Skip to main content
Log in

Modulation of tumor cell gene expression and phenotype by the organspecific metastatic environment

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Summary

The mechanistic basis of a metastatic cell's ability to proliferate in the parenchyma of certain organs and develop organ-specific metastases is under intense investigation. Signals from paracrine or autocrine pathways, alone or in combination, may regulate tumor cell proliferation with the eventual outcome dependent on the net balance of stimulatory and inhibitory factors. This article summarizes recent reports from our laboratory and others demonstrating that the organ microenvironment can profoundly influence the pattern of gene expression and the biological phenotype of metastatic tumor cells, including induction of melanocyte stimulating hormone receptor and production of melanin, regulation of terminal differentiation and apoptosis, resistance to chemotherapy, and regulation of growth at the organ-specific metastatic site. These recent data from both murine and human tumor models support the concept that the microenvironment of different organs can influence the pattern of gene expression and hence the phenotype of tumor cells at different steps of the metastatic process. These findings have obvious implications for the therapy of neoplasms in general and metastases in particular.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Fidler IJ: Special Lecture: Critical factors in the biology of human cancer metastasis: Twenty-eight G.H.A. Clowes Memorial Award Lecture. Cancer Res 50: 6130–6138, 1990

    Google Scholar 

  2. Nicolson GL: Cancer progression and growth: Relationship of paracrine and autocrine growth mechanisms to organ preference of metastasis. Expt Cell Res 204: 171–180, 1993

    Google Scholar 

  3. Fidler IJ, Radinsky R: Editorial: Genetic control of cancer metastasis. J Natl Cancer Inst 82: 166–168, 1990

    Google Scholar 

  4. Paget S: The distribution of secondary growths in cancer of the breast. Lancet 1: 571–573, 1889

    Google Scholar 

  5. Hart IR: ‘Seed and soil’ revisited: Mechanisms of site specific metastasis. Cancer Met Rev 1: 5–17, 1982

    Google Scholar 

  6. Tarin D, Price JE, Kettlewell MGW, Souter RG, Vass ACR, Crossley B: Mechanisms of human tumor metastasis studied in patients with peritoneovenous shunts. Cancer Res 44: 3584–3592, 1984

    Google Scholar 

  7. Ewing J: Neoplastic diseases. Ed. 6. W.B. Saunders, Philadelphia, 1928

    Google Scholar 

  8. Radinsky R: Paracrine growth regulation of human colon carcinoma organ-specific metastasis. Cancer Met Rev 12: 345–361, 1993

    Google Scholar 

  9. Radinsky R, Beltran P, Tsan R, Zhang R, Cone R, Fidler IJ: Transcriptional induction of the melanocyte stimulating hormone receptor in K1735 metastatic murine melanoma cells growing in the brain of nude mice. Cancer Res 55: 141–148, 1995

    Google Scholar 

  10. 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

    Google Scholar 

  11. Dong Z, Radinsky R, Fan D, Tsan R, Bucana CD, Wilmanns C, Fidler IJ: Organ-specific modulation of steadystatemdr gene expression and drug resistance in murine colon cancer cells. J Natl Cancer Inst 86: 913–920, 1994

    Google Scholar 

  12. Radinsky R, Risin S, Fan D, Dong Z, Bielenberg D, Bucana CD, Fidler IJ: Level and function of the epidermal growth factor receptor predict the metastatic potential of human colon carcinoma cells. Clin Cancer Res 1: 19–31, 1995

    Google Scholar 

  13. Menter DG, Herrmann JL, Nicolson GL: The role of trophic factors and autocrine/paracrine growth factors in brain metastasis. Clin Exp Metastasis 13: 67–88, 1995

    Google Scholar 

  14. Schackert G, Fidler IJ: Site-specific metastasis of mouse melanomas and fibrosarcoma in the brain or meninges of syngeneic animals. Cancer Res 48: 3478–3483, 1988

    Google Scholar 

  15. Fujimaki T, Fan D, Staroselsky AH, Gohji K, Bucana CD, Fidler IJ: Critical factors regulating site-specific brain metastasis of murine melanomas. Int J Oncol 3: 789–799, 1993

    Google Scholar 

  16. Price JE, Tarin D, Fidler IJ: Influence of the organ environment on pigmentation of a metastatic murine melanoma. Cancer Res 48: 2258–2264, 1988

