Ovarian Cancer pp 353-381 | Cite as

Angiogenesis and Metastasis

  • Gregory J. Sieczkiewicz
  • Mahrukh Hussain
  • Elise C. Kohn
Part of the Cancer Treatment and Research book series (CTAR, volume 107)


Epithelial ovarian cancer constitutes approximately 85% of all ovarian malignancies. The lack of overt symptoms and good screening strategies precludes early diagnosis and thus greater than 70% of patients present with extensive local disease and peritoneal spread (1). While the five-year survival for patients presenting with advanced disease has improved over the past decade, there has been no increase in the number or frequency of cures of advanced ovarian cancer. The symptoms of both early and late stage ovarian cancers are frequently nonspecific, including abdominal complaints, bloating, and altered bowel habits, in part due to local tumor growth confined in stages I and II to the ovaries or pelvic organs prior to serosal spread in the abdomen. With advanced stage, the peritoneum, diaphragm, and omentum are seeded with micro- and macro-metastases of tumor cells, resulting in solid tumor masses and ascites that cause further bloating, cramping, pain and bowel complaints. Unlike its solid tumor counterparts that invade blood vessels and lymphatics and metastasize early, epithelial ovarian cancer spreads initially by surface shedding. This is followed by invasive peritoneal implantation, growth and further invasion. Distant parenchymal metastases are less common at presentation but may be seen with progression of epithelial ovarian cancer. The growth of ovarian tumors is associated frequently with the development of ascites, which is rich in cytokines and growth factors.


Vascular Endothelial Growth Factor Ovarian Cancer Hepatocyte Growth Factor Ovarian Carcinoma Epithelial Ovarian Cancer 
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  1. 1.
    Brown, M. R., Masiero, L., and Kohn, E. C. Tumor Angiogenesis and Metastasis. In: W. J. Hoskins, C. A. Perez, and R. C. Young (eds.), Principles and Practice of Gynecologic Oncology: Lippincott Williams and Wiklins, 2000.Google Scholar
  2. 2.
    Mesiano, S., Ferrara, N., and Jaffe, R. B. Role of vascular endothelial growth factor in ovarian cancer: ihibition of ascites formation by immunoneutralization. Am J Path 1998; 153: 1249–56.CrossRefPubMedGoogle Scholar
  3. 3.
    Kohn, E. C. and Liotta, L. A. Molecular insights into cancer invasion: strategies for prevention and intervention. Cancer Res 1995; 55: 1856–1862.PubMedGoogle Scholar
  4. 4.
    Folkman, J. and Shing, Y. Angiogenesis, J Biol Chem 1992; 267: 10931–3.PubMedGoogle Scholar
  5. 5.
    D’Amore, P. A. and Thompson, R. W. Mechanisms of angiogenesis, Ann Rev Physiol 1987; 49: 453–64.CrossRefGoogle Scholar
  6. 6.
    Eberhard, A., Kahlert, S., Goede, V., Hemmerlein, B., Plate, K. H., and Augustin, H. G. Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies Cancer Res 2000; 60: 1388–93.Google Scholar
  7. 7.
    Folkman, J. Tumor angiogenesis: Therapeutic implications. N Engl J Med. 1971; 5: 1182–1186.Google Scholar
  8. 8.
    Hanahan, D. and Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86: 353–364.CrossRefPubMedGoogle Scholar
  9. 9.
    Liotta, L. A., Kleinerman, J., and Saidel, G. Quantitative relationships of intravascular tumor cells: tumor vessels and pulmonary metastases following tumor implantation. Cancer Res 1971; 34: 997–1003.Google Scholar
  10. 10.
    Folkman, J. and Klagsbrun, M. Angiogenic factors. Science 1987; 235: 442–447.CrossRefPubMedGoogle Scholar
  11. 11.
    Folkman, J. Clinical applications of research on angiogenesis. New Eng J Med 1996; 333: 1757–1763.Google Scholar
  12. 12.
    Yoneda, J., Kuniyasu, H., Crispens, M. A., Price, J. E., Bucana, C. D., and Fidler, 1. J. Expression of angiogenesis-related genes and progression of human ovarian carcinomas in nude mice. J Natl Cancer Inst 1988; 90: 447–454.CrossRefGoogle Scholar
  13. 13.
    Fang, X., Gaudette, D., Fumi, T., Mao, M., Estrella, V., Eder, A., Pustilnik, T., Sasagawa, T., Lapushin, R., Yu, S., Jaffe, R. B., Weiner, J. R., Erickson, J. R., and Mills, G. B. Lysophospholipid growth factors in the initiation, progression, metastases and management of ovarian cancer. Ann N Y Acad Sci 2000; 905: 188–208.CrossRefPubMedGoogle Scholar
  14. 14.
    Abulafia, O. and Sherer, D. M. Angiogenesis of the ovary. Am J Obstet Gynecol 2000; 182: 240–246.CrossRefPubMedGoogle Scholar
  15. 15.
    Gordon, J. D., Mesiano, S., Zaloudek, C. J., and Jaffe, R. B. Vascular endothelial growth factor localization in human ovary and fallopian tubes: possible role in reproductive function and ovarian cyst formation. J Clin Endocrin Metabol 1996; 81: 353–359.CrossRefGoogle Scholar
  16. 16.
    Ferrara, N., Chen, H., Davis Smyth, T., Gerber, H. P., Nguyen, T. N., Peers, D., Chisholm, V., Hilan, K. J., and Schwall, R. H. Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nature Med 1998; 4: 336–340.CrossRefPubMedGoogle Scholar
  17. 17.
    Augustin, H. G., Braun, K., Telemenakis, I., Modlich, U., and Kuhn, W. Ovarian angiogenesis: Phenotypic characterization of endothelial cells in a physiological model of blood vessel growth and regression. Am J Path. 147 1995; 339–351.PubMedGoogle Scholar
  18. 18.
    Neeman, M., Abramovitch, R., Schiffenbauer, Y. S., and Tempel, C. Regulation of angiogenesis by hypoxic stress: from solid tumors to the ovarian follicle. Int J Exp Pathol 1997; 78: 57–70.CrossRefPubMedGoogle Scholar
  19. 19.
    Hirschi, K. K. and D’Amore, P. A. Pericytes in the microvasculature. Cardiovasc Res 1996; 32: 687–98.PubMedGoogle Scholar
  20. 20.
