Cancer and Metastasis Reviews

, Volume 20, Issue 1–2, pp 133–143 | Cite as

Malignant Cells, Directors of the Malignant Process: Role of Transforming Growth Factor-beta

  • Beverly A. Teicher
Article

Abstract

Malignant cells survive and thrive by expressing growth and invasion 'programs' that many normal cell types recognize and respond to in 'programmed' patterns. An early event in the molecular evolution of many malignancies loss of response to growth control by transforming growth factor-beta TGF-β frequently due to mutation in the type I or type II TGF-β receptor or a Smad protein. The malignant cells secrete TFG-β that acts on the host to suppress antitumor immune responses, to enhance extracellular matrix production and to augment angiogenesis. These activities resemble those induced by TGF-β during embryonic development and account in part for the 'de-differentiated' nature of malignant disease. Clinically, TGF-β is often elevated in the plasma of breast cancer patients, lung cancer patients, hepatocellular carcinoma patients, and prostate cancer patients. Preclinically, several breast cancer models and prostate cancer models in vivo have demonstrated a connection between TGF-β expression and increased tumorigenicity, increased invasion and drug resistance. In other diseases such as colon, gastric, endometrial, ovarian, and cervical cancers and gliomas and melanoma, loss of response to TGF-β as a growth inhibitor and increased expression of TGF-β have been associated with malignant conversion and progression. Elevated levels of TGF-β are measurable in nude mice bearing a wide variety of human tumor xenografts; thus, these tumor models may serve as useful mimics of the human disease with respect to the TGF-β pathway. Cancer cure may be approached by blocking several of the major normal pathways used for tumor growth and survival in combination with cytotoxic therapies.

transforming growth factor-beta xenograft tumors malignancy combination therapy 

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References

  1. 1.
    Letterio JJ: Cancer models: manipulating the transforming growth factor-β pathway in mice. In: Teicher BA (ed.) Tumor Models in Cancer Research. The Humana Press, Inc., New Jersey, 2001Google Scholar
  2. 2.
    Letterio JJ,Bottinger EP: TGF-beta knockout and dominant-negative receptor transgenic mice. Miner Electrolyte Metabo 24: 161–167, 1998Google Scholar
  3. 3.
    Dunker N,Krieglstein K: Targeted mutations of transforming growth factor-beta genes reveal important roles in mouse development and adult homeostasis. Eur J Biochem 267: 6982–6988, 2000Google Scholar
  4. 4.
    Watanabe M,Whitman M: The role of transcription factors involved in TGFbeta superfamily signaling during development. Cell & Mol Biol 45: 537–543, 1999Google Scholar
  5. 5.
    Grande JP: Role of transforming growth factor-β in tissue injury and repair. Proc Soc Exp Biol Med 214: 27–40, 1997Google Scholar
  6. 6.
    Lawrence DA: Transforming growth factor-β: a general review. Eur Cytokine Netw 7: 363–374, 1996Google Scholar
  7. 7.
    Wright JA,Huang A: Growth factors in mechanisms of malignancy: roles for TGF-β and FGF. Histol Histopathol 11: 521–536, 1996Google Scholar
  8. 8.
    Piek E,Heldin C-H,ten Dijke P: Specificity, diversity and regulation in TGF-β superfamily signaling. FASEB J 13: 2105–2124, 1999Google Scholar
  9. 9.
    Padgett RW: TGF-β signaling pathways and human diseases. Cancer Met Rev 18: 247–259, 1999Google Scholar
  10. 10.
    Gold LI: The role for transforming growth factor-β(TGF-β) in human cancer. Crit Rev Oncogenesis 10: 303–360, 1999Google Scholar
  11. 11.
    Reiss M: TGF-β and cancer. Microbes Infect 1: 13278–1347, 1999Google Scholar
  12. 12.
    Piek E,Heldin C-H,ten Dijke P: Specificity, diversity and regulation in TGF-β superfamily signaling. FASEB J 13: 2105–2124, 1999Google Scholar
  13. 13.
    Wieser R: The transforming growth factor-β signaling pathway in tumorigenesis. Curr Opin Oncol 13: 70–77, 2001Google Scholar
  14. 14.
    Itoh S,Itoh F,Goumans M-J,ten Dijke P: Signaling of transforming growth factor-β family members through Smad proteins. Eur J Biochem 267: 6954–6967, 2000Google Scholar
  15. 15.
    Bouche M,Canipari R,Melchionna R,Willems D,Senni MI,Molinaro M: TGF-β autoccrine loop regulates cell growth and myogenic differentiation in human rhabdomyosarcoma cells. FASEB J 14: 1147–1158, 2000Google Scholar
  16. 16.
    Massague J,Wotton D: Transcriptional control by the TGF-β/Smad signaling system. EMBO J 19: 1745–1754, 2000Google Scholar
  17. 17.
    Norman SA,Rhodes SN,Treasurywala S,Hoelzinger DB,Shapiro JR,Scheck AC: Identification of transforming growth factor-β1-binding protein overexpression in carmustine-resistant glioma cells by mRNA differential display. Cancer 89: 850–862, 2000Google Scholar
  18. 18.
    Liu X,Sun Y,Ehrlich M,Lu T,Kloog Y,Weinberg RA,Lodish HF,Henis YI: Disruption of TGF-β growth inhibition by oncogenic ras is linked to p27kip1 mislocalization. Oncogene 19: 5926–5935, 2000Google Scholar
  19. 19.
    Pasche B,Kolachana P,Nafa K,Satagopan J,Chen Y-G,Lo RS,Brener D,Yang D,Kirstein L,Oddoux C,Ostrer H,Vineis P,Varesco L,Jhanwar S,Luzzatto L,Massague J,Offit K: TβR-1(6A) is a candidate tumor susceptibility allele. Cancer Res 59: 5678–5682, 1999Google Scholar
  20. 20.
    Kim IY,Zelner DJ,Sensibar JA,Ahn HJ,Park L,Kim JH,Lee C: Modulation of sensitivity to transforming growth factor-β1 (TGF-β1) and the level of type II TGF-β receptor in LNCaP cells by dihydrotestosterone. Exp Cell Res 222: 103–110, 1996Google Scholar
  21. 21.
    Kyprianou N,Isaacs JT: Identification of a cellular receptor for transforming growth factor-beta in rat ventral prostate and its negative regulation by androgens. Endocrinology 123: 2124–2131, 1988Google Scholar
  22. 22.