    Google Scholar 

  17. Eberle AN: The melanotropins: chemistry, physiology, and mechanism of action. Basel: Karger, 1988

    Google Scholar 

  18. Clive D, Snell DS: Effect of MSH on mammalian hair color. J Invest Dermatol 49: 314–321, 1972

    Google Scholar 

  19. Burchill SA, Virden R, Thody AJ: Regulation of tyrosinase and its processing in the hair follicular melanocytes of the mouse during melanogenesis and phaeomelanogenesis. J Invest Dermatol 93: 236–240, 1989

    Google Scholar 

  20. Pawelek J, Wong G, Sansone M, Morowitz J: Molecular controls in mammalian pigmentation. Yale J Biol Med 46: 430–443, 1973

    Google Scholar 

  21. 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

    Google Scholar 

  22. Fuller BB, Meyskins FL: Endocrine responsiveness in human melanocytes and melanoma cells in culture. J Natl Cancer Inst 66: 799–802, 1981

    Google Scholar 

  23. 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

    Google Scholar 

  24. Seechurn P, Thody AJ: The effect of UV-irradiation and MSH on tyrosinase activity in epidermal melanocytes of the mouse. J Dermatol Sci 1: 283–288, 1990

    Google Scholar 

  25. Halaban R, Pomerantz SH, Marshall S, Lerner AB: Tyrosinase activity and its abundance in Cloudman melanoma cells. Arch Biochem Biophys 230: 383–387, 1984

    Google Scholar 

  26. 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. Pigment Cell Res 2: 161–166, 1989

    Google Scholar 

  27. Salomon Y, Zohar M, DeJordy JO, Eshel Y, Shafir I, Lieba H, Garty NB, Schmidt-Sole J, Azrad 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

    Google Scholar 

  28. Mountjoy KG, Robbins LS, Mortrud MT, Cone RD: The cloning of a family of genes that encode the melanocortin receptors. Science 257: 1248–1251, 1992

    Google Scholar 

  29. Chhajlani V, Wiberg JES: Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA. FEBS Lett 3: 417–420, 1992

    Google Scholar 

  30. Kameyama K, Montague PM, Hearing VJ: Expression of melanocyte stimulating hormone receptors correlates with mammalian pigmentation and can be modulated by interferons. J Cell Physiol 137: 35–44, 1988

    Google Scholar 

  31. Solca FF, Chluba-de Tapia J, Iwata K, Eberle AN: B16G4F mouse melanoma cells: an MSH receptor-deficient cell clone. FEBS Lett 322: 177–180, 1993

    Google Scholar 

  32. Kameyama K, Tanaka S, Ishida Y, Hearing VJ: Interferons modulate the expression of hormone receptors on the surface of melanoma cells. J Clin Invest 83: 213–221, 1989

    Google Scholar 

  33. Sheppard JR, Koestler JP, Corwin SP, Buscarino C, Doll J, Lester B, Greig RG, Poste G: Experimental metastasis correlates with cyclic AMP accumulation in B16 melanoma clones. Nature 308: 544–547, 1984

    Google Scholar 

  34. Lunec J, Pieron C, Thody AJ: MSH receptor expression and the relationship to melanogenesis and metastatic activity in B16 melanoma. Melanoma Res 2: 5–12, 1992

    Google Scholar 

  35. Bennett DC, Dexter TJ, Ormerod EJ, Hart IR: Increased experimental metastatic capacity of a murine melanoma following induction of differentiation. Cancer Res 46: 3239–3244, 1986

    Google Scholar 

  36. Lakshmi MS, Parker C, Sherbet GV: Metastasis associated MTS1 and NM23 genes affect tubulin polymerisation in B16 melanomas: a possible mechanism of their regulation of metastatic behavior of tumours. Anticancer Res 13: 299–304, 1993

    Google Scholar 

  37. Cannon JG, Tatro JB, Reichlin S, Dinarello CA: Melanocyte stimulating hormone inhibits immunostimulatory and inflammatory actions of interleukin 1. J Immunol 137: 2232–2236, 1986

    Google Scholar 

  38. Krasagakis K, Garbe C, Orfanos CE: Cytokines in human melanoma cells: Synthesis, autocrine stimulation and regulatory functions - an overview. Melanoma Res 3: 425–433, 1993

    Google Scholar 

  39. Singh RK, Gutman G, Radinsky R: Heterogeneity of cytokine and growth factor gene expression in human melanoma cells with different metastatic potentials. J Interferon Cytokine Res 15: 81–87, 1995