    Cogan, D. G. and Kuwabara, T. The mural cell in perspective. Arch Ophthalmol 1967; 78: 133–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Herman, I. M. and D’Amore, P. A. Microvascular pericytes contain muscle and nonmuscle actins. J Cell Biology 1985; 101: 43–52.CrossRefGoogle Scholar
  22. 22.
    Larson, D. M., Carson, M. P., and Haudenschild, C. C. Junctional transfer of small molecules in cultured bovine brain microvascular endothelial cells and pericytes. Microvasc Res 1987; 34: 184–99.CrossRefPubMedGoogle Scholar
  23. 23.
    Larson, D. M., Haudenschild, C. C., and Beyer, E. Gap junction messenger RNA expression by vascular wall cells. Circulation Research. 1990; 66: 1074–80.CrossRefPubMedGoogle Scholar
  24. 24.
    Orlidge, A. and D’Amore, P. A. Inhibition of capillary endothelial cell growth by pericytes and smooth muscle cells. J Cell Biology. 1987; 105: 1455–62.CrossRefGoogle Scholar
  25. 25.
    Sato, Y. and Rifkin, D. B. Inhibition of endothelial cell movement by pericytes and smooth muscles: activation of a latent transforming growth factor-beta I -like molecule by plasmin during co-culture. J Cell Biol 1989; 109: 309–15.CrossRefPubMedGoogle Scholar
  26. 26.
    Antonelli-Orlidge, A., Saunders, K. B., Smith, S. R., and D’Amore, P. A. An activated form of transforming growth factor beta is produced by cocultures of endothelial cells and pericytes. Proceedings of the National Academy of Sciences U.S.A. 1989; 86: 4544–8.CrossRefGoogle Scholar
  27. 27.
    Sato, Y., Tsuboi, R., Lyons, R., Moses, H., and Rifkin, D. B. Characterization of the activation of latent TGF-beta by co-cultures of endothelial cells and pericytes or smooth muscle cells: a self-regulating system. J Cell Biol 1990; 111: 757–63.CrossRefPubMedGoogle Scholar
  28. 28.
    Benjamin, L. E., Golijanin, D., Itin, A., Pode, D., and Keshet, E. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest 1999; 103: 159–165.CrossRefPubMedGoogle Scholar
  29. 29.
    Lindahl, P., Johansson, B. R., Leveen, P., and Betsholtz, C. Pericyte loss and microaneurysm formation in PDGF-B deficient mice. Science 1997; 277: 242–5.CrossRefPubMedGoogle Scholar
  30. 30.
    Benjamin, L. E., Hemo, I., and Keshet, E. A plasticity window for blood vessel remodeling is defined by pericyte coverage of the preformed endothelial network and is reguated by PDGF-B and VEGF. Development 1998; 125: 1591–8.PubMedGoogle Scholar
  31. 31.
    Ferrara, N. and Alitalo, K. Clinical applications of angiogenic growth factors and their inhibitors. Nature Med 1999; 5: 1359–64.CrossRefPubMedGoogle Scholar
  32. 32.
    Senger, D. R., Galli, S. J., Dvorak, A. M., Perruzzi, C. A., Harvey, V. S., and Dvorak, H. F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983; 219: 983–985.CrossRefPubMedGoogle Scholar
  33. 33.
    Carmeliet, P. Mechanisms of angiogenesis and arteriogenesis. Nature Med 2000; 6: 389395.Google Scholar
  34. 34.
    Benjamin, L. E. and Keshet, E. Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: induction ofendothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal. Proceedings of the National Academy of Sciences U.S.A. 1997; 94: 8761–8766.CrossRefGoogle Scholar
  35. 35.
    Boocock, C. A., Charnock-Jones, S., Sharkey, A. M., McLaren, J., Barker, P. J., Wright, K. A., and al, e. Expression of vascular endothelial growth factor and its receptors flt and KDR in ovarian carcinoma. J Natl Cancer Inst. 1995; 87: 506–516.CrossRefPubMedGoogle Scholar
  36. 36.
    Klagsbrun, M. and D’Amore, P. A. Vascular endothelial growth factor and its receptors. Cyt Grow Fact Rev 1996; 1: 259–270.CrossRefGoogle Scholar
  37. 37.
    Goode, V., Schmidt, T., Kimmina, S., Kozian, D., and Augustin, H. G. Analysis of blood vessel maturation processes during cyclic ovarian angiogenesis, Lab Invest 1998; 78: 1385–1394.Google Scholar
  38. 38.
    Kamat, B. R., Brown, L. F., Manseau, E. J., Senger, D. R., and Dvorak, H. F. Expression of vascular permeability factor/ vascular endothelial growth factor by human granulosa and theca lutein cells. Am J Pathol 1995; 146: 157–65.PubMedGoogle Scholar
  39. 39.
    Abramov, T., Schenker, J. G., Lewin, A., Friedler, S., Nisman, B., and Barak, U. Plasma inflammatory cytokines correlate to the ovarian hyperstimulation syndrome. Hum Reprod 1996; 11: 1381–6.CrossRefPubMedGoogle Scholar
  40. 40.
    Doldi, N., Bassan, M., Messa, A., and Ferrari, A. Expression of vascular endothelial growth factor in human luteinizing granulosa cells and its correlation with the response to controlled ovarian hyperstimulation. Gynecol Endocrinol 1997; 11: 263–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Yeo, K. T., Wang, H. H., Hagy, J. A., Sioussat, T. M., Ledbetter, S. R., Hoogewerf, A. J., Zhou, Y., Masse, E. M., Senger, D. R., and Dvorak, H. F. Vascular permeability factor (vascular endothelial growth factor) in guinea pig and human tumor and inflammatory effusions. Cancer Res 1993; 53: 2912–8.PubMedGoogle Scholar
  42. 42.
    Abu-Jawdeh, G. M., Faix, J. D., Niloff, J., Tognazzi, K., Manseau, E., Dvorak, H. F. Strong expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in ovarian borderline and malignant neoplasms. Lab Invest 1996; 74: 1105 1115.Google Scholar
  43. 43.
    Fong, T. A., Shawver, L. K., Sun, L., Tang, C., App, H., Powell, T. J., Kim, Y. H., Schreck, R., Wang, X., Risau, W., Ullrich, A., Hirth, K. P., and McMahon, G. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization and growth of multiple tumor types. Cancer Res 1999; 59: 99–106.PubMedGoogle Scholar
  44. 44.