    Merle B,Malaval L,Lawler J,Delmas P,Clezardin P: Decorin inhibits cell attachement to thrombospondin-1 by binding to a KKTR-dependent cell adhesive site present within the N-terminal domain of thrombospondin-1. J Cell Biochem 67: 75–83, 1997Google Scholar
  23. 23.
    Wang TN,Qian X,Granick MS,Solomon MP,Rothman VL,Berger DH,Tuszynski GP: Thrombospondin-1 (TSP-1) promotes the invasive properties of human breast cancer. J Surg Res 63: 39–43, 1996Google Scholar
  24. 24.
    Murphy-Ullrich JE,Schultz-Cherry S,Hook M: Transforming growth factor-β complexes with thrombospondin. Mol Biol Cell 3: 181–188, 1992Google Scholar
  25. 25.
    Fidler IJ: Angiogenesis and cancer metastasis. Cancer J 6(Suppl 2): S134–S141, 2000Google Scholar
  26. 26.
    Bredow S,Lewin M,Hofmann B,Marecos E,Weissleder R: Imaging of tumor neovasculature by targeting the TGF-β binding receptor endoglin. Eur J Cancer 36: 675–681, 2000Google Scholar
  27. 27.
    Li C,Garland JM,Kumar S: Role of transforming growth factor-β signaling in cancer. J Natl Cancer Inst 93: 555–557, 2001Google Scholar
  28. 28.
    Huang A,Jin H,Wright JA: Drug resistance and gene amplification potential regulated by transforming growth factor â 1 gene expression. Cancer Res 55: 1758–1762, 1995Google Scholar
  29. 29.
    Mahara K,Kato J,Terui T,Takimoto R,Horimoto M,Murakami T,Mogi Y,Watanabe N,Kohgo Y,Niitsu Y: Transforming growth factor β1 secreted from scirrhoous gastric cancer cells is associated with excess collagen deposition in the tissue. Brit J Cancer 69: 777–783, 1994Google Scholar
  30. 30.
    Teicher BA,Maehara Y,Kakeji Y,Ara G,Keyes SR,Wong J,Herbst R: Reversal of in vivo drug resistance by the transforming growth factor-β inhibitor decorin. Int J Cancer 71: 49–58, 1997Google Scholar
  31. 31.
    Kakeji Y,Maehara Y,Ikebe M,Teicher BA: Dynamics of tumor oxygenation, CD31 staining and transforming growth factor-β levels after treatment with radiation or cyclophosphamide in the rat 13762 mammary carcinoma. Int J Rad Oncol Biol Phys 37: 1115–1123, 1997Google Scholar
  32. 32.
    Teicher BA,Holden SA,Ara G,Chen G: Transforming growth factor-β in in vivo resistance. Cancer Chemother Pharmacol 37(6): 601–609, 1996Google Scholar
  33. 33.
    Anscher MS,Peters WP,Reisenbichler H,Petros WP,Jirtle RL: Transforming growth factor-β as a predictor of liver and lung fibrosis after autologous bone marrow transplantation for advanced breast cancer. New Eng J Medicine 328: 1592–1598, 1993Google Scholar
  34. 34.
    Teicher BA,Chatterjee D,Liu J-T,Holden SA,Ara G: Protection of bone-marrow granulocyte-macrophage colony-forming units in mice bearing in vivo alkylating agent resistant EMT-6 tumors. Cancer Chemother Pharmacol 32: 315–319, 1993Google Scholar
  35. 35.
    Chatterjee D,Liu J-T,Northey D,Teicher BA: Molecular characterization of the in vivo alkylating agent resistant murine EMT-6 mammary carcinoma tumors. Cancer Chemother. Pharmacol 35: 423–431, 1995Google Scholar
  36. 36.
    Kobayashi H,Man S,Graham CH,Kapitain SJ,Teicher BA,Kerbel RS: Acquired multicellular-mediated resistance to alkylating agents in cancer. Proc Natl Acad Sci USA 90: 3294–3298, 1993Google Scholar
  37. 37.
    Teicher BA,Holden SA,Ara G,Chen G: Transforming growth factor-â in in vivo resistance. Cancer Chemother Pharmacol 37: 601–609, 1996Google Scholar
  38. 38.
    Liu P,Menon K,Alvarez E,Lu K,Teicher BA: Transforming growth factor-β and response to anticancer therapies in human liver and gastric tumors in vitro and in vivo. Int J Oncol 16: 599–610, 2000Google Scholar
  39. 39.
    Teicher BA,Ikebe M,Ara G,Keyes SR,Herbst R: Transforming growth factor-β overexpression produces drug resistance in vivo: reversal by decorin. In vivo 11: 463–472, 1997Google Scholar
  40. 40.
    Steiner MS: Transforming growth factor-â and prostate cancer. World J Urol 13: 329–336, 1995Google Scholar
  41. 41.
    Guo Y,Jacobs SC,Kyprianou N: Down-regulation of protein and mRNA expression for transforming growth factor-β (TGF-β) type I and type II receptors in human prostate cancer. Int J Cancer 71: 573–579, 1997Google Scholar
  42. 42.
    Kim IY,Ahn HJ,Zelner DJ,Shaw JW,Lang S,Kato M,Oefelein MG,Miyazono K,Nemeth JA,Kozlowski JM,Lee C: Loss of expression of transforming growth factor β type I and type II receptors correlates with tumor grade in human prostate cancer tissues. Clinical Cancer Res 2: 1255–1261, 1996Google Scholar
  43. 43.
    Williams RH,Stapleton AMF,Yang G,Truong LD,Rogers E,Timme TL,Wheeler TM,Scardino PT,Thompson TC: Reduced levels of transforming growth factor β receptor type II in human prostate cancer: an immunohistochemical study. Clinical Cancer Res 2: 635–640, 1996Google Scholar
  44. 44.
    Colleoni M,O'Neill A,Goldhirsch A,Gelber RD,Bonetti M,Thurlimann B,Price KN,Castiglione-Gertsch M,Coates AS,Lindtner J,Collins J,Senn H-J,Cavalli F,Forbes J,Gudgeon A,Simoncini E,Cartes-Funes H,Veronesi A,Fey M,Rudenstam C-M: Identifying breast cancer patients at high risk for bone metastases. J Clin Oncol 18: 3925-3935, 2000Google Scholar
  45. 45.
