.
Frost P, Kerbel RS, Tartamella-Blondo R: Generation of highly metastatic tumors in DBA/2 mice. Invasion Metastasis 1: 22–33, 1981.
Weitzman SA, Stossel TP: Mutation caused by human phagocytes. Science 212: 546–547, 1981.
Weitzman SA, Stossel TP: Effects of oxygen radical scavengers and antioxidants on phagocyte-induced mutagenesis. J Immunol 128: 2770–2772, 1982.
Kripke ML, Gruys E, Fidler IJ: Metastatic heterogeneity of cells from an ultraviolet light-induced murine fibrosarcoma of recent orgin. Cancer Res 38L: 2962–2967, 1978.
Nicolson GL, Winkelhake JL: Organ specificity of bloodborne metastasis determined by cell adhesion. Nature 299: 230, 1975.
Burger MM: The cell surface and metastasis. In: Biology of the cancer cell. Kugler, Amsterdam, 1980, pp 193–208.
Kerbel RS, Dennis JW, Lagarde AE, Frost P: Tumor progression in metastasis. An experimental approach using lectin-resistant tumor variants. Cancer Metastasis Rev 2: 99–140, 1982.
Fidler IJ, Gersten DM, Bodmen MB: Characterization in vivo and in vitro of tumor cells selected for resistance to syngeneic lymphocyte-mediated cytotoxicity. Cancer Res. 36: 3160–3169, 1976.
Frost P, Kerbel RS: Immunoselection in vitro of a nonmetastatic variant from a highly metastatic tumor. Int J Cancer 27: 381–385, 1981.
Bosslet K, Schirrmacher V: Escape of metastasizing clonal tumor cell variants from tumor-specific cytolytic T lymphocytes. J Exp Med 154: 557–562, 1981.
Poste G, Doll J, Fidler IJ: Interactions between clonal subpopulations affect the stability of the metastatic phenotype in polyclonal populations of B16 melanoma cells. Proc Natl Acad Sci USA 78: 6226–6230, 1981.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
De Baetselier, P., Roos, E., Brys, L. et al. Nonmetastatic tumor cells acquire metastatic properties following somatic hybridization with normal cells. Cancer Metast Rev 3, 5–24 (1984). https://doi.org/10.1007/BF00047690
Issue Date:
DOI: https://doi.org/10.1007/BF00047690