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Angiogenesis, Metastasis, and Endogenous Inhibition

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Abstract

Angiogenesis and the development of metastases are intrinsically connected. Experimental data suggest that establishment and growth of metastases are influenced by soluble factors secreted from the originating solid tumor. Among these factors are so-called endogenous inhibitors of angiogenesis which keep metastasis in a non-proliferating quiescent state. For a number of tumors it has been shown that this dormant state is mediated through inhibition of angiogenesis. This dormant state is characterized by normal proliferation, increased apoptosis, and insufficient neovascularization. Removal of inhibiting anti-angiogenic factors led to growth of dormant metastases. A number of endogenous inhibitors have been identified and have shown success in experimental therapeutic trials. This might be of special interest for the treatment of cerebral metastases which are the most common type of malignant brain tumors. Similar to the spread of metastases, it is known that single glioma cells can be found in distant parts of the brain. While local recurrence is a common phenomenon in glioma, formation of clinical apparent distant metastasis occurs rarely. Several lines of evidence suggest that growth inhibition of remote glioma cells may be mediated by an endogenous inhibitory mechanism.

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References

  1. Algire GH: The Biology of Melanomas. New York Academy of Science, New York, 1947

    Google Scholar 

  2. Ambs S, Dennis S, Fairman J, Wright M, Papkoff J: Inhibition of tumor growth correlates with the expression level of a human angiostatin transgene in transfected B16F10 melanoma cells. Cancer Res 59: 5773-5777, 1999

    Google Scholar 

  3. Black PM: Brain Tumors. Part I. New England J Med 324: 1471-1476, 1991

    Google Scholar 

  4. Black PM: Brain Tumors. Part II. New England J Med 324: 1555-1564, 1991

    Google Scholar 

  5. Blezinger P, Wang J, Gondo M, Quezada A, Mehrens D, French M, Singhal A, Sullivan S, Rolland A, Ralston R, Min W: Systemic inhibition of tumor growth and tumor metastases by intramuscular administration of the endostatin gene. Nat Biotechnol 17: 343-348, 1999

    Google Scholar 

  6. Braun S, Pantel K: Micrometastatic bone marrow involvement: detection and prognostic significance. Med Oncol 16: 154-165, 1999

    Google Scholar 

  7. Brem S, Brem H, Folkman J, Finkelstein D, Patz A: Prolonged tumor dormancy by prevention of neovascularization in the vitreous. Cancer Res 36: 2807-2812, 1976

    Google Scholar 

  8. Burger PC, Heinz ER, Shibata T, Kleihues P: Topographic anatomy and CT correlations in the untreated glioblastoma multiforme. J Neurosurg 68: 698-704, 1988

    Google Scholar 

  9. Burger PC, Vollmer RT: Histologic factors of prognostic significance in the glioblastoma multiforme. Cancer 46: 1179-1186, 1980

    Google Scholar 

  10. Cao Y, O'Reilly MS, Marshall B, Flynn E, Ji RW, Folkman J: Expression of angiostatin cDNA in a murine fibrosarcoma suppresses primary tumor growth and produces long-term dormancy of metastases (published erratum appears in J Clin Invest 1998 December 1; 102(11): 2031). J Clin Invest 101: 1055-1063, 1998

    Google Scholar 

  11. Chen QR, Kumar D, Stass SA, Mixson AJ: Liposomes complexed to plasmids encoding angiostatin and endostatin inhibit breast cancer in nude mice. Cancer Res 59: 3308-3312, 1999

    Google Scholar 

  12. Chicoine MR, Silbergeld DL: Assessment of brain tumor cell motility in vivo and in vitro. J Neurosurg 82: 615-622, 1995

    Google Scholar 

  13. Chicoine MR, Silbergeld DL: Invading C6 glioma cells maintaining tumorigenicity. J Neurosurg 83: 665-671, 1995

    Google Scholar 

  14. Crowley NJ, Seigler HF: Relationship between disease-free interval and survival in patients with recurrent melanoma. Arch Surg 127: 1303-1308, 1992

    Google Scholar 

  15. Demicheli R, Abbattista A, Miceli R, Valagussa P, Bonadonna G: Time distribution of the recurrence risk for breast cancer patients undergoing mastectomy: further support about the concept of tumor dormancy. Breast Cancer Res Treat 41: 177-185, 1996

    Google Scholar 

  16. Demicheli R, Terenziani M, Valagussa P, Moliterni A, Zambetti M, Bonadonna G: Local recurrences following mastectomy: support for the concept of tumor dormancy. J Natl Cancer Inst 86: 45-48, 1994