    McEarchern JA,Kobie JJ,Mack V,Wu RS,Meade-Tollin L,Arteaga CL,Dumont N,Besselsen D,Seftor E,Hendrix MJC,Katsanis E,Akporiaye ET: Invasion and metasasis of a mammary tumor involves TGF-β signaling. Int J Cancer 91: 76–81, 2001Google Scholar
  46. 46.
    Chua CC,Hamdy RC,Chua BHL: Mechanism of transforming growth factor-β1-induced expression of vascular endothelial growth factor in murine osteoblastic MC3T3-E1 cells. Biochim Biophys Acta 1497: 69–76, 2000Google Scholar
  47. 47.
    Tumber A,Morgan HM,Meikle MC,Hill PA: Human breast-cancer cells stimulate the fusion, migration and resorptive activity of osteoclasts in bone explants. Int J Cancer 91: 665–672, 2001Google Scholar
  48. 48.
    Yin JJ,Selander K,Chirgwin JM,Dallas M,Grubbs BG,Wieser R,Massague J,Mundy GR,Guise TA: TGF-b signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest 103: 197–206, 1999Google Scholar
  49. 49.
    Yamada Y,Ando F: Transforming growth factor-β1 gene polymorphism and bone mineral density. JAMA 285: 167–169, 2001Google Scholar
  50. 50.
    Winding B,Misander H,Sveigaard C,Therkildsen B,Jakobsen M,Overgaard T,Oursler MJ,Foged NT: Human breast cancer cells induce angiogenesis, recruitment and activation of osteoclasts in osteolytic metastasis. J Cancer Res Clin Oncol 126: 631–640, 2000Google Scholar
  51. 51.
    Ziv E,Cauley J,Morin PA,Saiz R,Browner WS: Association between the T29-> C polymorphism in the transforming growth factor β1 gene and breast cancer among elderly white women. JAMA 285: 2859–2863, 2001Google Scholar
  52. 52.
    Muir GH,Butta A.Shearer RJ,Fisher C,Dearnaley DP,Flanders KC,Sporn MB,Colletta AA: Induction of transforming growth factor beta in hormonally treated human prostate cancer. Brit J Cancer 69: 130–134, 1994Google Scholar
  53. 53.
    Kim IY,Ahn HJ,Zelner DJ,Shaw JW,Sensibar JA,Kim JH,Kato M,Lee C: Genetic change in transforming growth factor β (TGF-β) receptor type I gene correlates with insensitivity to TGF-β1 in human prostate cancer cells. Cancer Res 56: 44–48, 1996Google Scholar
  54. 54.
    Letterio JJ,Roberts AB: TGF-β: A critical modulator of immune cell function. Clin Immunol Immunopathol. 84: 244–250, 1997Google Scholar
  55. 55.
    Arteaga C,Hurd S,Winnier A,Johnson M,Fendly B,Forbes J: Anti-transforming growth factor (TGF)-β antibodies inhibit breast cancer cell tumorigenicity and increase mouse spleen natural killer cell activity. J Clin Invest 92: 2569–2576, 1993Google Scholar
  56. 56.
    Levitsky HI: Augmentation of host immune responses to cancer: overcoming the barrier of tumor antigen-specific T-cell tolerance. Cancer J 6(Suppl 3): S281–S290, 2000Google Scholar
  57. 57.
    Tada T,Ohzeki S,Utsumi K,Takiuchi H,Muramatsu M,Li XF,Shimizu J,Fujiwara H,Hamaoka T: Transforming growth factor-beta-induced inhibition of T cell function. Susceptibility difference in T cells of various phenotypes and functions and its relevance to immunosupression in the tumor-bearing state. J Immunol 146: 1077–1082, 1991Google Scholar
  58. 58.
    Torre-Amione G,Beauchamp RD,Koeppen H,Park BH,Schreiber H,Moses HL,Rowley DA: A highly immunogenic tumor transfected with a murine transforming growth factor type beta 1 cDNA escapes immune surveillance. Proc Natl Acad Sci USA 87: 1486–1490, 1990Google Scholar
  59. 59.
    Park JA,Wang E,Kurt RA,Schluter SF,Hersh EM,Akporiaye ET: Expression of an antisense transforming growth factor-b1 transgene reduces tumorigenicity of EMT6 mammary tumor cells. Cancer Gene Ther 4: 42–50, 1997Google Scholar
  60. 60.
    Wojtowicz-Praga S: Reversal of tumor-induced immunosupression: a new approach to cancer therapy. J Immunother 20: 165–177, 1997Google Scholar
  61. 61.
    Matthews E,Yang T,Janulis L,Goodwin S,Kundu SD,Karpus WJ,Lee C: Down-regulation of TGF-b1 production restores immunogenicity in prostate cancer cells. Brit J Cancer 83: 519–525, 2000Google Scholar
  62. 62.
    Werner F,Jain MK,Feinberg MW,Sibinga ES,Pellacani A,Wiesel P,Chin MT,Topper JN,Perrella MA,Lee M-E: Transforming growth factor-b1 inhibition of macrophage activation is mediated via Smad3. J Biol Chem 275: 36653–36658, 2000Google Scholar
  63. 63.
    Ahmad S,Choudhry MA,Shankar R,Sayeed MM: Transforming growth factor-β negatively modulates T-cell responses in sepsis. FEBS Letts 402: 213–218, 1997Google Scholar
  64. 64.
    Borkowski TA,Letterio JJ,Mackall CL,Saitoh A,Wang XJ,Roop DR,Gress RE,Udey MC: A role for TGFβ1 in Langerhans cell biology: Further characterization of the epidermal Langerhans cell defect in TGFβ null mice. J Clin Invest 100: 575–581, 1997Google Scholar
  65. 65.
    Menke A,Yamaguchi H,Gress TM,Adler G: Extracellular matrix is reduced by inhibition of transforming growth factor b1 in pancreatitis in the rat. Gastroenterology 113: 295–303, 1997Google Scholar
  66. 66.
    Hirsch CS,Ellner JJ,Blinkhorn R,Toossi Z: In vitro restoration of T-cell responses in tuberculosis and augmentation of monocyte effector function against Mycobacterium tuberculosis by natural inhibitors of transforming growth factor beta. Proc Natl Acad Sci USA 94: 3926–3931, 1997Google Scholar
  67. 67.
    Ming M,Ewen ME,Pereira ME: Trypanosome invasion of mammalian cells requires activation of the TGF-beta signaling pathway. Cell 82: 287–296, 1995Google Scholar
  68. 68.