    Inoue, K., Slaton, J. W., Davis, D. W., Hicklin, D. J., McConkey, D. J., Karashima, T., Radinsky, R., and Dinney, C. P. Treatment of human metastatic transitional cell carcinoma of the bladder in a murine model with the anti-vascular endothelial growth factor receptor monoclonal antibody DC101 and paclitaxel. Clin Cancer Res 2000; 6: 2635–43.PubMedGoogle Scholar
  45. 45.
    Zhu, Z., Lu, D., Kotanides, H., Santiago, A., Jimenez, X., Simcox, T., Hicklin, D. J., Bohlen, P., and Witte, L. Inhibition of vascular endothelial growth factor induced mitogenesis of human endothelial cells by a chimeric anti-kinase insert domain-containing receptor antibody. Cancer Lett 1999; 136: 203–13.CrossRefPubMedGoogle Scholar
  46. 46.
    Gale, N. W. and Yancopoulos, G. D. Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev 1999; 13: 1055–66.CrossRefPubMedGoogle Scholar
  47. 47.
    Suri, C., Jones, P. F., Patan, S., Bartunkova, S., Maisonpierre, P. C., Davis, S., Sato, T. N., and Yancopoulos, G. D. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 1996; 87: 1171–1180.CrossRefPubMedGoogle Scholar
  48. 48.
    Kim, I., Kim, H. W., Moon, S.-O., Chae, S. W., So, J.-N., Koh, K. N., Ahn, B. C., and Koh, G. Y. Angiopoietin-1 induces endothelial cell sprouting through the activation of focal adhesion kinase and plasmin secretion. Circ Res 2000; 86: 952–9.CrossRefPubMedGoogle Scholar
  49. 49.
    Maisonpierre, P. C., Suri, C., Jones, P. F., Bartunkova, S., Wiegand, S. J., Radziejewski, C., Compton, D., McClain, J., Aldrich, T. H., Papadopoulos, N., Daly, T. J., Davis, S., Sato, T. N., and Yancopoulos, G. D. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997; 277: 55–60.CrossRefPubMedGoogle Scholar
  50. 50.
    Hanahan, D. Signaling vascular morphogenesis and maintenance. Science 1997; 277: 48–50.CrossRefPubMedGoogle Scholar
  51. 51.
    Thurston, G., Suri, C., Smith, K., McClain, J., Sato, T. N., Yancopoulos, G. D., and McDonald, D. M. Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 1999; 286: 2511–4.CrossRefPubMedGoogle Scholar
  52. 52.
    Brown, L. F., Dezube, B. J., Tognazzi, K., Dvorak, H. F., and Yancopoulos, G. D. Expression of Tiel, Tie2, and angiopoietins 1,2 and 4 in Kaposi’s sarcoma and cutaneous angiosarcoma. Am J Pathol 2000; 156: 2179–83.CrossRefPubMedGoogle Scholar
  53. 53.
    Takahama, M., Tsutsumi, M., Tsujichi, T., Nezu, K., Kushibe, K., Taniguchi, S., Kotake, Y., and Konishi, Y. Enhanced expression of Tie2, its ligand angiopoietin-1, vascular endothelial growth factor, and CD31 in human non-small cell lung carcinomas. Clin Cancer Res 1999; 5: 2506–10.PubMedGoogle Scholar
  54. 54.
    Gerwins, P., Skoldenberg, E., and Claesson-Welsh, L. Function of fibroblast growth factors and vascular endothelial growth factors and their receptors in angiogenesis. Crit Rev Oncol Hematol 2000; 34: 185–94.CrossRefPubMedGoogle Scholar
  55. 55.
    Clark, J. L., Jones, K. I., Gospodarowicz, D., and Sato, G. H. Growth response to hormones by a new rat ovary cell line. Nat New Biol 1972; 236: 180–1.CrossRefPubMedGoogle Scholar
  56. 56.
    Armelin, H. A. Pituitary extracts and steroid hormones in the control of 3T3 cell growth. Proc Natl Acad Sci USA 1973; 70: 2702–6.CrossRefPubMedGoogle Scholar
  57. 57.
    Gospodarowicz, D. Purification of a fibroblast growth factor from bovine pituitary. J Biol Chem 1975; 250: 2515–20.PubMedGoogle Scholar
  58. 58.
    Healy, A. M. and Herman, I. M. Density-dependent accumulation of basic fibroblast growth factor in the subendothelial matrix. Eur J Cell Bio 1992; 59 56–67.Google Scholar
  59. 59.
    Moscatelli, D., Presta, M., and Rifkin, D. B. Purification of a factor from human placenta that stimulates capillary endothelial cell protease production, DNA synthesis and migration. Proceedings of the National Academy of Science U.S.A. 1986; 83: 2091–5.CrossRefGoogle Scholar
  60. 60.
    Basilico, C. and Moscatelli, D. The FGF family of growth factors and oncogenes. Advances in Cancer Research 1992; 59: 115–65.CrossRefPubMedGoogle Scholar
  61. 61.
    Takahashi, K., Mulliken, J. B., Koszkewich, H. P., Rogers, R. A., Folkman, J., and Ezekowitz, R. A. B. Cellular markers that distinguish the phases of hemangioma during infancy and childhood. J Clin Invest 1994; 93: 2357–64.CrossRefPubMedGoogle Scholar
  62. 62.
    Barton, D. P., Cai, A., Wendt, K., Young, M., Gamero, A., and DeCesare, S. Angiogenic protein expression in advanced epithelial ovarian cancer. Clin Cancer Res 1997; 3: 157986.Google Scholar
  63. 63.
    Crickard, K., Gross, J. L., Crickard, U., Yoonessi, M., Lele, S., Herblin, W. F., and Eidsvoog, K. Basic fibroblast growth factor and receptor expression in human ovarian cancer. Gynecol Oncol 1994; 55: 277–84.CrossRefPubMedGoogle Scholar
  64. 64.
    Nguyen, M., Watanabe, H., Budson, A. E., Richie, J. P., Hayes, D. F., and Folkman, J. Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancers. J Natl Cancer Inst 1994; 86: 356–361.CrossRefPubMedGoogle Scholar
  65. 65.
    Lewis, C. E., Leek, R., Hams, A., and McGee, J. O. Cytokine regulation of angiogenesis in breast cancer: the role of tumor-associated macrophages. J. Leukoc Biol 1995; 57: 747–51.PubMedGoogle Scholar
  66. 66.