    Google Scholar 

  17. Dhanabal M, Ramchandran R, Waterman MJ, Lu H, Knebelmann B, SegalM, Sukhatme VP: Endostatin induces endothelial cell apoptosis. J Biol Chem 274: 11721-11726, 1999

    Google Scholar 

  18. Dhanabal M, Volk R, Ramchandran R, Simons M, Sukhatme VP: Cloning, expression, and in vitro activity of human endostatin. Biochem Biophys Res Commun 258: 345-352, 1999

    Google Scholar 

  19. Dong Z, Kumar R, Yang X, Fidler IJ: Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma. Cell 88: 801-810, 1997

    Google Scholar 

  20. Dong Z, Yoneda J, Kumar R, Fidler IJ: Angiostatin-mediated suppression of cancer metastases by primary neoplasms engineered to produce granulocyte/macrophage colonystimulating factor. J Exp Med 188: 755-763, 1998

    Google Scholar 

  21. Ellis LM, Fidler IJ: Angiogenesis and metastasis. Eur J Cancer 32A: 2451-2460, 1996

    Google Scholar 

  22. Ewing J: Neoplastic diseases. W.B. Saunders Co., Philadelphia, 1928

    Google Scholar 

  23. Fan D, Price J, Schackert H, Seid C, Wilmanns C, Chakrabarty S, Fidler IJ: Antiproliferative activity of liposome-encapsulated transforming growth factor-beta against MDA-MB-435 human breast carcinoma cells. Cancer Commun 1: 337-343, 1989

    Google Scholar 

  24. Feldman AL, Restifo NP, Alexander HR, Bartlett DL, Hwu P, Seth P, Libutti SK: Antiangiogenic gene therapy of cancer utilizing a recombinant adenovirus to elevate systemic endostatin levels in mice. Cancer Res 60: 1503-1506, 2000

    Google Scholar 

  25. Fidler IJ: Metastasis: quantitative analysis of distribution and fate of tumor cell emboli labeled with 125I-5-iododeoxyuridine. J Natl Cancer Inst 45: 773-782, 1970

    Google Scholar 

  26. Fidler IJ: Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res 50: 6130-6138, 1990

    Google Scholar 

  27. Folkman J: Tumor angiogenesis: Therapeutic implications. J Exp Med 133: 275-288, 1971

    Google Scholar 

  28. Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1: 27-31, 1995

    Google Scholar 

  29. Folkman J: Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. New England J Med 333: 1757-1763, 1995

    Google Scholar 

  30. Folkman J, Cole P, Zimmerman S: Tumor behavior in isolated perfused organs: in vitro growth and metastases of biopsy material in rabbit thyroid and canine intestinal segment. Ann Surg 164: 491-502, 1966

    Google Scholar 

  31. Folkman J, Shing Y: Angiogenesis. J Biol Chem 267: 10931-10934, 1992

    Google Scholar 

  32. Frank S, Muller J, Bonk C, Haroske G, Schackert HK, Schackert G: Transmission of glioblastoma multiforme through liver transplantation. Lancet 352: 31, 1998

    Google Scholar 

  33. FujiiY, Fukui I, Kihara K, Tsujii T, KageyamaY, Oshima H: Late recurrence and progression after a long tumor-free period in primary Ta and T1 bladder cancer. Eur Urol 36: 309-313, 1999

    Google Scholar 

  34. Gimbrone Jr MA, Leapman SB, Cotran RS, Folkman J: Tumor dormancy in vivo by prevention of neovascularization. J Exp Med 136: 261-276, 1972

    Google Scholar 

  35. Gorski DH, Mauceri HJ, Salloum RM, Gately S, Hellman S, Beckett MA, Sukhatme VP, Soff GA, Kufe DW, Weichselbaum RR: Potentiation of the antitumor effect of 179 ionizing radiation by brief concomitant exposures to angiostatin. Cancer Res 58: 5686-5689, 1998

    Google Scholar 

  36. Greene HSN, Harvey EK: Metastasis from heterologously transplanted tumors. Cancer Res 24: 1678-1687, 1964

    Google Scholar 

  37. Greene HSN, Harvey H: Metastasis from the brain. Cancer Res 24: 1021-1027, 1964

    Google Scholar 

  38. Griscelli F, Li H, Bennaceur-Griscelli A, Soria J, Opolon P, Soria C, Perricaudet M, Yeh P, Lu H: Angiostatin gene transfer: inhibition of tumor growth in vivo by blockage of endothelial cell proliferation associated with a mitosis arrest. Proc Natl Acad Sci USA 95: 6367-6372, 1998

