Abstract
Brain metastases are clinically diagnosed in the majority of patients with metastatic melanoma. The prognosis for patients with melanoma brain metastasis is poor with a median survival time of 6 months after diagnosis. Development of better therapies requires a better understanding of the biology of melanoma brain metastasis. The development of a relevant in vivo model offers this possibility. The intracarotid injection of different murine or human melanoma cells into syngeneic or nude mice produces metastases in different regions of the brain. This site-specific metastasis is not due to patterns of initial cell arrest, motility, or invasiveness, but rather to the ability of melanoma cells to proliferate in the brain parenchyma or the meninges. The blood–brain barrier is intact in metastases that are smaller than 0.25 mm in diameter. Although in larger metastases the blood–brain barrier is leaky, the lesions are resistant to many chemotherapeutic drugs. We have also analyzed the malignant behavior of several melanoma cell lines isolated from brain or visceral metastases of patients. The cells from brain metastases showed a slower growth rate and exhibited lower metastatic potential than cells from visceral metastases, indicating that brain metastases do not necessarily represent the end stage in the metastatic cascade. Rather, brain metastases are likely to originate from a unique subpopulation of cells within the primary neoplasm.
Similar content being viewed by others
References
Akslen LA, Hove LM, Hartveit F: Metastatic distribution in malignant melanoma. A 30-year autopsy study. Inv Metastasis 7: 253-263, 1987
Takakura K, Sano K, Hojo S, Hirano A: Metastatic Tumors of the Central Nervous System. Igaku-Shoin, Ltd., Tokyo, Japan, 1982
Madjewicz ST, Karakousis C, West CR, Caracandas J, Avellanosa AM: Malignant melanoma brain metastases. Review of Roswell Park Memorial Institute experience. Cancer 53: 2550-2562, 1984
Kornblith PL, Walker MD, Cassady JR: Neoplasms of the central nervous system. In: DeVita VT, Hellman S, Rosenberg SA (eds) Cancer: Principles and Practice of Oncology, 2nd ed, J B Lippincott, Philadelphia, 1985, pp 1437-1566
Schackert G, Fildler IJ: Development of in vivo models for studies of brain metastasis. Int J Cancer 41: 589-594, 1988
Fidler IJ, Gruys E, Cifone MA, Barnes Z, Bucana CD: Demonstration of multiple phenotypic diversity in a murine melanoma of recent origin. J Natl Cancer Inst 67: 947-956, 1981
Price JE, Aukerman SL, Fidler IJ: Evidence that the process of murine melanoma metastasis is sequential and selective and contains stochastic elements. Cancer Metastasis Rev 46: 5172-5178, 1986
Mandybur TI: Metastatic brain tumors induced by injection of syngeneic tumor cells into cerebral arterial circulation in rats. Acta Neuropathol 53: 57-64, 1981
Fujimaki T, Fan D, Staroselky AH, Gohji K, Bucana CD, Fidler IJ: Critical factors regulating site-specific brain metastasis of murine melanomas. Int J Oncol 3: 789-799, 1993
Fidler IJ: Critical factors in the biology of human cancer metastasis: twenty-eighth GHA Clowes Memorial Award Lecture. Cancer Res 50: 6130-6138, 1990
Poste G, Fidler IJ: The pathogenesis of cancer metastasis. Nature (Lond) 283: 139-146, 1980
Schackert G, Fidler IJ: Site-specific metastasis of mouse melanomas and a fibrosarcoma in the brain or the meninges of syngeneic animals. Cancer Res 48: 3478-3484, 1988
Schackert G, Price JE, Zhang RD, Bucana CD, Itoh K, Fidler IJ: Regional growth of different human melanomas as metastases in the brain of nude mice. Am J Pathol 136: 95-102, 1990