    Dinney, C. P., Bielenberg, D. R., Perrotte, P., Reich, R., Eve, B. Y., Bucana, C. D., and Fidler, I. J. Inhibition of basic fibroblast growth factor expression, angiogenesis, and growth of human bladder carcinoma in mice by systemic interferon-alpha administration. Cancer Res 1998; 58: 808–14.PubMedGoogle Scholar
  67. 67.
    DiPietro, L. A., Nebgen, D. R., and Pelverini, P. J. Downregulation of endothelial cell thrombospondin 1 enhances in vitro angiogenesis. J Vasc Res 1994; 31: 178–85.CrossRefPubMedGoogle Scholar
  68. 68.
    Kanda, S., Shono, T., Tomasini-Johansson, B., Klint, P., and Saito, Y. Role of thrombospondin-l-derived peptide, 4NIK, in FGF-2-induced angiogenesis. Exp Cell Res 1999; 252: 262–72.CrossRefPubMedGoogle Scholar
  69. 69.
    Rosen, E. M. and Goldberg, I. D. Regulation of angiogenesis by scatter factor. Exs 1997; 79: 193–208.PubMedGoogle Scholar
  70. 70.
    Corps, A. N., Sowter, H. M., and Smith, S. K. Hepatocyte growth factor stimulates motility, chemotaxis and mitogenesis in ovarian carcinoma cells expressing high levels of c-met. Int J Cancer 1997; 73: 151–5.CrossRefPubMedGoogle Scholar
  71. 71.
    Sowter, H. M., Corps, A. N., and Smith, S. K. Hepatocyte growth factor (HGF) in ovarian epithelial tumour fluids stimulates the migration of ovarian carcinoma cells. Int J Cancer 1999; 83: 476–80.CrossRefPubMedGoogle Scholar
  72. 72.
    Wong, A. S., Leung, P. C., and Auersperg, N. Hepatocyte growth factor promotes in vitro scattering and morphogenesis of human cervical carcinoma cells. Gynecol Oncol 2000; 78: 158–65.CrossRefPubMedGoogle Scholar
  73. 73.
    Ueoka, Y., Kato, K., Kuriaki, Y., Horiuch, S., Terao, Y., Nishida, J., Ueno, H., and Wake, N. Hepatocyte growth factor modulates motility and invasiveness of ovarian carcinomas via Ras-mediated pathway. Br J Cancer 2000; 82 891–9.CrossRefPubMedGoogle Scholar
  74. 74.
    Dameron, K. M., Volpert, O. V.,., Tainsky, M. A., and Bouck, N. Control of Angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 1994; 265: 1582–1584.Google Scholar
  75. 75.
    Siemeister, G., Weindel, K., Mohrs, K., Barleon, B., Martiny-Baron, G., and Manne, D. Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel-Lindau tumor suppressor protein. Cancer Res 1996; 56: 2299–01.PubMedGoogle Scholar
  76. 76.
    Wizigmann-Voos, S., Breier, G., Risau, W., and Plate, K. H. Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas. Cancer Res 1995; 55: 1358–64.PubMedGoogle Scholar
  77. 77.
    Rak, J., Mitsuhashi, Y., Sheehan, C., Tamir, A., Viloria-Petit, A., Filmus, J., Mansour, S. J., Ahn, N. G., and Kerbel, R. S. Oncogenes and tumor angiogenesis: differential modes of vascular endothelial growth factor up-regulation in ras-transformed epithelial cells and fibroblasts. Cancer Res 2000; 60: 490–8.PubMedGoogle Scholar
  78. 78.
    Ferrara, N., Clapp, C., and Weiner, R. The 16K fragment of prolactin specifically inhibits basal or fibroblast growth factor stimulated growth of capillary endothelial cells. Endocrinol 1991; 129: 896–900.CrossRefGoogle Scholar
  79. 79.
    Clapp, C., Martial, J. A., Guzman, R. C., Rentier-Delure, F., and Weiner, R. I. The 16kilodalton N-terminal fragment of human prolactin is a potent inhibitor of angiogenesis. Endocrinol 1993; 133: 1292–9.CrossRefGoogle Scholar
  80. 80.
    O’Reilly, M. S. and Holmgren, L. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994; 79: 315–328.CrossRefPubMedGoogle Scholar
  81. 81.
    O’Reilly, M. S., Boehm, T., Shing, Y., Fuhai, N., Vasios, G., Lane, W. S., Flynn, E., Birkhead, J. R., Olsen, B. R., and Folkman, J. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997; 88: 277–285.CrossRefPubMedGoogle Scholar
  82. 82.
    Lucas, R., Holmgren, L., Garcia, I., Jimenez, B., Mandriota, S. J., Borlat, F., Sim, B. K., Wu, Z., Grau, G. E., Shing, Y., Soff, G. A., Bouck, N., and Pepper, M. S. Multiple forms of angiostatin induce apoptosis in endothelial cells. Blood 1998; 92: 4730–41.PubMedGoogle Scholar
  83. 83.
    Hohenester, E., Sasaki, T., Olsen, B. R., and Timpl, R. Crystal structure of the angiogenesis inhibitor endostatin at 1.5 A resolution. EMBO 1998; 17: 1656–64.CrossRefGoogle Scholar
  84. 84.
    Yokoyama, Y., Dhanabal, M., Griffioen, A. W., Sukhatme, V. P., and Ramakrishnan, S. Synergy between angiostatin and endostatin: inhibition of ovarian cancer growth. Cancer Res 2000; 60: 2190–2196.PubMedGoogle Scholar
  85. 85.
    Chang, Z., Choon, A., and Friedl, A. Endostatin binds to blood vessels in situ independent of heparan sulfate and does not compete for fibroblast growth factor-2 binding. Am J Path 1999; 155: 71–6.CrossRefPubMedGoogle Scholar
  86. 86.
    Gorski, D. H., Mauceri, H. J., Salloum, R. M., Gately, S., Hellman, S., Beckett, M. A., Sukhatme, V. P., Soff, G. A., Kufe, D. W., and Weichselbaum, R. R. Potentiation of the antitumor effect of ionizing radiation by brief concomitant exposures to angiostatin. Cancer Res 1998; 58: 5686–9.PubMedGoogle Scholar
  87. 87.
    Mauceri, H. J., Hanna, N. N., Beckett, M. A., Gorski, D. H., Staba, M. J., Stellato, K. A., Bigelow, K., Heimann, R., Gately, S., Dhanabal, M., Soff, G. A., Sukhatme, V. P., Kufe, D. W., and Weichselbaum, R. R. Combined effects of angiostatin and ionizing radiation in antitumour therapy. Nature 1998; 394: 287–91.CrossRefPubMedGoogle Scholar
  88. 88.