    Google Scholar 

  40. Gutman M, Singh RK, Radinsky R, Bar-Eli M: Intertumoral heterogeneity of receptor-tyrosine kinases expression in human melanoma cell lines with different metastatic capabilities. Anticancer Res 14: 1759–1766, 1994

    Google Scholar 

  41. Siegrist W, Stutz S, Eberle AN: Homologous and heterologous regulation of α-melanocyte-stimulating hormone receptors in human and mouse melanoma cell lines. Cancer Res 54: 2604–2610, 1994

    Google Scholar 

  42. Fisher PB, Grant S: Effects of interferon on differentiation of normal and tumor cells. Pharmacol Ther 27: 143–166, 1985

    Google Scholar 

  43. Giacomini P, Imberti L, Agussi A, Fisher PB, Trinchieri G, Ferrone S: Immunocytochemical analysis of the modulation of human melanoma-associated antigens by DNA recombinant immune interferon. J Immunol 135: 2887–2894, 1985

    Google Scholar 

  44. Lotan R, Lotan D: Enhancement of melanotic expression in cultured mouse melanoma cell by retinoids. J Cell Physiol 106: 179–189, 1981

    Google Scholar 

  45. Hosoi J, Abe E, Suda T, Kuroki T: Regulation of melanin synthesis of B16 mouse melanoma cells by 1,25-dihydroxy vitamin D3 and retinoic acid. Cancer Res 45: 1474–1478, 1985

    Google Scholar 

  46. Friedman PS, Gilchrest BA: Ultraviolet radiation directly induces pigment production by cultured human melanocytes. J Cell Physiol 133: 88–94, 1987

    Google Scholar 

  47. Lu D, Willard D, Patel IR, Kadwell S, Overton L, Kost T, Luther M, Chen W, Woychik RP, Wilkison BO, Cone RD: Agouti protein is an antagonist of the melanocyte-stimulating hormone receptor. Nature 371: 799–802, 1994

    Google Scholar 

  48. Varga JM, Asato N, Lande S, Lerner AB: Melanotropin-daunomycin conjugate shows receptor-mediated cytotoxicity in cultured murine melanoma cells. Nature 267: 56–58, 1977

    Google Scholar 

  49. Liu MA, Nussbaum SR, Eisen HN: Murine, not human, cell line. Science 239: 1227, 1988

    Google Scholar 

  50. Nigro JM, Baker SJ, Preisinger AC, Jessup JM, Hostetter R, Cleary K, Bigner SH, Davidson N, Baylin S, Devilee P, Glover T, Collins FS, Weston A, Modali R, Harris CC, Vogelstein B: Mutations in the p53 gene occur in diverse human tumour types. Nature 342: 705–708, 1989

    Google Scholar 

  51. Hollstein M, Sidransky D, Vogelstein B, Harris C: p53 mutations in human cancers. Science 253: 49–53, 1991

    Google Scholar 

  52. Sidransky D, Mikkelsen T, Schwechheimer K, Rosenblum ML, Cavanee W, Vogelstein B: Clonal expansion of p53 mutant cells is associated with brain tumour progression. Nature 355: 846–847, 1992

    Google Scholar 

  53. Vogelstein B, Kinzler KW: p53 function and dysfunction. Cell 70: 523–526, 1992

    Google Scholar 

  54. Gannon JV, Greaves R, Iggo R, Lane DP: Activating mutations in p53 produce a common conformational effect. EMBO J 9: 1595–1602, 1990

    Google Scholar 

  55. Kern SE, Kinzler KW, Baker SJ, Nigro JM, Rotter V, Levine AJ, Friedman P, Prives C, Vogelstein B: Abnormal DNA-binding and phosphorylation of mutant p53 proteinin vitro. Oncogene 6: 131–136, 1991

    Google Scholar 

  56. Diller L, Kassel J, Nelson CE, Gryka MA, Litwak G, Gebhardt M, Bressac B, Oztork M, Baker SJ, Vogelstein B, Friend SH: p53 functions as a cell cycle control protein in osteosarcomas. Mol Cell Biol 10: 5772–5781, 1990

    Google Scholar 

  57. Motyka B, Reynolds JD: Apoptosisis is associated with the extensive B cell death in the sheep ileal Peyer's patch and the chicken bursa ofFabricius: A possible role in B cell selection. Eur J Immunol 21: 1951–1958, 1991