Fidler IJ: Metastasis: quantitative analysis of distribution and fate of tumor emboli labeled with 125I-5-iodo-2′-deoxyuridine. J Natl Cancer Inst 45: 773-782, 1970
Fidler IJ: Selection of successive tumor lines for metastasis. Nature (New Biol) 242: 148-149, 1973
Felgenhauer K: The blood-brain barrier redefined. J Neurol 233: 193-194, 1986
Shapiro WR, Hiesiger EM, Cooney GA, Gasler GA, Lipschutz LE, Posner JP: Temporal effects of dexamethasone on blood-to-brain and blood-to-tumor transport of 14C-alpha-aminoisobutyric acid in rat C6 glioma. J Neurooncol 8: 997-12041, 1990
Hart IR, Fidler IJ: Role of organ selectivity in the determination of metastatic patterns of B16 melanoma. Cancer Res 40: 2281-2287, 1980
Nicolson GL: Metastatic tumor cell interaction with endothelium, basement membrane and tissue. Curr Opin Cell Biol 1: 1009-1019, 1989
Fidler IJ: The relationship of embolic homogeneity, number, size and viability to the incidence of experimental metastasis. Eur J Cancer 9: 223-227, 1973
Haynes BF, Telen MJ, Hale LP, Denning SM: CD44 — a molecule involved in leukocyte adherence and T-cell activation. Immunol Today 10: 423-428, 1989
Birch M, Mitchell S, Hart IR: Isolation and characterization of human melanoma cell variants expressing high and low levels of CD44. Cancer Res 51: 6660-6667, 1991
Hart IR, Birch M, Marshall JF: Cell adhesion receptor expression during melanoma progression and metastasis. Cancer Metastasis Rev 10: 115-128, 1991
Lotan R, Amos B, Watanabe H, Raz A: Suppression of motility factor receptor expression by retinoic acid. Cancer Res 52: 4878-4884, 1992
Nakajima M, Welch DR, Belloni PN, Nicolson GL: Degradation of basement membrane type IV collagen and lung subendothelial matrix by rat mammary adenocarcinoma cell clones of differing metastatic potential. Cancer Res 47: 4869-4876, 1987
Nakajima M, Irimura T, Di Ferrante N, Nicolson G: Heparan sulfate degradation: relation to tumor invasive and metastatic properties of mouse B16 melanoma sublines. Science 220: 611-613, 1983
Liotta LA, Rao CN, Barsky SH: Tumor invasion and the extracellular matrix. Lab Invest 49: 636-649, 1983
Nicolson GL, Cavanaugh PG, Inoue T: Differential stimulation of the growth of lung-metastasizing tumor cells by lung (paracrine) growth factors: identification of transferrin-like mitogens in lung tissue-conditioned medium (monograph). J Natl Cancer Inst 13: 153-161, 1992
Kerbel RS: Expression of multi-cytokine resistance and multi-growth factor independence in advanced stage metastatic cancer: malignant melanoma as a paradigm. Am J Pathol 141: 519-524, 1992
Fan D, Chakrabarty C, Seid C, Bell CW, Schackert H, Morikawa K, Fidler IJ: Clonal stimulation or inhibition of human colon carcinomas and human renal carcinomas mediated by transforming growth factor-β 1. Cancer Commun 1: 117-125, 1989
Chakrabarty C, Fan D, Varani J: Modulation of differentiation and proliferation in human colon carcinoma cells by transforming growth factor-β 1 and-β 2. Int J Cancer 46: 493-499, 1990
Boerner P, Resnick RJ, Racker E: Stimulation of glycolysis and amino uptake in NRK-49F cells by transforming growth factor-β and epidermal growth factor. Proc Natl Acad Sci USA 82: 1350-1353, 1985
Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehrl JH, Fauci AS: Transforming growth factor type β: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci USA 83: 4167-4717, 1968
Ignotz RA, Massague J: Transforming growth factor-β stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem 261: 4337-4347, 1986