    Pike, S. E., Yao, L., Jones, K. D., Chemey, B., Appella, E., Sakaguchi, K., Nakhasi, H., Teruya-Feldstein, J., Wirth, P., Gupta, G., and Tosato, G. Vasostatin, a calreticulin fragment, inhibits angiogenesis and supports tumor growth. J Exp Med 1998; 188: 234956.Google Scholar
  89. 89.
    Dupont, E., Savard, P. E., Jourdain, C., Juneau, C., Thibodeau, A., Ross, N., Marenus, K., Macs, D. H., Pelletier, G., and Sauder, D. N. Antiangiogenic properties of a novel shark cartilage extract: potential role in the treatment of psoriasis. J Cutan Med Surg 1998; 2: 146–52.PubMedGoogle Scholar
  90. 90.
    Wojtowicz-Praga, S. Clinical potential of matrix metalloprotease inhibitors. Drugs R D 1999; 1: 117–29.CrossRefPubMedGoogle Scholar
  91. 91.
    Laird, A. D., Vajkoczy, P., Shawver, L. K., Thumher, A., Liang, C., Mohammadi, M., Schlessinger, J., Ullrich, A., Hubbard, S. R., Blake, R. A., Fong, T. A., Strawn, L. M., Sun, L., Tang, C., Hawtin, R., Tang, F., Shenoy, N., Hirth, K. P., McMahon, G., and Cherington, J. M. SU6668 is a potent antiangiogenic and antitumor agent that induces tumor regression of established tumors. Cancer Res 2000; 60: 4152–60.PubMedGoogle Scholar
  92. 92.
    Strawn, L. M., Kabbinavar, F., Schwartz, D. P., Mann, E., Shawver, L. K., Slamon, D. J., and Cherington, J. M. Effects of SU101 in combination with cytotoxic agents on the growth of subcutaneous tumor xenografts. Clin Cancer Res 2000; 6: 2931–4.PubMedGoogle Scholar
  93. 93.
    Ciardiello, F., Caputo, R., Bianco, R., Damiano, V., Pomatico, G., DePlacido, S., Bianco, A. R., and Tortora, G. Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 2000; 6: 2053–63.PubMedGoogle Scholar
  94. 94.
    Gore, M., A’Hern, R., Stankiewicz, M., and Slevin, M. Tumour marker levels during marimastat therapy. Lancet 1996; 348: 263–264.CrossRefPubMedGoogle Scholar
  95. 95.
    Shalinsky, D. R., Brekken, J., Zou, H., McDermott, C. D., Forsyth, P., Edwards, D., Margosiak, S., Bender, S., Truitt, G., Wood, A., Varki, N. M., and Appelt, K. Broad antitumor and antiangiogenic activities of AG3340, a potent and selective MMP inhibitor undergoing advanced oncology clinical trials. Ann N Y Acad Sci 1999; 878: 236–70.CrossRefPubMedGoogle Scholar
  96. 96.
    Heath, E. I. and Grochow, L. B. Clinical potential of matrix metalloprotease inhibitors in cancer therapy. Drugs 2000; 59: 1043–55.CrossRefPubMedGoogle Scholar
  97. 97.
    Akhter, S., Nath, S. K., Tse, C. M., Williams, J., Zasloff, M., and Donowitz, M. Squalamine, a novel cationic steroid, specifically inhibits the brush-border Na+/H+ exchanger isoform NHE3. Am J Physiol 1999; 276: C136–44.PubMedGoogle Scholar
  98. 98.
    Kohn, E. C., Alessandro, R., Spoonster, J., Wersto, R. P., and Liotta, L. A. Angiogenesis: role of calcium-mediated signal transduction. Proc. Natl. Acad. Sci. USA. 1995; 92: 1307 1311.Google Scholar
  99. 99.
    Brew, K., Dinakarpandian, D., and Nagase, H. Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta 2000; 1477: 267–83.CrossRefPubMedGoogle Scholar
  100. 100.
    Baselga, J., Pfister, D., Cooper, M. R., Cohen, R., Burtness, B., Bos, M., D’Andrea, G., Seidman, A., Norton, L., Gunnett, K., Falcey, J., Anderson, V., Waksal, H., and Mendelsohn, J. Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin, J Clin Oncol 2000; 18: 904–14.PubMedGoogle Scholar
  101. 101.
    Brooks, P. C., Clark, R. A. F., and Cheresh, D. A. Requirement of vascular integrin avb3 for angiogenesis. Science 1994; 264: 569–571.CrossRefPubMedGoogle Scholar
  102. 102.
    Klauber, N., Parangi, S., Flynn, E., Hamel, E., and D’Amato, R. J. Inhibition of angiogenesis and breast cancer in mice by the microtubule inhibitors 2-methoxyestradiol and taxol. Cancer Res 1997; 57: 81–6.PubMedGoogle Scholar
  103. 103.
    Sills, A. K., Williams, J. I., Tyler, B. M., Epstein, D. S., Sipos, E. P., Davis, J. D., McLane, M. P., Pitchford, S., Cheshire, K., Gannon, F. H., Kinney, W. A., Chao, T. L., Donowitz, M., Laterra, J., Zasloff, M., and Brem, H. Squalamine inhibits angiogenesis and solid tumor growth in vivo and perturbs embryonic vasculature. Cancer Res 1998; 58: 2784–2792.PubMedGoogle Scholar
  104. 104.
    Ohene-Abuakwa, Y. and Pignatelli, M. Adhesion molecules in cancer biology. Adv Exp Med Biol 2000; 465: 115–26.CrossRefPubMedGoogle Scholar
  105. 105.
    Aberle, H., Schwartz, H., and Kemler, R. Cadherin-catenin complex: protein interactions and their implications for cadherin function. J Cell Biochem 1996; 61: 514–23.CrossRefPubMedGoogle Scholar
  106. 106.
    Jou, T. S., Stewart, D. B., Stappert, J., Nelseon, W. J., and Marrs, J. A. Genetic and biochemical dissection of protein linkages in the cadherin-catenin complex. Proc. Natl. Acad.Sci. U.S.A. 1995; 92: 5067–5071.CrossRefPubMedGoogle Scholar
  107. 107.