    Google Scholar 

  58. Lin D, Shields MT, Ullrich SJ, Appella E, Mercer WE: Growth arrest induced by wild-type p53 protein blocks cells prior to or near the restriction point in late G1 phase. Proc Natl Acad Sci USA 89: 9210–9214, 1992

    Google Scholar 

  59. Foti A, Ahuja HG, Allen SL, Koduru P, Schuster MW, Schulman P, Bar-Eli M, Cline MJ: Correlation between molecular and clinical events in the evolution of CML to blast crisis. Blood 77: 2441–2444, 1991

    Google Scholar 

  60. Ahuja HG, Bar-Eli M, Arlin Z, Advani S, Allen S, Goldman J, Snyder D, Foti A, Cline MJ: The spectrum of molecular alterations in the evolution of chronic myelogenous leukemia. J Clin Invest 87: 2042–2047, 1991

    Google Scholar 

  61. Masuda H, Miller C, Koeffler HP, Battifora H, Cline MJ: Rearrangement of the p53 gene in human osteosarcomas. Proc Natl Acad Sci USA 84: 7716–7719, 1987

    Google Scholar 

  62. Oren M: The involvement of oncogenes and tumor suppressor genes in the control of apoptosis. Cancer Metastasis Rev 11: 141–148, 1992

    Google Scholar 

  63. Lane DP: A death in the life of p53. Nature 362: 786–787, 1993

    Google Scholar 

  64. Owen-Schaub LB, Zhang W, Cusack JC, Angelo LS, Santee SM, Fujiwara T, Roth JA, Deisseroth AB, Zhang W-W, Kruzel E, Radinsky R: Wild-type human p53 and a temperature-sensative mutant induce Fas/APO-1 expression. Mol Cell Biol 15: 3032–3040, 1995

    Google Scholar 

  65. Yonish-Rouach E, Resnitzky D, Lotem J, Sachs L, Kimchi A, Oren M: Wild-type p53 induces apoptosis of myeloid leukemia cells that is inhibited by interleukin-6. Nature 352: 345–347, 1991

    Google Scholar 

  66. Shaw P, Bovey R, Tardy S, Sahli R, Sordat B, Costa J: Induction of apoptosis by wild-type p53 in a human colon tumor-derived cell line. Proc Natl Acad Sci USA 89: 4495–4499, 1992

    Google Scholar 

  67. Shaulsky G, Goldfinger N, Rotter V: Alterations in tumor developmentin vivo mediated by expression of wild type or mutant p53 proteins. Cancer Res 51: 5232–5327, 1991

    Google Scholar 

  68. Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML, Wyllie AH: Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 362: 849–852, 1993

    Google Scholar 

  69. Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T: p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362: 847–884, 1993

    Google Scholar 

  70. Bar-Shavit Z, Teitelbaum SL, Reitsma P, Hall A, Pegg LE, Trial J, Kahn AJ: Induction of monocytic differentiation and bone resorption by 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci USA 80: 5907–5911, 1983

    Google Scholar 

  71. Key L, Carnes D, Cole S, Holtrop M, Bar-Shavit Z, Shapiro F, Arceci R, Steinberg J, Gundberg C, Kahn A, Teitelbaum S, Anast C: Treatment of congenital osteoperosis with high-dose calcitriol. N Engl J Med 310: 409–415, 1984

    Google Scholar 

  72. Rodan GA, Rodan SB: Expression of the osteoblastic phenotype. In: Peck WA (ed) Advances in Bone and Mineral Research, Annual II pp 244–285 Amsterdam: Excerpta Medica, 1984

    Google Scholar 

  73. Rodan SB, Imai Y, Thiede MA, Wesolowski G, Thompson D, Bar-Shavit Z, Shull S, Mann K, Rodan GA: Characterization of a human osteosarcoma cell line (Saos-2) with osteoblastic properties. Cancer Res 47: 4961–4966, 1987

    Google Scholar 

  74. Spiess YR, Price PA, Deftos JL, Manolagas SC: Phenotype-associated changes in the effects of 1,25-dihydroxyvitamin D3 on alkaline phosphatase and bone GLA-protein of rat osteoblastic cells. Endocrinology 118: 1340–1346, 1986

    Google Scholar 

  75. Elias L, Berry CO: Induction of differentiation by tumour necrosis factor in HL-60 cells is associated with the formation of large DNA fragments. Leukemia 5: 879–885, 1991