Laiho M, deCaprio JA, Ludlow JW, Livingston DM, Massague J: Growth inhibition by TGF-β linked to suppression of retinoblastoma protein phosphorylation. Cell 62: 175-185, 1990
Knabbe C, Lippman ME, Wakefield LM, Flanders AK, Derynck R, Dickson RB: Evidence that transforming growth factor is a hormonally regulated negative growth factor in human breast cancer cells. Cell48: 417-4128, 1987
Tucker RF, Shipley GD, Moses HL, Holley RW: Growth inhibitor from BSC-1 cells closely related platelet type beta transforming growth factor. Science 226: 705-707, 1984
Anzano MA, Roberts AB, Sporn MB: Anchorage-independent growth of primary rat embryo cells is induced by platelet-derived growth factor and inhibited by type-beta transforming growth factor. J Cell Physiol 126: 312-318, 1986
Baird A, Drukin T: Inhibition of endothelial cell proliferation by type-beta transforming growth factor: interaction with acid and basic fibroblast growth factors. Biochem Biophys Res Commun 138: 476-482, 1986
Fan D, Chakrabarty S, Seid C, Bell CW, Schackert H, Fidler IJ: Clonal stimulation or inhibition of human colon carcinomas and human renal carcinomas mediated by transforming growth factor-β 1. Cancer Commun 1: 117-125, 1989
Geiser AG, Burnester JK, Wewink R, Roberts AB, Sporn MB: Inhibition of growth by transforming growth factors following fusion of two nonresponsive human carcinoma cell lines. J Biol Chem 267: 2588-2593, 1992
Unsicker K, Flanders KC, Cissel DS, Lafyatis R, Sporn MB: Transforming growth factor beta isoforms in the adult rat central and peripheral nervous system. Neuroscience 44: 513-525, 1991
Flanders KC, Ludecke G, Engles S, Cissel DS, Roberts AB, Kondaiah P, Lafyatis R, Sporn MB, Unsicker K: Localization and actions of transforming growth factor-β in the embryonic nervous system. Development 113: 183-191, 1991
Saad B, Constam DB, Ortmann R, Moos M, Fontana A, Achachner M: Astrocyte-derived TOF-β 1 and NGF differently regulate neural recognition molecule expression by cultured astrocytes. J Cell Biol 115: 473-484, 1991
Miller DA, Lee A, Pelton RW, Chen EY, Moses HL, Derynck R: Murine transforming growth factor-β 2 cDNA sequence and expression in adult tissues and embryos. Mol Endocrinol 3: 1108-1114, 1989
Schackert G, Price JE, Zhang RD, Bucana CD, Itoh K, Fidler IJ: Regional growth of different human melanomas as metastases in the brain of nude mice. Am J Pathol 136: 95-102, 1990
Fujimaki T, Price JE, Fan D, Bucana CD, Itoh K, Kirino T, Fidler IJ: Selective growth of human melanoma cells in the brain parenchyma of nude mice. Melanoma Res 6: 363-371, 1996
Tsukuda T, Fouad A, Pickren JW: Central nervous system metastasis from breast carcinoma: autopsy study. Cancer 52: 2349-2354, 1983
Viadana E, Bross IDJ, Pickren JW: The metastatic spread of cancers of the digestive system in man. Oncology 35: 114-126, 1978
Weiss L: Principles of Metastasis. Academic Press, Orlando, 1985
Kanematsu T, Matsumata T, Takenaka K, Yoshida T, Higashi H, Sugimachi K: Clinical management of recurrent hepatocellular carcinoma after primary resection. Br J Surg 75: 203-206, 1988
Nicolson GL: Organ specificity of tumor metastasis: role of preferential adhesion, invasion, and growth of malignant cells at specific secondary sites. Cancer Metastasis Rev 7: 143-188, 1988
Brunson KW, Beattie G, Nicolson G: Selection and altered properties of brain colonizing metastatic melanoma. Nature 272: 543-545, 1978