    Caveda, L., Martin-Padura, I., Navarro, P., Breviario, F., Corada, M., Gulino, D., Lampugnani, M. G., and Dejana, E. Inhibition of cultured cell growth by vascular endothelial cadherin (cadherin-SNE-cadherin). J Clin Invest 1996; 98: 886–92.CrossRefPubMedGoogle Scholar
  108. 108.
    Vittet, D., Buchou, T., Schweitzer, A., Dejana, E., and Huber, P. Targeted null-mutation in the vascular endothelial-cadherin gene impairs the organization of vascular-like structures in embryoid bodies. Proceedings of the National Academy of Sciences U.S.A. 1997; 94: 6273–8.CrossRefGoogle Scholar
  109. 109.
    Hoffman, A. G., Burghardt, R. C., Tilley, R., and Auersperg, N. An in vitro model of ovarian epithelial carcinogenesis: changes in cell-cell comunication and adhesion occurring during neoplastic progression. Int J Cancer 1993; 54: 828–838.CrossRefPubMedGoogle Scholar
  110. 110.
    Ahmad, A. and Hart, I. R. Mechanisms of metastasis, Crit Rev Oncol/Hematol 1997; 26: 163–73.CrossRefGoogle Scholar
  111. 111.
    Vleminckx, K., Vakaet, L., Marcel, M., Fiers, W., and van Roy, F. Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 1991; 66: 107–119.CrossRefPubMedGoogle Scholar
  112. 112.
    Sudfeldt, K., Piontkewitz, Y., Ivarsson, K., Nilsson, O., Hellberg, P., Brannstrom, M., Janson, P. 0., Enerback, S., and Hedin, L. E-cadherin expression in human epithelial ovarian cancer and normal ovary. Int J Cancer 1997; 74: 275–80.CrossRefGoogle Scholar
  113. 113.
    Auersperg, N., Pan, J., Grove, B. D., Peterson, T., Fisher, J., Maines-Bandiera, S., Somasiri, A., and Roskelley, C. D. E-cadherin induces mesenchymal-to-epithelial transition in human ovarian surface epithelium, Proc Natl Acad Sci USA. 1999; 96: 624954.Google Scholar
  114. 114.
    Veatch, A. L., Carson, L. F., and Ramakrishman, S. Differential expression of the cell-cell adhesion molecule E-cadherin in ascites and solid human ovarian tumor cells. Int J Cancer 1994; 58: 393–9.CrossRefPubMedGoogle Scholar
  115. 115.
    Gille, J. and Swerlick, R. A. Integrins: role in cell adhesion and communication., Ann N Y Acad Sci 1996; 797: 93–107.CrossRefPubMedGoogle Scholar
  116. 116.
    Varner, A. J. and Cheresh, D. A. Integrins and Cancer. Curr Opin Cel Biol 1996; 8: 724730.Google Scholar
  117. 117.
    Ruoslahti, E. and Reed, J. Anchorage independence, integrins and apoptosis. Cell 1994; 77: 477–478, 1994.CrossRefGoogle Scholar
  118. 118.
    Meredith, J. E. and Schwartz, M. Integrins, adhesion, and apoptosis. Trend Cell Biol 1997; 7: 146–150.CrossRefGoogle Scholar
  119. 119.
    Chicurel, M. E., Singer, R. H., Meyer, C. J., and Ingber, D. E. Integrin binding and mechanical tension induce movement of mRNA and ribosomes to focal adhesions. Nature 1998; 392: 730–733.CrossRefPubMedGoogle Scholar
  120. 120.
    Schwartz, M. A., Schaller, M. D., and Ginsberg, M. H. integrins: emerging paradigms of signal transduction. Ann Rev Cell Dev Biol 1995; 11: 549–599.CrossRefGoogle Scholar
  121. 121.
    Yamada, K. M. and Miyamoto, S. Integrin transmembrane signaling and cytoskeletal control. Curr Opin Cel Biol 1995; 7: 681–689.CrossRefGoogle Scholar
  122. 122.
    Giancotti, F. G. Integrin signaling: specificity and control of cell survival and cell cycle progression. Curr Opin Cel Biol 1997; 9: 691–700.CrossRefGoogle Scholar
  123. 123.
    Hynes, R. O. and Bader, B. L. Targeted mutations in integrins and their ligands: their implications for vascular biology. Thromb Haemost 1997; 78: 83–7.PubMedGoogle Scholar
  124. 124.
    Brooks, P. C., Stromblad, S., Klemke, R., Visscher, D., Sarkar, F. H., and Cheresh, D. A. Anti-integrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin. J Clin Invest 1995; 96: 1815–1822.CrossRefPubMedGoogle Scholar
  125. 125.
    Varner, J. A., Brooks, P. C., and Cheresh, D. A. The integrin avb3: angiogenesis and apoptosis. Cell Adhes Comm 1995; 3: 367–374.CrossRefGoogle Scholar
  126. 126.
    Cannistra, S. A., Ottensmeier, C., Niloff, J., Orta, B., and DiCarlo, J. Expression and function of beta 1 and alpha v beta 3 integrins in ovarian cancer. Gynecol Oncol 1995; 58: 216–225.CrossRefPubMedGoogle Scholar
  127. 127.
    Liapis, H., Adler, L. M., Wick, M. R., and Rader, J. S. Expression of alpha(v)beta3 integrin is less frequent in ovarian epithelial tumors of low malignant potential in contrast to ovarian carcinomas. Human Path 1997; 28: 443–449.CrossRefGoogle Scholar
  128. 128.
    Ingber, D. Extracellular matrix and cell shape: potential control points for inhibition of angiogenesis. J Cell Biochem 1991; 47: 236–41.CrossRefPubMedGoogle Scholar
  129. 129.
    Nelson, A. R., Fingleton, B., Rothenberg, M. L., and Matrisian, L. M. Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol 2000, 18: 1135–49.PubMedGoogle Scholar
  130. 130.
    DeClerck, Y. A. Interactions between tumour cells and stromal cells and proteolytic modification of the extracellular matrix by metalloproteinases in cancer. Eur J Cancer 2000; 36: 1258–68.CrossRefPubMedGoogle Scholar
  131. 131.
    Haas, T. L. and Madri, J. A. Extracellular matrix-driven matrix metalloproteinase production in endothelial cells: implications for angiogenesis. Trends Cardiovasc Med 1999; 9: 70–7.CrossRefPubMedGoogle Scholar
  132. 132.
    Haas, T. L., Davis, S. J., and Madri, J. A. Three dimensional type I collagen lattices induce coordinate expression of matrix metalloproteinases MTl-MMP and MMP-2 in microvascular endothelial cells. J Biol Chem 1998; 273: 3604–10.CrossRefPubMedGoogle Scholar
  133. 133.