    Google Scholar 

  76. Deisseroth AB, Roth JA: Editorial: Applications and advances in gene therapy. Ca Bulletin 45: 107–108, 1993

    Google Scholar 

  77. Chin K-V, Pastan I, Gottesman MM: Function and regulation of the human multidrug resistance gene. Adv Ca Res 60: 157–180, 1993

    Google Scholar 

  78. Germann UA, Pastan I, Gottesman MM: P-glycoproteins: Mediators of multidrug resistance. Semin Cell Biol 4: 63–76, 1993

    Google Scholar 

  79. Rothenberg M, Ling V: Multidrug resistance: Molecular biology and clinical relevance. J Natl Cancer Inst 81: 907–910, 1989

    Google Scholar 

  80. Croop JM, Gros P, Housman DE: Genetics of multidrug resistance. J Clin Invest 81: 1303–1309, 1988

    Google Scholar 

  81. Kanamaru H, Kakehi Y, Yoshida O, Nakanishi S, Pastan I, Gottesman MM: MDR1 RNA levels in human renal cell carcinomas: Correlation with grade and prediction of reversal of doxorubicin resistance by quinidine in tumor explants. J Natl Cancer Inst 81: 844–849, 1989

    Google Scholar 

  82. Chabner BA, Foji A: Multidrug resistance: P-glycoprotein and its allies - the elusive foes. J Natl Cancer Inst 81: 910–913, 1989

    Google Scholar 

  83. Goldstein LJ, Galski H, Fojo A, Willingham M, Lai SL, Gazdar A, Pinker R, Green A, Grist W, Brodeur GM, Lieber M, Cossman J, Gottesman MM, Pastan I: Expression of a multidrug resistance gene in human tumors. J Natl Cancer Inst 81: 116–124, 1989

    Google Scholar 

  84. Weinstein RS, Shriram JM, Dominguez JM, Lebovitz MD, Koukoulis GK, Kuszak JR, Klusens LF, Grogen TM, Saclarides TJ, Ronnison IB, Coon JS: Relationship of the expression of the multidrug resistance gene product (P-glycoprotein) in human colon carcinoma to local tumor aggressiveness and lymph node metastasis. Cancer Res 51: 2720–2726, 1991

    Google Scholar 

  85. Park J, Kramer BS, Lai S, Goldstein LJ, Gazdar AF: Chemosensitivity patterns and expression of human multidrug resistance-associated MDR1 gene by human gastric and colorectal carcinoma cell lines. J Natl Cancer Inst 82: 193–198, 1990

    Google Scholar 

  86. Morrow CS, Cowan KH: Mechanisms and clinical significance of multidrug resistance. Oncology 2: 55–63, 1988

    Google Scholar 

  87. Dalton WS, Grogan TM: Does P-glycoprotein predict response to chemotherapy, and if so, is there a reliable way to detect it? J Natl Cancer Inst 83: 80–81, 1991

    Google Scholar 

  88. Raymond M, Rose E, Housman DE, Gros P: Physical mapping, amplification, and overexpression of the mousemdr gene family in multidrug-resistant cells. Molec Cell Biol 10: 1642–1651, 1990

    Google Scholar 

  89. Croop JM, Raymond M, Haber D, Devault A, Arceci RJ, Gros P, Housman DE: The three mouse multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal mouse tissues. Molec Cell Biol 9: 1346–1350, 1989

    Google Scholar 

  90. Devault A, Gros P: Two members of the mousemdr gene family confer multidrug resistance with overlapping but distinct drug specificities. Molec Cell Biol 10: 1652–1663, 1990

    Google Scholar 

  91. Hsu SIH, Lothstein L, Horwitz SB: Differential overexpression of threemdr gene family members in multidrug resistant J774.2 cells. Evidence that distinct P-glycoprotein precursors are encoded by uniquemdr genes. J Biol Chem 246: 12053–12062, 1989

    Google Scholar 

  92. Ruetz S, Gros P: Phosphatidylcholine translocase: A physiological role for themdr 2 gene. Cell 77: 1071–1081, 1994

    Google Scholar 

  93. Arceci RJ, Croop JM, Horwitz SB, Housman DE: The gene encoding multidrug resistance is induced and expressed at high levels during pregnancy in the secretory epithelium of the uterus. Proc Natl Acad Sci USA 85: 4350–4354, 1988