Zhang RD, Price JE, Schackert G, Itoh K, Fidler IJ: Malignant potential of cells isolated from lymph node or brain metastases of melanoma patients and implications for prognosis. Cancer Res 51: 2029-2035, 1991
Li L, Price JE, Fan D, Zhang R, Bucana CD, Fidler IJ: Correlation of growth capacity of human tumor cells in hard agarose with their in vivo proliferative capacity at specific metastatic sites. J Natl Cancer Inst 81: 1406-1412, 1989
Tomlinson E: Theory and practice of site-specific drug delivery. Adv Drug Del Rev 1: 187-198, 1987
Johansson BB: The physiology of the blood-brain barrier. Adv Exp Med Biol 274: 25-39, 1990
Gregoire N: The blood-brain barrier. J Neuroradiol 16: 238-250, 1989
Pardridge WM, Oldendorf WH, Cancilla P, Frank HJ: Blood-brain barrier: interface between internal medicine and the brain clinical conference. Ann Intern Med 105: 82-95, 1986
Medawar PB: Immunity to homologous grafted skin: III. The fate of skin homografts transplated to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol 29: 58-69, 1948
Scheinberg LC, Edelman FL, Levy WA: Is the brain 'an immunologically privileged site'? Arch Neurol 11: 248-264, 1964
Felgenhauer K: The blood-brain barrier redefined. J Neurol 233: 193-194, 1986
Shapiro WR, Shapiro JR: Principles of brain tumor chemotherapy. Semin Oncol 13: 56-69, 1986
Debbage PL, Gabius HJ, Bise K, Marguth F: Cellular glyco-conjugates and their potential endogenous receptors in the cerebral microvasculature of man: a glycohistochemical study. Eur J Cell Biol 46: 425-434, 1988
Steward PA, Hayakawa K, Farrell CL, Del Maestro RF: Quantitative study of microvessel ultrastructure in human peritumoral brain tissue. Evidence for a blood-brain barrier defect. J Neurosurg 67: 697-705, 1987
Zagzag D, Goldenberg M, Brem S: Angiogenesis and blood-brain barrier breakdown modulate CT contrast enhancement: an experimental study in a rabbit brain-tumor model. AJR 153: 141-146, 1989
Iannotti F, Fleschi C, Alfano B, Picozzi P, Mansi L, Pozzili C, Punzo A, Del Vecchio G, Lenzi GL, Salvatore M: Simplified, noninvasive PET measurement of blood brain barrier permeability. J Comput Assist Tomogr 11: 390-397, 1987
Frong D, Israel O, Kohn S, Nir I: The blood-tissue barrier of human brain tumors: correlation of scintigraphic and ultrastructural findings (concise communication). J Nucl Med 25: 461-465, 1984
Kohn S, Front D, Nir I: Blood-brain barrier permeability of human gliomas as determined by quantitation of cytoplasmic vesicles of the capillary endothelium and scintigraphic findings. Cancer Invest 7: 313-321, 1989
Nir I, Levanon D, Iosilevsky G: Permeability of blood vessels in experimental gliomas: uptake of 99Tc-glucoheptonate and alteration in blood-brain barrier as determined by cytochemistry and election microscopy. Neurosurgery 25: 523-532, 1989
Coomber BL, Stewart PA, Hayakawa K, Farrell CL, Del Maestro RF: Quantitative morphology of human gliobalstoma multiform microvessels: structural basis of blood-brain barrier defect. J Neurooncol 5: 299-307, 1987
Vriesendorp FJ, Peagram C, Bigner DD, Groothuis DR: Concurrent measurements of blood flow and transcapillary transport in xenotransplated human gliomas in immunosuppressed rats. J Natl Cancer Inst 79: 123-130, 1987
Nicolson GL: Organ specificity of cancer metastasis is determined, in part, by tumor cell properties and cytokines expressed at particular organ sites. Am Assoc Cancer Res 31: 506-507, 1990
Schlingemann RO, Rivetveld FJ, De Wall RM, Ferrone S: Expression of the high molecular weight melanoma-associated antigen by pericytes during angiogenesis in tumors and in healing wounds. Am J Pathol 136: 1393-1405, 1990