    Barral-Netto M,Barral A,Brownell CE,Skeiky YA,Ellingsworth LR,Twardzik DR,Reed SG: Transforming growth factor-beta in leishmanial infection: a parasite escape mechanism. Science 257: 545–548, 1992Google Scholar
  69. 69.
    Gilboa E: How tumors escape immune destruction and what we can do about it. Cancer Immunol Immunotherap 48: 382–385, 1999Google Scholar
  70. 70.
    Maeda H,Tsuru S,Shiraishi A: Improvement of macrophage dysfunction by administration of antitransforming growth factor-â antibody in EL4-bearing hosts. Jpn J Cancer Res 85: 1137–1143, 1994Google Scholar
  71. 71.
    Letterio JJ,Roberts AB: Regulation of immune responses by TGF-beta. Annu Rev Immunol 16: 137–161, 1998Google Scholar
  72. 72.
    Jennings M,Kaariainen I,Gold L,Maciunas R,Commers P: TGFβ1 and TGFβ2 are potential growth regulators for medulloblastomas, primitive neuroectodermal tumors, and ependymomas: evidence in support of an autocrine hypothesis. Human Pathol 25: 464–475, 1994Google Scholar
  73. 73.
    Stander M,Naumann U,Dumitrescu L,Heneka M,Loschmann P,Gulbins E,Dichgans J,Weller M: Decor in gene transfer-mediated supression of TGF-beta synthesis abrogates experimental glioma growth in vivo. Gene Therapy 5: 1187–1194, 1998Google Scholar
  74. 74.
    MacCallum J,Bartlett JMS,Thompson AM,Keen JC,Dixon JM,Miller WR: Expression of transforming growth factor beta mRNA isoforms in human breast cancer. Br J Cancer 69: 1006–1009, 1994Google Scholar
  75. 75.
    Wakefield L,Letterio J,Chen T,Danielpour D,Allison R,Pai L,Denicoff A,Noone M,Cowan K,O'shaughnessy J,Sporn M: Transforming growth factor-β1 circulates in normal human plasma and is unchanged in advanced metastatic breast cancer. Clin Cancer Res 1: 129–136, 1995Google Scholar
  76. 76.
    Amoils K,Seyoum L,Bezwoda W: Comparison between oestrogen receptor and transforming growth factor β in breast cancer. Brit J Cancer 73: 1255–1259, 1996Google Scholar
  77. 77.
    Walker RA,Dearing SJ,Gallacher B: Relationship of transforming growth factor β1 to extracellular matrix and stromal infiltrates in invasive breast carcinoma. Br J Cancer 69: 1160–1165, 1994Google Scholar
  78. 78.
    Murray P,Gomm J,Ricketts D,Powles T,Coombes R: The effect of endocrine therapy on the levels of oestrogen and progesterone receptor and transforming growth factorâ 1 in metastatic human breast cancer: an immunocytochemical study. Europ J Cancer 30A: 218–1222, 1994Google Scholar
  79. 79.
    MacCallum J,Keen J,Bartlett J,Thompson A,Dixon J,Miller W: Changes in expression of transforming growth factor beta mRNA isoforms in patients undergoing tamoxifen therapy. Brit J Cancer 74: 474–478, 1996Google Scholar
  80. 80.
    Vrana J,Stang M,Grande J,Getz M: Expression of tissue factor in tumor stroma correlates with progression to invasive human breast cancer: paracrine regulation by carcinoma cell-derived members of the transforming growth factor β in breast cancer. Cancer Res 56: 5063–5070, 1996Google Scholar
  81. 81.
    Anscher MS,Peters WP,Reisenbichler H,Petros WP,Jirtle RL: Transforming growth factor β as a predictor of liver and lung fibrosis after autologous bone marrow transplantation for advanced breast cancer. NewEng J Med 328: 1592–1598, 1993Google Scholar
  82. 82.
    Lafon C,Mazars P,Guerr in M,Barboule N,Charcosset J-Y,Valette A: Early gene responses associated with transforming growth factor-β1 growth inhibition and autoinduction in MCF-7 (transforming growth factor-β1) on the cell cycle regulation of human breast adenocarcinoma (MCF-7) cells. FEBS Lett 362: 295–300, 1995Google Scholar
  83. 83.
    Herman ME,Katzenellenbogen BS: Alterations in transforming growth factor-β and-β production and cell responsiveness during the progression of MCF-7. Cancer Res. 54: 5867–5874, 1994Google Scholar
  84. 84.
    Sun LZ,Wu G,Willson JKV,Zborowska E,Yang J,Rajkarunanayake I,Wang J,Gentry LE,Wang X-F,Brattain MG: Expression of transforming growth factor β type II receptor leads to reduced malignancy in human breast cancer MCF-7 cells. J Biol Chem 269: 26449–26455, 1994Google Scholar
  85. 85.
    Arnold SF,Tims E,Bluman EM,McGrath BE: Regulation of transforming growth factor β1 by radiation in cells of two human breast cancer cell lines. Radiat Res 152: 487–492, 1999Google Scholar
  86. 86.
    Arteaga C,Dugger T,Winnier A,Forbes J: Evidence for a positive role of transforming growth factor-β in human breast cancer cell tumorgenesis. J Cellular Biochem 17G: 187–193, 1993Google Scholar
  87. 87.
    Arteaga C,Carty-Dugger T,Moses H,Hurd S,Pietenpol J: Transforming growth factor β1 can induce estrogenindependent tumorgenicity of human breast cancer cells in athymic mice. Cell Growth Diff 4: 193–201, 1993Google Scholar
  88. 88.
    Elizalde P,Guerra F,Lanari C,Kordon E,Charreau E,Lupu R: Correlation of TGF-β expression with medroxiprogesterone acetate responsiveness in mouse mammary adenocarcinomas. Cancer Invest 13: 173–180, 1995Google Scholar
  89. 89.
    Baille R,Coombes R,Smith J: Multiple forms of TGF-β1 in breast tissues: biologically breast adenocarcinoma cells. Biochim Biophys Acta 1266: 288–295, 1995Google Scholar
  90. 90.
    Arnoletti J,Albo D,Granick M,Castiglioni A,Rothman V,Tuszynski G: Thrombospondin and transforming growth factor-beta 1 increase expression of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 in human MDA-MB-231 breast cancer cells. 998, 1995Google Scholar
  91. 91.
    Sun LZ,Chen C: Expression of transforming growth factor β type III receptor supresses tumorigenicity of human breast cancer MDA-MB-231 cells. J Biol Chem 272: 25367–25372, 1997Google Scholar
  92. 92.