    Google Scholar 

  94. Slack NH, Bross JDJ: The influence of site of metastasis on tumor growth and response to chemotherapy. Br J Cancer 32: 78–86, 1975

    Google Scholar 

  95. Donelli MG, Russo R, Garattini S: Selective chemotherapy in relation to the site of tumor transplantation. Int J Cancer 32: 78–86, 1975

    Google Scholar 

  96. Teicher BA, Herman TS, Holden SA, Wang Y, Pfeffer MR, Crawford JW, Frei E: Tumor resistance to alkylating agents conferred by mechanisms operative onlyin vivo. Science 247: 1457–1461, 1990

    Google Scholar 

  97. Wilmanns C, Fan D, O'Brian CA, Bucana CD, Fidler IJ: Orthotopic and ectopic organ environments differentially influence the sensitivity of murine colon carcinoma cells to doxorubicin and 5-fluorouracil. Int J Cancer 52: 98–104, 1992

    Google Scholar 

  98. Staroselsky A, Fan D, O'Brian CA, Gupta KP, Fidler IJ: Site-dependent differences in response of the UV-2237 murine fibrosarcoma to systemic therapy with Adriamycin. Cancer Res 50: 7775–7780, 1990

    Google Scholar 

  99. Wilmanns C, Fan D, O'Brian CA, Radinsky R, Bucana CD, Tsan R, Fidler IJ: Modulation of doxorubicin sensitivity and level of P-glycoprotein expression in human colon carcinoma cells by ectopic and orthotopic environments in nude mice. Int J Oncol 3: 412–422, 1993

    Google Scholar 

  100. Bradley G, Sharma R, Rajalakshmi S, Ling V: P-glycoprotein expression during tumor progression in the rat liver. Cancer Res 52: 5154–5161, 1992

    Google Scholar 

  101. Herzog CE, Tsokos M, Bates SE, Fojo AT: Increased mdr-1/P-glycoprotein expression after treatment of human colon carcinoma cells with P-glycoprotein antagonists. J Biol Chem 268: 2946–2952, 1993

    Google Scholar 

  102. Schuurhuis GJ, Broxterman HJ, de Lange JH, Pinedo HM, van Heijningen TH, Kuiper CM, Scheffer GL, Scheper RJ, van Kalken CK, Baak JP: Early multidrug resistance, defined by changes in intracellular doxorubicin distribution, independent of P-glycoprotein. Br J Cancer 64: 857–861, 1991

    Google Scholar 

  103. Fidler IJ, Wilmanns C, Staroselsky A, Radinsky R, Dong Z, Fan D: Modulation of tumor cell response to chemotherapy by the organ environment. Cancer Met Rev 13: 209–222, 1994

    Google Scholar 

  104. Kerbel RS, Kobayashi H, Graham CH: Intrinsic or acquired drug resistance and metastasis: Are they linked phenotypes? J Cell Biochem 56: 37–47, 1994

    Google Scholar 

  105. Russell AH, Tong D, Dawson LE, Wisbeck W: Adenocarcinoma of the proximal colon: Sites of initial dissemination and patterns of recurrence following surgery alone. Cancer 53: 360–367, 1984

    Google Scholar 

  106. Giavazzi R, Campbell DE, Jessup JM, Cleary KR, Fidler IJ: Metastatic behavior of tumor cells from primary and metastatic human colorectal carcinomas implanted into different sites in nude mice. Cancer Res 46: 1928–1933, 1986

    Google Scholar 

  107. Giavazzi R, Jessup JM, Campbell DE, Walker SM, Fidler IJ: Experimental nude mouse model of human colorectal cancer liver metastases. J Natl Cancer Inst 77: 1303–1308, 1986

    Google Scholar 

  108. Morikawa K, Walker SM, Jessup JM, Fidler IJ:In vivo selection of highly metastatic cells from surgical specimens of different primary human colon carcinomas implanted into nude mice. Cancer Res 48: 1943–1948, 1988

    Google Scholar 

  109. Morikawa K, Walker SM, Nakajima M, Pathak S, Jessup JM, Fidler IJ: Influence of organ environment on the growth, selection, and metastasis of human colon carcinoma cells in nude mice. Cancer Res 48: 6863–6871, 1988

    Google Scholar 

  110. Gutman M, Singh RK, Price JE, Fan D, Fidler IJ: Accelerated growth of human colon cancer cells in nude mice undergoing liver regeneration. Invasion Metastasis 95: 362–371, 1994