Zuelch KG: Brain tumors: their biology and pathology, 3rd edn, Springer-Verlag, Berlin, 1986, pp 480-498
Greig NH: Optimizing drug delivery to brain tumors. Cancer Treat Rev 13: 1-28, 1987
Genka S, Deutsch J, Stahle PL, Shetty UH, John V, Robinson C, Rapoport SI, Greig NH: Brain and plasma pharmacokinetics and anticancer activities of cyclophosphamide and phosphoamide mustard in the rat. Cancer Chemother 27: 1-7, 1990
Greig NH, Soncrant TT, Shetty HU, Momma S, Smith QR, Rapoport SI: Brain uptake and anticancer activities of vincristine and vinblastine are restricted by their low cerebrovascular permeability and binding to plasma constituents in rat. Cancer Chemother Pharmacol 26: 263-268, 1990
Owman C, Hardebo JE: Functional heterogeneity of the cerebrovascular endothelium. Brain Behav Evol 32: 65-75, 1988
Fenstermacher J, Gross P, Sposito N, Acuff V, Pettersen S, Gruber K: Structural and functional variations in capillary systems within the brain. Ann NY Acad Sci 529: 21-30, 1988
Baur HC, Tontsch U, Amberger A, Bauer H: Gamma-glutamyl-transpeptidase (GGTP) and NA+K(+)-ATPase activities in different subpopulations of cloned cerebral endothelial cells: responses to glial stimulation. Biochem Biophys Res Commun 168: 358-363, 1990
Schackert G, Simmons RD, Buzbee TM, Hume DA, Fidler IJ: Macrophage infiltration into experimental brain metastases: occurrence through an intact blood-brain barrier. J Natl Cancer Inst 80: 1027-1034, 1988
Nakagawa Y, Fujimoto N, Matsumoto K, Cervos Navarro J: Morphological changes in acute cerebral ischemia after occlusion and reperfusion in the rat. Adv Neurol 52: 21-27, 1990
Kawamura S, Schurer L, Goetz A, Kempski O, Schumucker B, Baethmann A: An improved closed cranial window technique for investigation of blood-brain barrier function and cerebral vasomotor control in the rat. Int J Microcirc Clin Exp 9: 369-383, 1990
Malmgren LT, Olsson Y: Differences between the peripheral and the central nervous system in permeability to sodium fluoresein. J Comp Neurol 191: 103-117, 1980
Zhang R, Price JE, Fujimaki T, Bucana CD, Fidler IJ: Differential permeability of the blood-brain barrier in experimental brain metastases produced by human neoplasms implanted into nude mice. Am J Pathol 141: 1115-1124, 1992
Ballinger WE Jr, Schimpff RD: An experimental model for cerebral metastasis: preliminary light and ultrastructural studies. J Neuropath Exp Neurol 38: 19-34, 1979
Hirano A, Zimmerman HM: Fenestrated blood vessels in metastatic renal carcinoma in the brain. Lab Invest 26: 465-468, 1972
Dietrich WD, Busto R, Hailey M, Valdes I: The importance of brain temperature in alterations of the blood-brain barrier following cerebral ischemia. J Neuropathol Exp Neurol 49: 486-497, 1990
Goldstein GW: Endothelial cell-astrocyte interactions: a cellular model of the blood-brain barrier. Ann NY Acad Sci 529: 31-39, 1988
Eberle AN: The Melanotropins: Chemistry, Physiology, and Mechanisms of Action. Karger, Basel, 1988
Clive D, Snell DS: Effect of MSH on mammalian hair color. J Invest Dermatol 49: 314-321, 1972
Burchill SA, Virden R, Thody AJ: Regulation of tyrosinase and its processing in the hair follicular melanocytes of the mouse during melanogenesis an phacomelanogenesis. J Invest Dermatol 93: 236-240, 1989
Pawelek J, Wong G, Sansone J, Morowitz J: Molecular controls in mammalian pigmentation. Yale J Biol Med 46: 430-443, 1973
Halaban R, Pomerantz SH, Marshall S, Lambert DT, Lerner AB: Regulation of tyrosinase in human melanocytes grown in culture. J Cell Biol 97: 480-488, 1983