    Google Scholar 

  39. Hamby JM, Showalter HD: Small molecule inhibitors of tumor-promoted angiogenesis, including protein tyrosine kinase inhibitors. Pharmacol Ther 82: 169-193, 1999

    Google Scholar 

  40. Hart IR, Fidler IJ: Role of organ selectivity in the determination of metastatic patterns of B16 melanoma. Cancer Research 41: 1281-1287, 1981

    Google Scholar 

  41. Hirsch-Ginsberg C: Detection of minimal residual disease: relevance for diagnosis and treatment of human malignancies. Annu Rev Med 49: 111-122, 1998

    Google Scholar 

  42. Holmgren L, O'Reilly MS, Folkman J: Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1: 149-153, 1995

    Google Scholar 

  43. Hsu E, Keene D, Ventureyra E, Matzinger MA, Jimenez C, Wang HS, Grimard L: Bone marrow metastasis in astrocytic gliomata. J Neuro-Oncol 37: 285-293, 1998

    Google Scholar 

  44. Karrison TG, Ferguson DJ, Meier P: Dormancy ofmammary carcinoma after mastectomy. J Natl Cancer Inst 91: 80-85, 1999

    Google Scholar 

  45. Kirsch M, Strasser J, Allende R, Bello L, Zhang J, Black PM: Angiostatin suppresses malignant glioma growth in vivo. Cancer Res 58: 4654-4659, 1998

    Google Scholar 

  46. Lannutti BJ, Gately ST, Quevedo ME, Soff GA, Paller AS: Human angiostatin inhibits murine hemangioendothelioma tumor growth in vivo. Cancer Res 57: 5277-5280, 1997

    Google Scholar 

  47. Laws Jr. ER, Goldberg WJ, Bernstein JJ: Migration of human malignant astrocytoma cells in the mammalian brain: Scherer revisited. Int J Dev Neurosci 11: 691-697, 1993

    Google Scholar 

  48. LoRusso PM, Tapazoglou E, Zarbo RJ, Cullis PA, Austin D, Al Sarraf M: Intracranial astrocytoma with diffuse bone marrow metastasis: a case report and review of the literature. J Neuro-Oncol 6: 53-59, 1988

    Google Scholar 

  49. Matsuda KM, Madoiwa S, Hasumi Y, Kanazawa T, Saga Y, Kume A, Mano H, Ozawa K, Matsuda M: A novel strategy for the tumor angiogenesis-targeted gene therapy: generation of angiostatin from endogenous plasminogen by protease gene transfer. Cancer Gene Ther 7: 589-596, 2000

    Google Scholar 

  50. Mauceri HJ, Hanna NN, Beckett MA, Gorski DH, Staba MJ, Stellato KA, BigelowK, Heimann R, Gately S, Dhanabal M, Soff GA, SukhatmeVP, Kufe DW, Weichselbaum RR: Combined effects of angiostatin and ionizing radiation in antitumour therapy. Nature 394: 287-291, 1998

    Google Scholar 

  51. Meltzer A: Dormancy and breast cancer. J Surg Oncol 43: 181-188, 1990

    Google Scholar 

  52. Murray C: Tumor dormancy: not so sleepy after all. Nature Med 1: 117-118, 1995

    Google Scholar 

  53. Newman HF, Howard GC, Reid PM: Metastatic oligodendroglioma presenting as a leukoerythroblastic anaemia. Eur J Surg Oncol 11: 287-288, 1985

    Google Scholar 

  54. O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J: Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88: 277-285, 1997

    Google Scholar 

  55. O'Reilly MS, Holmgren L, Chen C, Folkman J: Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med 2: 689-692, 1996

    Google Scholar 

  56. O'Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Cao Y, Moses M, Lane WS, Sage EH, Folkman J: Angiostatin: a circulating endothelial cell inhibitor that suppresses angiogenesis and tumor growth. Cold Spring Harbor Symposia Quantita Biol 59: 471-482, 1994

    Google Scholar 

  57. O'Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses MLW, Cao Y, Sage EH, Folkman J: Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79: 315-328, 1994

    Google Scholar 

  58. Paget S: The distribution of secondary growth in cancer of the breast. Lancet 1: 571-573, 1889

    Google Scholar 

  59. Perletti G, Concari P, Giardini R, Marras E, Piccinini F, Folkman J, Chen L: Antitumor activity of endostatin against carcinogen-induced rat primary mammary tumors. Cancer Res 60: 1793-1796, 2000