    Google Scholar 

  111. Grupposo PA, Mead JE, Fausto N: Transforming growth factor receptors in liver regeneration following partial hepatectomy in the rat. Cancer Res 50: 1464–1469, 1990

    Google Scholar 

  112. Mead JE, Fausto N: Transforming growth factor α may be a physiological regulator of liver regeneration by means of an autocrine mechanism. Proc Natl Acad Sci USA 86: 1558–1562, 1989

    Google Scholar 

  113. Noji S, Tashiro K, Koyama E, Nohno T, Ohyama K, Taniguchi S, Nakamura T: Expression of hepatocyte growth factor gene in endothelial and Kupffer cells of damaged rat livers, as revealed byin situ hybridization. Biochem Biophys Res Common 173: 42–47, 1990

    Google Scholar 

  114. Markowitz SD, Molkentin K, Gerbic C, Jackson J, Stellato T, Willson JKV: Growth stimulation by coexpression of transforming growth factor - and epidermal growth factor receptor in normal and adenomatous human colon epithelium. J Clin Invest 86: 356–362, 1990

    Google Scholar 

  115. Van der Geer P, Hunter T, Lindberg RA: Receptor proteintyrosine kinases and their signal transduction pathways. Annu Rev Cell Biol 10: 251–337, 1994

    Google Scholar 

  116. Sainsbury JRC, Sherbert GV, Farndon JR, Harris AL: Epidermal growth factor receptors and oestrogen receptors in human breast cancer. Lancet i: 364–366, 1986

    Google Scholar 

  117. Bigner SH, Humphrey PA, Wong AJ, Vogelstein B, Mark J, Friedman HS, Bigner DD: Characterization of the epidermal growth factor receptor in human glioma cell lines and xenografts. Cancer Res 50: 8017–8022, 1990

    Google Scholar 

  118. Harris AL, Neal DE: Epidermal growth factor and its receptor in human cancer. In: Sluyser M (ed) Growth Factors and Oncogenes in Breast Cancer, pp 60–90, 1987

  119. Neal DE, Marsh C, Bennet MK, Abel PD, Hall RR, Sainsbury JRC, Harris AL: Epidermal growth factor receptor in human bladder cancer: Comparison of invasive and superficial tumours. Lancet i: 366–368, 1985

    Google Scholar 

  120. Gullick WJ, Marsden JJ, Whittle N, Ward B, Bobrow L, Waterfield MD: Expression of epidermal growth factor receptors on human cervical, ovarian, and vulvar carcinomas. Cancer Res 46: 285–292, 1986

    Google Scholar 

  121. Ullrich AL, Coussens L, Hayflick JS, Dull TJ, Gray A, Tam AW, Lee J, Yarden Y, Libermann TA, Schlessinger J, Downward J, Whittle ELV, Waterfield MD, Seeburg PH: Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature (London) 309: 418–425, 1984

    Google Scholar 

  122. Scher HI, Sarkis A, Reuter V, Cohen D, Netto G, Petrylak D, Lianes P, Fuks Z, Mendelsohn J, Cordon-Cardo C: Changing patterns of expression of the epidermal growth factor receptor and transforming growth factor a in the progression of prostatic neoplasms. Clin Ca Res 1: 545–550, 1995

    Google Scholar 

  123. Gross ME, Zorbas MA, Daniels YJ, Garcia R, Gallick GE, Olive M, Brattain MG, Boman BM, Yeoman LC: Cellular growth response to epidermal growth factor in colon carcinoma cells with an amplified epidermal growth factor receptor derived from a familial adenomatous polyposis patient. Cancer Res 51: 1452–1459, 1991

    Google Scholar 

  124. Steiner MG, Harlow SP, Colombo E, Bauer KD: Chromosomes 8, 12, and 17 copy number in Astler-Coller stage C colon cancer in relation to proliferative activity and DNA ploidy. Cancer Res 53: 681–686, 1993

    Google Scholar 

  125. Waldman FM, Carroll PR, Kerschmann R, Cohen MB, Field FG, Mayall BH: Centromeric copy number of chromosome 7 is strongly correlated with tumor grade and labeling index in human bladder cancer. Cancer Res 51: 3807–3813, 1991

    Google Scholar 

  126. Kern SE, Fearon ER, Tersmette KWF, Enterline JP, Leppert M, Nakamura Y, White R, Vogelstein B, Hamilton SR: Allelic loss in colorectal carcinoma. JAMA 261: 3099–3103, 1989