Fuller BB, Meyskins FL: Endocrine responsiveness in human melanocytes and melanoma cells in culture. J Natl Cancer Inst 66: 799-802, 1981
Friedman PS, Wren F, Buffey J, MacNeil S: α-MSH causes a small rise in cAMP but has no effect on basal or ultraviolet-stimulated melanogenesis in human melanocytes. Br J Dermatol 123: 145-151, 1990
Seechrun P, Thody AJ: The effect of UV-irradiation and MSH on tyrosinase activity in epidermal melanocyte of the mouse. J Dermatol Sci 1: 283-288, 1990
Halaban R, Pomerantz SH, Marshall S, Lerner AB: Tyrosinase activity and its abundance in Cloudman melanoma cells. Arch Biochem Biophys 230: 383-387, 1984
Hill S, Buffey J, Thody AJ, Oliver I, Bleehen SS, MacNeil S: Investigation of the regulation of pigmentation in melanocyte-stimulating hormone responsive and unresponsive cultured B16 murine melanoma cells. Pigm Cell Res 2: 161-166, 1989
Salomon Y, Zohar M, DeJordy JO, Eshel Y, Shafir I, Lieba H, Garty NB, Schmidt-Sole J, Azard A, Shai E, Degani H: Signaling mechanisms controlled by melanocortins in melanoma, lacrimal, and brain astroglia cells. Ann NY Acad Sci 680: 364-380, 1993
Mountjoy KG, Robbins LS, Mortrud MT, Cone RD: The cloning of a family of genes that encode the melanocortin receptors. Science (Washington, DC) 257: 1248-1251, 1992
Chhajlani V, Wiberg JES: Molecular cloning and expression of the human melanocyte-stimulating hormone receptor cDNA. FEBS Lett 3: 417-420, 1992
Nakajima M, Morikawa K, Fabra A, Bucana CD, Fidler IJ: Influence of organ environment on extracellular matrix degradative activity and metastasis of human colon carcinoma cells. J Natl Cancer Inst 82: 1890-1898, 1990
Fabra A, Nakajima M, Bucana CD, Fidler IJ: Modulation of the invasive phenotype of human colon carcinoma cells by fibroblasts from orthotopic or ectopic organs of nude mice. Differentiation 52: 101-110, 1992
Gohji K, Fidler IJ, Fabra A, Bucana CD, von Eschenbach AC, Nakajima M: Regulation of gelatinase production in metastatic renal cell carcinoma by organ-specific fibroblasts. Jpn J Cancer Res 85: 152-160, 1994
Fidler IJ: Modulation of the organ microenviornment for the treatment of cancer metastasis (commentary). J Natl Cancer Inst 87: 1588-1592, 1995
Singh RK, Gutman M, Radinsky R, Bucana CD, Fidler IJ: Expression of interleukin-8 correlates with the metastatic potential of human melanoma cells in nude mice. Cancer Res 54: 3242-3247, 1994
Gutman M, Singh RK, Xie K, Bucana CD, Fidler IJ: Regulation of IL-8 expression in human melanoma cells by the organ environment. Cancer Res 55: 2470-2475, 1995
Dong Z, Radinsky R, Fan D, Tsan R, Bucana CD, Wilmanns C, Fidler IJ: Organ-specific modulation of steady-state mdr gene expression and drug resistance in murine colon cancer cells. J Natl Cancer Inst 86: 913-920, 1994
Radinsky R, Fidler IJ, Price JE, Esumi N, Tsan R, Petty CM, Bucana CD, Bar-Eli M: Terminal differentiation and apoptosis in experimental lung metastases of human osteogenic sarcoma cells by wild type p53. Oncogene 9: 1877-1883, 1994
Radinsky R, Beltran PJ, Tsan R, Zhang R, Cone RD, Fidler IJ: Transcriptional induction of the melanocyte stimulating hormone receptor in brain metastases of murine K-1735 melanoma. Cancer Res 55: 141-148, 1995
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Fidler, I.J., Schackert, G., Zhang, Rd. et al. The Biology of Melanoma Brain Metastasis. Cancer Metastasis Rev 18, 387–400 (1999). https://doi.org/10.1023/A:1006329410433
Issue Date:
DOI: https://doi.org/10.1023/A:1006329410433