    Galardy, R., Grobelney, D., Foellmer, H. G., and Fernandez, L. A. Inhibition of angiogenesis by the matrix metalloprotease inhibitor N-12R-2- (hydroxamidocarbonymethyl)-4 methylpentanoyl)]-L-tryptophan methylamide. Cancer Res 1994; 54: 4715–4718.PubMedGoogle Scholar
  134. 134.
    Wojtowicz-Praga, S. M., Dickson, R. B., and Hawkins, M. J. Matrix metalloproteinase inhibitors. Invest New Drugs 1997; 15: 61–75.CrossRefPubMedGoogle Scholar
  135. 135.
    Itoh, T., Tanioka, M., Yoshida, H., Yoshida, T., Nishimoto, H., and Itohara, S. Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res 1998; 58: 1048–51.PubMedGoogle Scholar
  136. 136.
    Vu, T. H., Shipley, J. M., Bergers, G., Berger, J. E., Helms, J. A., Hanahan, D., Shapiro, S. D., Senior, R. M., and Werb, Z. MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 1998; 93: 411–422.CrossRefPubMedGoogle Scholar
  137. 137.
    Liotta, L. A. and Stetler-Stevenson, W. G. Tumor invasion and metastasis: an imbalance of positive and negative regulation. Cancer Res 1991; 51: 5054–5059.Google Scholar
  138. 138.
    Coussens, L. M. and Werb, Z. Matrix metalloproteinases and the development of cancer. Chem Biol 1996; 3: 895–904.CrossRefPubMedGoogle Scholar
  139. 139.
    Stack, M. S., Ellerbroek, S. M., and Fishman, D. A. The role of protolytic enzymes in the pathology of epithelial ovarian carcinoma. Int. J Oncol 1998; 12: 569–76.PubMedGoogle Scholar
  140. 140.
    Kohn, E. C., Francis, A., Liotta, L. A., and Schiffmann, E. Heterogeneity of the motility responses in malignant tumor cells: a biological basis for the diversity and homing of metastatic cells. Int J Cancer 1990; 46: 287.CrossRefPubMedGoogle Scholar
  141. 141.
    Fishman, D., Bafetti, L. M., Banionis, S., Kearns, A. S., Chilukuri, K., and Stack, M. S. Production of extracellular matrix-degrading proteinases by primary cultures of human epithelial ovarian carcinoma cells. Cancer 1997; 80: 1457–1463.CrossRefPubMedGoogle Scholar
  142. 142.
    Young, T. N., Rodriguez, G. C., Rinehart, A. R., Bast, R. C., Pizzo, S. V., and Stack, M. S. Characterization of gelatinases linked to extracellular matrix invasion in ovarian adenocarcinoma: purification of matrix metalloproteinase 2. Gynecol Oncol 1996; 62: 8999.CrossRefGoogle Scholar
  143. 143.
    Naylor, M. S., Stamp, G. W., Davies, B., and Balkwill, F. R. Expression and activity of MMPs and their regulators in ovarian cancer. Int J Cancer 1994; 58: 50–56.CrossRefPubMedGoogle Scholar
  144. 144.
    Liebman, J. M., Burbelo, P. D., Yamada, Y., Fridman, R., and Kleinman, H. K. Altered expression of basement membrane components and collagenases in ascitic xenografts of OVCAR-3 ovarian cancer cells. Int J Cancer 1993; 55: 102–9.CrossRefPubMedGoogle Scholar
  145. 145.
    Ellerbroek, S. M., Fishman, D. A., Kearns, A. S., Bafetti, L. M., and Stack, M. S. Ovarian carcinoma regulation of matrix metaloproteinase-2 and membrane type 1 matrix metaloproteinase through beta 1 integrin, Cancer Res 1999; 59: 1635–1641.PubMedGoogle Scholar
  146. 146.
    Campo, E., Merino, M. J., Tavassoli, F. A., Charonis, A. S., Stetler-Stevenson, W. G., and Liotta, L. A. Evaluation of basement membrane components and the 72 KDa Type IV collagenase in serous tumors of the ovary. The American Journal of Surgical Pathology 1992; 16: 500–507.CrossRefPubMedGoogle Scholar
  147. 147.
    DeNictolis, M., Garbisa, S., Lucarini, G., Goteri, G., Masiero, L., Ciavattini, A., Garzetti, G. G., Stetler-Stevenson, W. G., Fabris, G., Biagini, G., and Prat, J. 72 kilodalton type IV collagenase, type IV collagen and Ki-67 antigen in serous tumors of the ovary: a clinicopathologic, immunohistochemical and serological study. Int J Gynecol Path 1996 15: 1996.Google Scholar
  148. 148.
    Autio-Harmainen, H., Kaurunen, T., Hurskainen, T., Hoyhtya, M., Kauppila, A., and Tryggvason, K. Expression of 72 kDA type IV collagenase (gelatinase A) in benign and malignant ovarian tumors. Lab Invest 1993; 69: 312–21.PubMedGoogle Scholar
  149. 149.
    Afzal, S., Lalani, E., Foulkes, W. D., Boyce, B., Tickle, S., Cardillo, M. R., Baker, T., Pignatelli, M., and Stamp, G. W. Matrix metalloproteinase-2 and tissue inhibitor of maetalloproteinase-2 expression and syntehtic matrix metalloproteinase-2 inhibitor binding in ovarian carcinomas and tumor cell lines. Lab Invest 1996; 74: 406–421.PubMedGoogle Scholar
  150. 150.
    Garzetti, G. G., Ciavattin, A., Lucarini, G., Goteri, G., Romanini, C., and Biagini, G. Increased serum 72 kDa metalloproteinase in serous ovarian tumors: comparison with CA 125. Anticancer Res 1996; 16.Google Scholar
  151. 151.
    Davies, B., Brown, P. D., N, E., J, C. M., and Blakwill, F. R. A synthetic matrix metalloproteinase inhibitor decreases tumor burden and prolongs survival of mice bearing human ovarian carcinoma xenografts. Cancer Res 1993; 194: 2087–2091.Google Scholar
  152. 152.
    Beattie, G. J. and Smyth, J. F. Phase I study of intraperitoneal metalloproteinase inhibitor BB94 in patients with malignant ascites. Clin Cancer Res 1998; 4.Google Scholar
  153. 153.