    Bandyopadhyay A,Zhu Y,Cibull ML,Bao L,Chen C,Sun L: A soluble transforming growth factor β type III receptor supresses tumorigenicity and metastasis of human breast cancer MDA-MB-231 cells. Cancer Res 59: 5041–5046, 1999Google Scholar
  93. 93.
    Nash MA,Loercher AE,Freedman RS: In vitro growth inhibition of ovarian cancer cells by decorin: synergism between decorin and carboplatin. Cancer Res 59: 6192–6196, 2000Google Scholar
  94. 94.
    Kong F,Jirtle RL,Huang DH,Clough RW,Anscher MS: Plasma transforming growth factor-β1 level before radiotherapy correlates with long term outcome of patients with lung carcinoma. Cancer 86: 1712–1719, 1999Google Scholar
  95. 95.
    Bartlett J,Rabiasz G,Langdon S,Miller E,Miller W: Transforming growth factor-β (TGF-β) mRNA expression and growth control in human lung squamous carcinoma cell lines. Int J Oncol 4: 475–479, 1994Google Scholar
  96. 96.
    Albo D,Arnoletti J,Castiglioni A,Granick M,Soloman M,Rothman V,Tuszynski G: Thrombospondin (TSP) and transforming growth factor beta1 (TGF-β) promote human A549 lung carcinoma cell plasminogen activator inhibitor type 1 (PAI-1) production and stimulate tumor cell attachment in vitro. Biochem Biophys Res Commun 203: 857–865, 1994Google Scholar
  97. 97.
    Norgaard P,Spang-Thomsen M,Poulsen H: Expression and autoregulation of transforming growth factor β receptor mRNA in small-cell lung cancer cell lines. Brit J Cancer 73: 1037–1043, 1996Google Scholar
  98. 98.
    Iyer SN,Gurujeyalakshmi G,Giri SN: Effects of pirfenidone on transforming growth factor-β gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. J Pharmacol Exp Therap 291: 367–373, 1999Google Scholar
  99. 99.
    Anscher M,Murase T,Prescott D,Marks L,Reisenbichler H,Bentel G,Spencer D,Sherouse G,Jirtle R: Changes in plasma TGFβ levels during pulmonary radiotherapy as a predictor of the risk of developing radiation pneumonitis. Int J Radiat Oncol Biol Phys 30: 671–676, 1994Google Scholar
  100. 100.
    Hasagawa Y,Takanashi S,Kanehira Y,Tsushima T,Imai T,Okumura K: Transforming growth factor-β1 level correlates with angiogenesis, tumor progression, and prognosis in patients with nonsmall cell lung carcinoma. Cancer 91: 964–971, 2001Google Scholar
  101. 101.
    Ito N,Kawata S,Tamura S,Shirai Y,Kiso S,Tsushima H,Matsuzawa Y: Positive correlation of plasma transforming growth factor-β1 levels with tumor vascularity in hepatocellular carcinoma. Cancer Letts 89: 45–48, 1995Google Scholar
  102. 102.
    Tsai JF,Jeng JE,Chuang LY,Yang ML,Ho MS,Chang WY,Hsieh MY,Lin ZY,Tsai JH: Elevated urinary transforming growth factor-β1 level as a tumor marker and predictor of poor survival in cirrhotic hepatocellular carcinoma. Brit J Cancer 76: 244–256, 1997Google Scholar
  103. 103.
    Castilla A,Prieto J,Fausto N: Transforming growth factor-β1 and a in chronic liver disease. New Eng J Medicine 324: 933–940, 1991Google Scholar
  104. 104.
    Castilla A,Prieto J,Fausto N: Transforming growth factor β1 and a in chronic liver disease: effects of interferon-α therapy. New Eng J Medicine 324: 993–940, 1991Google Scholar
  105. 105.
    Bedossa P,Peltier E,Terris B,Franco D,Poynard T: Transforming growth factor-β1 (TGF-β1) and TGF-β1 receptors in normal, cirrhotic and neoplastic human livers. Hepatology 21: 760–766, 1995Google Scholar
  106. 106.
    Shirai Y,Kawata S,Tamura S,Ito N,Tsusima H,Takaishi K,Kiso S,Matsuzawa Y: Plasma transforming growth factor-β1 in patients with hepatocellular carcinoma. Cancer 73: 2275–2279, 1994Google Scholar
  107. 107.
    Matsuzaki K,Date M,Furukawa F,Tahashi Y,Matsushita M,Sakitani K,Yamashiki N,Seki T,Saito H,Nishizawa M,Fujisawa J,Inoue K: Autocrine stimulatory mechanism by transforming growth factor β in human hepatocellular carinoma. Cancer Res 60: 1394–1402, 2000Google Scholar
  108. 108.
    Ito N,Kawata S,Tamora S,Takaishi K,Shirai Y,Kiso S,Yabeurchi I,Matsuda Y,Nishioka M,Tarui S: Elevated levels of transforming growth factor β messenger RNA and its polypeptide in human hepatocellular carcinoma. Cancer Res 51: 4080–4083, 1991Google Scholar
  109. 109.
    Factor VM,Kao CY,Santoni-Rugiu E,Woitach JT,Jensen MR,Thorgeirsson SS: Constitutive expression of mature transforming growth factor β1 in the liver accelerates hepatocarcinogenesis in transgenic mice. Cancer Res 57: 2089–2095, 1997Google Scholar
  110. 110.
    Gressner AM,Lahme B,Mannherz HG,Polzar B: TGF-β-mediated hepatocellular apoptosis by rat and human hepatoma cells and primary rat hepatocytes. J Hepatology 26: 1079–1092, 1997Google Scholar
  111. 111.
    Sun D,Kar S,Carr BI: Differentially expressed genes in TGF-β1 sensitive and resistant human hepatoma cells. Cancer Letts 89: 73–79, 1995Google Scholar
  112. 112.
    Nakatsukasa H,Evarts RP,Hsia C,Marsdaen E,Thorgeirsson SS: Expression of transforming growth factor-β1 during chemical hepatocarcinogenesis in the rat. Lab Investag 65: 511–517, 1991Google Scholar
  113. 113.
    Jirtle RL,Meyer SA: Liver promotion: effect of phenobarbital on EGF and protein kinase C signal transduction and transforming growth factor-β1 expression. Dig Dis Sci 36: 659–668, 1991Google Scholar
  114. 114.