    Google Scholar 

  127. Collard JG, Roos E, La Riviere G, Habets GGM: Genetic analysis of invasion and metastasis. Cancer Surveys 7: 691–710, 1988

    Google Scholar 

  128. Koprowski H, Herlyn M, Balaban G, Parmiter A, Ross A, Nowell P: Expression of the receptor for epidermal growth factor correlates with increased dosage of chromosome 7 in malignant melanoma. Somatic Cell Molec Genet 11: 297–302, 1985

    Google Scholar 

  129. Korc M, Meltzer P, Trent J: Enhanced expression of epidermal growth factor receptor correlates with alterations of chromosome 7 in human pancreatic cancer. Proc Natl Acad Sci USA 83: 5141–5144, 1986

    Google Scholar 

  130. Henn W, Blin N, Zang K: Polysomy of chromosome 7 is correlated with overexpression of theerbB oncogene in human glioblastoma cell lines. Hum Genet 74: 104–106, 1986

    Google Scholar 

  131. Radinsky R, Bucana CD, Ellis LE, Sanchez R, Cleary KR, Brigati DJ, Fidler IJ: A rapid colorimetricin situ messenger RNA hybridization technique for analysis of epidermal growth factor receptor in paraffin-embedded surgical specimens of human colon carcinomas. Cancer Res 53: 937–943, 1993

    Google Scholar 

  132. Khazaie K, Schirrmacher V, Lichtner RB: EGF receptor in neoplasia and metastasis. Cancer Metastasis Rev 12: 255–274, 1993

    Google Scholar 

  133. Modjtahedi H, Dean C: The receptor for EGF and its ligands: Expression, prognostic value and target for therapy in cancer (Review). Int J Oncol 4: 277–296, 1994

    Google Scholar 

  134. Mendelsohn J: The epidermal growth factor receptor as a target for therapy with antireceptor monoclonal antibodies. Semin Cancer Biol 1: 339–344, 1990

    Google Scholar 

  135. Baselga J, Norton L, Masui H, Pandiella A, Coplan K, Miller Jr WH, Mendelsohn J: Antitumor effects of doxorubicin in combination with anti-epidermal growth factor receptor monoclonal antibodies. J Natl Cancer Inst 85: 1327–1333, 1993

    Google Scholar 

  136. Fan Z, Masui H, Altaws I, Mendelsohn J: Blockade of epidermal growth factor receptor function by bivalent and monovalent fragments of 225 anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 53: 4322–4328, 1993

    Google Scholar 

  137. Phillips PC, Levow C, Catterall M, Colvin OM, Pastan, Brem H: Transforming growth factor-α-Pseudomonas exotoxin fusion protein (TGF-α-PE38) treatment of subcutaneous and intracranial human glioma and medulloblastoma xenografts in athymic mice. Cancer Res 54: 1008–1015, 1994

    Google Scholar 

  138. Siegall CB, FitzGerald DJ, Pastan I: Selective killing of tumor cells using EGF or TGFα-Pseudomonas exotoxin chimeric molecules. Semin Cancer Biol 1: 345–350, 1990

    Google Scholar 

  139. Lofts FJ, Hurst HC, Sterberg MJE, Gullick WJ: Specific short transmembrane sequences can inhibit transformation by the mutantneu growth factor receptorin vitro andin vivo. Oncogene 8: 2813–2820, 1993

    Google Scholar 

  140. Fry DW, Kraker AJ, McMichael A, Ambroso LA, Nelson JM, Leopoid WR, Connors RW, Bridges AJ: A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science 265: 1093–1095, 1994

    Google Scholar 

  141. Kashles O, Yarden Y, Fischer R, Ullrich A, Schlessinger J: A dominant negative mutation suppresses the function of normal epidermal growth factor receptors by heterodimerization. Mol Cell Biol 11: 1454–1463, 1991

    Google Scholar 

  142. Selva E, Raden DL, Davis RJ: Mitogen-activated protein kinase stimulation by a tyrosine kinase-negative epidermal growth factor receptor. J Biol Chem 268: 2250–2254, 1993

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Radinsky, R. Modulation of tumor cell gene expression and phenotype by the organspecific metastatic environment. Cancer Metast Rev 14, 323–338 (1995). https://doi.org/10.1007/BF00690601

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00690601

Key words

Navigation