    Parsons, S. L., Watson, S. A., and Steele, R. J. Phase I/I1 trial of batimastat, a matrix metalloproteinase inhibitor, in patients with malignant ascites. European Journal of Surgical Cancer 1997; 23: 526–31.Google Scholar
  154. 154.
    Nagase, H. and Woessner, J. F. Matrix metalloproteinases. J Biol Chem 1999; 274: 214912 1494.Google Scholar
  155. 155.
    Gomez, D. E., Alonso, D. F., Yoshiji, H., and Thorgeirsson, U. P. Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol 1997; 74: 111–122.PubMedGoogle Scholar
  156. 156.
    Corcoran, M. L., Kleiner, D. E., and Stetler-Stevenson, W. G. Regulation of matrix metalloproteinases during extracellular matrix turnover. Adv Exp Med Biol 1995; 385: 151–9.PubMedGoogle Scholar
  157. 157.
    Schnaper, H. W., Grant, D. S., Stetler-Stevenson, W. G., Fridman, R., D’Orazi, G., Murphy, A. N., Bird, R. E., Hoythya, M., Fuerst, T. R., and French, D. L. Type IV collagenase(s) and TIMPs modulate endothelial cell morphogenesis in vitro. Journal of Cell Physiology 1993; 156: 235–46.CrossRefGoogle Scholar
  158. 158.
    Murphy, A. N., Unsworth, E. J., and Stetler-Stevenson, W. G. Tissue inhibitor of metalloproteinases-2 inhibits bFGF-induced human microvascular endothelial cell proliferation. J Cell Physiol 1993; 157: 351–358.CrossRefPubMedGoogle Scholar
  159. 159.
    Lamoreaux, W. J., Fitzgerald, M. E., Reiner, A., Hasty, K. A., and Charles, S. T. Vascular endothelial growth factor increases release of gelatinase A and decreases release of tissue inhibitor of metalloproteinases by microvascular endothelial cells in vitro. Microvasc Res 1998; 55: 29–42.CrossRefPubMedGoogle Scholar
  160. 160.
    Moser, T. L., Young, T. N., and Rodriguez, G. C. Secretion of extracellular matrix-degrading proteinases is increased in epithelial ovarian carcinoma. Int J Cancer 1994; 56: 552–559.CrossRefPubMedGoogle Scholar
  161. 161.
    Takemura, M., Azuma, C., Kimura, T., Kanai, T., Saji, F., and Tanizawa, O. Type-IV collagenase and tissue inhibitor of metalloproteinase in ovarian cancer tissues. Int J Gynaecol Obstet 1994; 46: 303–9.CrossRefPubMedGoogle Scholar
  162. 162.
    Mignatti, P. and Rifkin, D. B. Plasminogen activators and matrix metalloproteinases in angiogenesis. Enzyme Protein 1996; 49: 117–37.PubMedGoogle Scholar
  163. 163.
    Andreasen, P. A., Kjoller, L., Christensen, L., and Duffy, M. J. The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 1997; 72: 1–22.Google Scholar
  164. 164.
    Conese, M. and Blasi, F. The urokinase/urokinase-receptor system and cancer invasion. Baillieres Clin Haemat 1995; 8: 365–389.CrossRefGoogle Scholar
  165. 165.
    Karlan, B. Y., Amin, W., Band, V., Zurawski, V. R., and Littlefield, B. A. Plasminogen activator secretion by established lines of human ovarian carcinoma cells in vitro. Gynecol Oncol 1988; 31: 103–12.CrossRefPubMedGoogle Scholar
  166. 166.
    Schmitt, M., Wilhelm, O., Janicke, F., Magdolen, V., Reuning, U., Ohi, H., Moniwa, N., Kobayashi, H., Weidle, U., and Graeff, H. Urokinase-type plasminogen activator (uPA) and its receptor (CD87): a new target in tumor invasion and metastasis. J Obstet Gynaecol 1995; 21: 151–165.Google Scholar
  167. 167.
    Pedersen, H., Brunner, N., Francis, D., Osterlind, K., Ronne, E., Hansen, H. H., Dano, K., and Grondahl-Hansen, J. Prognostic impact of urokinase, urokinase receptor, and type 1 plasminogen activator inhibitor in squamous and large cell lung cancer tissue. Cancer Res 1994; 54: 4671–4675.PubMedGoogle Scholar
  168. 168.
    Pujade-Lauraine, H., Lu, H., Mirshahi, S., Soria, J., Soria, C., Bemadou, A., Kruithof, E. K. O., Lijnen, H. R., and Burtin, P. The plasminogen activation system in ovarian tumors. Int J Cancer 1993; 55: 27–31.CrossRefPubMedGoogle Scholar
  169. 169.
    Ho, C. H., Yuan, C. C., and Liu, S. M. Diagnostic and prognostic values of plasma levels of fibrinolytic markers in ovarian cancer. Gynecol Oncol 1999; 75: 397–400.CrossRefPubMedGoogle Scholar
  170. 170.
    Kuhn, W., Schmalfeldt, B., Reuning, U., Pache, L., Berger, U., Ulm, K., Harbeck, N., Spathe, K., Dettmar, P., Hofler, H., Janicke, F., Schmitt, M., and Graeff, H. Prognostic significance of urokinase (uPA) and its inhibitor PAI-1 for survival in advanced ovarian carcinoma stage FIGO IIIc. Br J Cancer 1999; 79: 1746–51.CrossRefPubMedGoogle Scholar
  171. 171.
    Abendstein, B., Daxenbichler, G., Windbichler, G., Zeimet, A. G., Geurts, A., Sweep, F., and Marth, C. Predictive value of uPA, PAI-1, HER-2, and VEGF in the serum of ovarian cancer patients. Anticancer Res 2000; 20: 569–72.PubMedGoogle Scholar
  172. 172.
    Hoffmann, G., Pollow, K., Weikel, W., Strittmatter, H. J., Bach, J., Schaffrath, M., Knapstein, P., Melchert, F., and Pollow, B. Urokinase and plasminogen activator-inhibitor (PAI-1) status in primary ovarian carcinomas and ovarian metastases compared to benign ovarian tumors as a funcion of histopathological parameters. Clin Chem Lab Med 1999; 37: 47–54.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Gregory J. Sieczkiewicz
    • 1
  • Mahrukh Hussain
    • 1
  • Elise C. Kohn
    • 1
  1. 1.Molecular Signaling Section, Laboratory of PathologyNational Cancer InstituteBethesdaUSA

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