    Jakowlew SB,Mead JE,Danielpour D,Wu J,Roberts AB,Fausto N: Transforming growth factor-β (TGF-β) isoforms in rat liver regeneration: messenger RNA expression and activation of latent TGF-β. Cell Regulation 2: 535–548, 1991Google Scholar
  115. 115.
    Jirtle RL,Carr BI,Scott CD: Modulation of insulin-like growth factor-II/mannose 6-phosphate receptors and transforming growth factor-β1 during liver regeneration. J Biol Chem 266: 22444–22450, 1991Google Scholar
  116. 116.
    Nakatsukasa H,Nagy P,Evarts RP,Hsia CC,Marsden E, Thorgeirsson: Cellular distribution of transforming growth factor-β1 and procollagen types I, III and IV transcripts in carbon tetrachloride-induced rat liver fibrosis. J Clin Investag 85: 1833–1843, 1990Google Scholar
  117. 117.
    Czaja MJ,Weiner FR,Flanders KC,Giambrone MA,Wind R,Biempica L,Zern MA: In vitro and in vivo association of transforming growth factor-β1 with hepatic fibrosis. J Cell Biol 108: 2477–2482, 1989Google Scholar
  118. 118.
    Huggett AC,Ellis PA,Ford CP,Hampton LL,Rimoldi D,Thorgeirsson SS: Development of resistance to the growth inhibitory effects of transforming growth factor β1 during the spontaneous transformation of rat liver epithelial cells. Cancer Res 51: 5929–5936, 1991Google Scholar
  119. 119.
    George J,Roulot D,Koteliansky VE,Bissell DM: In vivo inhibition of rat stellate cell activation by soluble transforming growth factor β type II receptor: a potential new therapy for hepatic fibrosis. Proc Natl Acad Sci USA 96: 12719–12724, 1999Google Scholar
  120. 120.
    Abdel-Razzak Z,Corcos L,Fautrel A,Campoin J-P,Guillouzo A: Transforming growth factor-β1 downregulates basal and polycyclic aromatic hydrocarbon induced cytochromes P-450 1A1 and 1A2 in adult human hepatocytes in primary culture. Mol Pharmacol 46: 1100–1110, 1994Google Scholar
  121. 121.
    Sun D,Kar S,Carr B: Differentially expressed genes in TGF-β1 sensitive and resistant human hepatoma cells. Cancer Lett, 89: 73–79, 1995Google Scholar
  122. 122.
    Kayanoki Y,Fujii J,Suzuki K,Kawata S,Matsuzawa Y,Taniguchi N: Suppression of antioxidative enzyme expression by transforming growth factor-β1 in rat hepatocytes. J Biol Chem 269: 15488–15492, 1994Google Scholar
  123. 123.
    Patel B,Khaliq A,Jarvis-Evans J,McLeod D,Mackness M,Boulton M: Oxygen regulation of TGF-β1 mRNA in human hepatoma (HEP G2) cells. Biochem Moil Biol International 34: 639–644, 1994Google Scholar
  124. 124.
    Sanderson N,Factor V,Nagy P,Kopp J,Kondaiah P,Wakefield L,Roberts A,Sporn M,Thorgeirsson S: Hepatic expression of mature transforming growth factor β1 in transgenic mice results in multiple tissue lesions. Proc. Nat. Acad Sci USA 92: 2572–2576, 1995Google Scholar
  125. 125.
    Steiner M,Wand G,Barrack E: Effects of transforming growth factor β1 on the adenylyl cyclase-cAMP pathway in prostate cancer. Growth Factors 11: 283-290, 1994Google Scholar
  126. 126.
    Steiner M,Barrack E: Transforming growth factor-β1 overproduction in prostate cancer: effects on growth in vivo and in vitro. Mol Endocrinology 6: 15–25, 1992Google Scholar
  127. 127.
    Steiner M,Zhou Z-Z,Tonb D,Barrack E: Expression of transforming growth factor-β1 in prostate cancer. Endocrinology 135: 2240–2247, 1994Google Scholar
  128. 128.
    Lee C,Sintich SM,Mathews EP,Shah AH,Kundu SD,Perry KT,Cho JS,Ilio KY,Cronauer MV,Janulis L,Sensibar JA: Transforming growth factor-β in benign and malignant prostate. The Prostate 39: 285–290, 1999Google Scholar
  129. 129.
    Klingler HC,Bretland AJ,Reid SV,Chapple CR,Eaton CL: Regulation of prostatic stromal cell growth and function by transforming growth factor beta (TGFβ). The Prostate 41: 110–120, 1999Google Scholar
  130. 130.
    Tang B,de Castro K,Barnes HE,s WT,Stewart L,Bottinger EP,Danielpour D,Wakefield LM: Loss of responsiveness to transforming growth factor β induces malignant transformation of non-tumorigenic rat prostate epithelial cells. Cancer Res 59: 4834–4842, 1999Google Scholar
  131. 131.
    Merz V,Arnold A,Studer U: Differential expression of transforming growth factor-β1 and β3 as well as C-FOS mRNA in normal human prostate, benign prostatic hyperplasia and prostatic cancer. World J Urol 12: 96–98, 1994Google Scholar
  132. 132.
    Barrack ER: TGFβ in prostate cancer: a growth inhibitor that can enhance tumorigenicity. The Prostate 31: 61–70, 1997Google Scholar
  133. 133.
    Muir GH,Butta A,Shearer RJ,Fisher C,Dearnaley DP,Flanders KC,Sporn MC,Coetta AA: Induction of transforming growth factor beta in hormonally treated human prostate cancer. Brit J Urol 69: 130–134, 1994Google Scholar
  134. 134.
    Kyprianou N,Isaacs JT: Expression of transforming growth factor-beta in the rat ventral prostate during castrationinduced programmed cell death: Mol Endocrinol 3: 1515–1522, 1989Google Scholar
  135. 135.
    Martikainen P,Kyprianou N,Isaacs JT. Effect of transforming growth factor-β1 on proliferation and death of rat prostatic cells. Endocrinology 127: 2963–2968, 1990Google Scholar
  136. 136.
    Hsing AY,Kadomatsu K,Bonham MJ,Danielpour D: Regulation of apoptosis induced by transforming growth factor-β1 in non-tumorigenic and tumorigenic rat prostatic epithelial cell lines. Cancer Res 56: 5146–5149, 1996Google Scholar
  137. 137.
    Myeroff LL,Parsons R,Kim SJ,Hedrick L,Cho KR,Orth K,Mathis M,Kinzler KW,Lutterbaugh JL,Park K,Bang YJ,Lee HY,Park JG,Lynch HT,Roberts AB,Vogelstein B,Markowitz SD: A transforming growth factor â receptor type II gene mutation common in colon and gastric but rare in endometrial cancers. Cancer Res 55: 5545–5547, 1995Google Scholar
  138. 138.
    Roberts A,Sporn M: Peptide growth factors and their receptors. In: Roberts A,Sporn M. (eds) Handbook of Experimental Pharmacology, Springer-Verlag, Heidelberg, 1990, pp. 419–472Google Scholar
  139. 139.
    Moses H,Yang E,Pietenpol J: TGF-β stimulation and inhibition of cell proliferation: new mechanistic insights. Cell 63: 245–247, 1990Google Scholar
  140. 140.
    Bratain M,Howell G,Sun L,Willson JKV: Growth factor balance and tumor progression. Curr Opin Oncol 7: 77–81, 1994Google Scholar
  141. 141.
    Markowitz SD,Myeroff L,Cooper M,Traicoff J,Kochera M,Lutterbaugh J,Swiriduk M,Willson JKV: A benign cultured colon adenoma bears three genetically altered colon cancer oncogenes, but progresses to tumorigenicity and transforming growth factor-β independence without inactivating the p53 tumor supressor gene. J Clin Invest 93: 1005–1013, 1994Google Scholar
  142. 142.
    Filmus J,Kerbel R: Development of resistance mechanisms to the growth inhibitory effects of transforming growth factor-β during tumor progression. Curr Opin Oncol 5: 123–129, 1993Google Scholar
  143. 143.
    Eshleman JR,Markowitz SD: Microsatellite instability in inherited and sporadic neoplasms. Curr Opin Oncol 7: 83–89, 1995Google Scholar
  144. 144.
    Marra G,Boland CR: Hereditary nonpolyposis colorectal cancer: the syndrome, the genes and historical perspectives. J Natl Cancer Inst 87: 1114–1125, 1995Google Scholar
  145. 145.
    Markowitz S,Wang J,Myeroff L,Parsons R,Sun L,Lutterbaugh J,Fan RS,Zborowska E,Kinzler KW,Vogelstein B,Braittain M,Willson JKV: Inactivation of the type II TGF-β receptor in colon cancer cells with microsatellite instability. Science (Washington DC) 268: 1336–1338, 1995Google Scholar
  146. 146.
    Parsons R,Myeroff L,Liu B,Willson JKV,Markowitz S,Kinzler KW,Vogelstein B: Microsatellite instability and mutations of the transforming growth factor β type II receptor gene in colorectal cancer. Cancer Res 55: 5548–5550, 1995Google Scholar
  147. 147.
    Shin K-H,Park YJ,Park J-G: Mutational analysis of the transforming growth factor β receptor type II gene in hereditary nonpolyosis colorectal cancer and early-onset colorectal cancer patients. Clin Cancer Res 7: 537–540, 2000Google Scholar
  148. 148.
    Kai T,Taketazu F,Kawakami M,Shimanuki K,Yamada S,Miyazono K,Kato M,Miyata M: Distribution of transforming growth factor-β and its receptors in gastric carcinoma tissue. Jpn J Cancer Res 87: 296–304, 1996Google Scholar
  149. 149.
    Mahara K,Kato J,Terui T,Takimoto R,Horimoto M,Murakami T,Mogi Y,Watanabe N,Kohgo Y,Niitsu Y: Transforming growth factor β1 secreted from scirrhous gastric cancer cells is associated with excess collagen deposition in the tissue. Brit J Cancer 69: 777–783, 1994Google Scholar
  150. 150.
    Lu L,Shen R-N,Lin Z-H,Aukerman SL,Ralph P,Broxmeyer HE: Anti-tumor effects of recombinant human macrophage colony-stimulating factor, alone or in combination with local irradiation, in mice inoculated with Lewis lung carcinoma cells. Int J Cancer 47: 143–147, 1991Google Scholar
  151. 151.
    Parsons R,Myeroff L,Liu B,Willson J,Markowitz S,Kinzler K,Vogelstein B: Microsatellite instability and mutations of the transforming growth factor β type II receptor gene in colorectal cancer: Cancer Res 55: 5548–5550, 1995Google Scholar
  152. 152.
    Myeroff L,Parsons R,Kim S,Hedrick L,Cho K,Orth K,Mathis M,Kinzler K,Lutterbaugh J,Park K,Bang Y,Lee H,Park J,Lynch H,Roberts A,Yogelstein B,Markowitz S: Atransforming growth factor β receptor type II gene mutation common in colon and gastric but rare in endometrial cancers with microsatellite instability. Cancer Res 55: 5545–5547, 1995Google Scholar
  153. 153.
    Garrigue-Antar L,Munoz-Antonia T,Antonia S,Gesmonde J,Vellucci V,Reiss, M: Missense mutations of the transforming growth factor β type II receptor in human head and neck squamous carcinoma cells. Cancer Res 55: 3982–3987, 1995Google Scholar
  154. 154.
    Hsu S,Huang F,Hafez M,Winawer S,Friedman E: Colon carcinoma cells switch their response to transforming growth factor β1 with tumor progression. Cell Growth Diff 5: 267–275, 1994Google Scholar
  155. 155.
    Ohue M,Tomita N,Monden T,Miyoshi Y,Ohnishi T,Izawa H,Kawabata Y,Sasaki M,Sekimoto M,Nishisho I,Shiozai H,Monden M: Mutations of the transforming growth factor â type II receptor gene and microsatellite instability in gastric cancer. Int J Cancer 68: 203–206, 1996Google Scholar
  156. 156.
    Kai T,Taketazu F,Kawakami M,Shimanuki K,Yamada S,Miyazono K,Kato M,Miyata M: Distribution of transforming growth factor-β and its receptors in gastric carcinoma tissue. Jpn J Cancer Res 87: 296–304 1996Google Scholar
  157. 157.
    Mahara K,Kato J,Terui T,Takimoto R,Horimoto M,Murakami T,Mogi Y,Watanabe N,Kohgo Y,Niitsu Y: Transforming growth factor β1 secreted from scirrhous gastric cancer cells is associated with excess collagen deposition in the tissue. Brit J Cancer 69: 777–783, 1994Google Scholar
  158. 158.
    Muro-Cacho CA,Rosario-Ortiz K,Livingston S,Munoz-Antonia T: Defective transforming growth factor β signaling pathway in head and neck squamous cell carcinoma as evidenced by the lack of expression of activated Smad2. Clin Cancer Res 7: 1618–1626, 2001Google Scholar
  159. 159.
    Shimizu S,Nishikawa Y,Kuroda K,Takagi S,Kozaki K,Hyuga S,Saga S,Matsuyama M: Involvement of transforming growth factor β1 in autocrine enhancement of gelatinase B secretion by murine metastatic colon carcinoma cells. Cancer Res 56: 3366–3370, 1996Google Scholar
  160. 160.
    Lieubeau B,Garrigue L,Barbieux I,Meflah K,Gregoire M: The role of transforming growth factor β1 in the fibroblastic reaction associated with rat colorectal tumor development. Cancer Res 54: 6526–6532, 1994Google Scholar
  161. 161.
    Chaudhry A,Oberg K,Gobl A,Heldin C-H,Funa K: Expression of transforming growth factor β1, β2, β3 in neuroendocrine tumors of the digestive system. Anticancer Res 14: 2085–2092, 1994Google Scholar
  162. 162.
    Kormann M,Tangvoranuntakul P,Korc M: TGF-b1 up-regulates cycl in D1 expression of COLO-357 cells, whereas supression of cyclin D1 levels is associated with down-regulation of the type 1 TGF-β receptor. Int J Cancer 83: 247–254, 1999Google Scholar
  163. 163.
    Ramp U,Jaquet K,Reinecke P,Nitsch T,Gabbert HE,Gerharz CD: Acquisition of TGF-β1 resistance: an important factor in human renal cell carcinoma. Lab Invest 76: 739-749, 1997Google Scholar
  164. 164.
    Gold LI,Saxena B,Mittal KR,Marmor M,Goswami S,Nactigal L,Korc M,Demopoulos RI: Increased expression of transforming growth factor βisoforms and basic fibroblast growth factor in complex hyperplasia and adenocarcinoma of the endometrium: evidence for paracrine and autocrine action. Cancer Res 54: 2347-2358, 1994Google Scholar
  165. 165.
    Bruner K,Rodgers W,Gold L,Korc M,Hargrove J,Matrisian L,Osteen K: Transforming growth factor β mediates the progesterone suppression of an epithelial metalloproteinase by adjacent stroma in the human endometrium. Proc Nat Acad Sci USA 92: 7362–7366 1995Google Scholar
  166. 166.
    Parekh TV,DelPriore G,Schatz F,Demopoulos R,Korc M,Gold LI: Decreased growth inhibitory response of primary cultures of endometrial carcinoma cells to TGF-beta1 is accompanied by altered response to gonadal steroids. Proc Amer Assoc Cancer Res 38: 452, 1977Google Scholar
  167. 167.
    Parekh TV,DelPriore G,Demopoulos R,Gold LI: Transforming growth factor-beta-related mechanisms of loss of growth control in endometrial carcinoma. Proc Amer Assoc Cancer Res 39: 79, 1998Google Scholar
  168. 168.
    Chegini N,Williams RS: Immunocytochemical localization of transforming growth factors (TGFs) TGF-β and TGF-β in human ovarian tissues. J Clin Endocrinol Metab 74: 973–980, 1992Google Scholar
  169. 169.
    Agarwal C,Hembree JR,Rorke EA,Eckert RL: Transforming growth factor-β1 regulation of metalloproteinase production in cultured human cervical epithelial cells. Cancer Res 54: 943–949, 1994Google Scholar
  170. 170.
    Merzak A,McCrea S,Koocheckpour S,Pilkington G: Control of human glioma cell growth, migration and invasion pp. in vitro by transforming growth factor β1. Brit J Cancer 70: 199–203, 1994Google Scholar
  171. 171.
    Fujiwara T,Mukhopadhyay T,Cai D,Morris D,Roth J,Grimm E: Retroviral-mediated transduction of p53 gene increases TGF-β expression in a human glioblastoma cell line. Int J Cancer 56: 834-839, 1994Google Scholar
  172. 172.
    Yamada N,Kato M,Yamashita H,Nister M,Miyazono K,Heldin C-H,Funa K: Enhanced expression of transforming growth factor-β and its type-I and type-II receptors in human glioblastoma. Int J Cancer 62: 386–392, 1995Google Scholar
  173. 173.
    Paulin C,Avallet O,Tardy F,Saez J,Fusco A,Fabien N: Production of TGFâ and HGF. Cancer Res 54: 575–581, 1994Google Scholar
  174. 174.
    Krasagakis K,Garbe C,Schrier P,Orfanos C: Paracrine and autocrine regulation of human melanocyte and melanoma cell growth by transforming growth factor beta in vitro. Anticancer Res 14: 2565–2572, 1994Google Scholar
  175. 175.
    Sellheyer K,Bickenbach J,Rothnagel J,Bundman D,Longley M,Krieg T,Roche N,Roberts, A,Roop D: Inhibition of skin development by overexpression of transforming growth factor β1 in the epidermis of transgenic mice. Proc Nat Acad Sci USA 90: 5237–5241, 1993Google Scholar
  176. 176.
    Rodeck U,Bossler A,Graeven U,Fox F,Nowell P,Knabbe C,Kari, C: Transforming growth factor β production and responsiveness in normal human melanocytes and melanoma cells. Cancer Res 54: 575–581, 1994Google Scholar
  177. 177.
    Cui W,Fowlis D,Bryson S,Duffie E,Ireland, H,Balmain A,Akhurst R: TGFβ1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell 86: 531–542, 1996Google Scholar
  178. 178.
    Randall K,Boggle J: Expression of transforming growth factorβ1 in mouse skin during the acute phase of radiation damage. Int J Radiat Biol 68: 301–309, 1995Google Scholar
  179. 179.
    Perlino E,Ciampollino A,Maiorano E,Pannone E,Viale G,Giorgino R,Marra E: Transforming growth factor β1 (TGFβ1) expression in proliferating thyroid disease. Int J Oncol 9: 83–88, 1996Google Scholar
  180. 180.
    Teicher BA: A systems approach to cancer therapy (antiangiogenics + standard cytotoxics' mechanism(s) of interaction). Cancer Metastasis Reviews 15(2): 247–272, 1996Google Scholar

Copyright information

© Kluwer Academic Publishers 2001

Authors and Affiliations

  • Beverly A. Teicher
    • 1
  1. 1.Lilly Research LaboratoriesLilly Corporate CenterIndianapolisUSA

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