    Google Scholar 

  60. Posner JB: Management of brain metastases. Rev Neurol 148: 477-487, 1992

    Google Scholar 

  61. Rivas MJ, Arii S, Furutani M, Harada T, Mizumoto M, Nishiyama H, Fujita J, Imamura M: Expression of human macrophage metalloelastase gene in hepatocellular carcinoma: correlation with angiostatin generation and its clinical significance. Hepatology 28: 986-993, 1998

    Google Scholar 

  62. Roder JD, Thorban S, Pantel K, Siewert JR: Micrometastases in bone marrow: prognostic indicators for pancreatic cancer. World J Surg 23: 888-891, 1999

    Google Scholar 

  63. Sauter BV, Martinet O, Zhang WJ, Mandeli J, Woo SL: Adenovirus-mediated gene transfer of endostatin in vivo results in high level of transgene expression and inhibition of tumor growth and metastases. Proc Natl Acad Sci USA 97: 4802-4807, 2000

    Google Scholar 

  64. Schackert G, Fidler IJ: Development of in vivo models for studies of brain metastasis. Internatl J Cancer 41: 589-594, 1988

    Google Scholar 

  65. Schackert G, Fidler IJ: Site-specific metastasis of mouse melanomas and a fibrosarcoma in the brain or meninges of syngeneic animals. Cancer Res 48: 3478-3484, 1988

    Google Scholar 

  66. Schackert G, Price JE, Zhang RD, Bucana CD, Itoh K, Fidler IJ: Regional growth of different human melanomas as metastases in the brain of nude mice. Amer J Pathol 136: 95-102, 1990

    Google Scholar 

  67. Sim BK, O'Reilly MS, Liang H, Fortier AH, He W, Madsen JW, Lapcevich Nacy CA: A recombinant human angiostatin protein inhibits experimental primary and metastatic cancer. Cancer Res 57: 1329-1334, 1997

    Google Scholar 

  68. Spratt JS, Meyer JS, Spratt JA: Rates of growth of human solid neoplasms: Part I. J Surg Oncol 60: 137-146, 1995

    Google Scholar 

  69. Spratt JS, Meyer JS, Spratt JA: Rates of growth of human neoplasms: Part II. J Surg Oncol 61: 68-83, 1996

    Google Scholar 

  70. Sten-Linder M, Linder C, Strander H, Munck-Wikland E, Wersall P, Linder S, Wiman B: Angiostatin fragments in urine from patients with malignant disease. Anticancer Res 19: 3409-3414, 1999

    Google Scholar 

  71. Stewart TH, Hollinshead AC, Raman S: Tumour dormancy: initiation, maintenance and termination in animals and humans. Can J Surg 34: 321-325, 1991

    Google Scholar 

  72. Tanaka T, Cao Y, Folkman J, Fine HA: Viral vector-targeted antiangiogenic gene therapy utilizing an angiostatin complementary DNA. Cancer Res 58: 3362-3369, 1998

    Google Scholar 

  73. Terheggen HG, Muller W: Extracerebrospinal metastases in glioblastoma. Case report and review of the literature. Eur J Pediatr 124: 155-164, 1977

    Google Scholar 

  74. Thorban S, Roder JD, Nekarda H, Funk A, Pantel K, Siewert JR: Disseminated epithelial tumor cells in bone marrow of patients with esophageal cancer: detection and prognostic significance. World J Surg 20: 567-572, 1996

    Google Scholar 

  75. Thybusch-Bernhardt A, Klomp HJ, Maas T, Kremer B, Juhl H: Immunocytological detection of isolated tumour cells in the bone marrow of malignant melanoma patients: a new method for the detection of minimal residual disease. Eur J Surg Oncol 25: 498-502, 1999

    Google Scholar 

  76. Walker AE, Robins M, Weinfeld FD: Epidemiology of brain tumors: the national survey of intracranial neoplasms. Neurology 35: 219-226, 1985

    Google Scholar 

  77. Wu Z, O'Reilly MS, Folkman J, Shing Y: Suppression of tumor growth with recombinant murine angiostatin. Biochem Biophys Res Commun 236: 651-654, 1997

    Google Scholar 

  78. Yamaguchi N, Anand-Apte B, Lee M, Sasaki T, Fukai N, Shapiro R, Que I, Lowik C, Timpl R, Olsen BR: Endostatin inhibits VEGF-induced endothelial cell migration and tumor growth independently of zinc binding. EMBO J 18: 4414-4423, 1999

    Google Scholar 

  79. Yokoyama Y, Dhanabal M, Griffioen AW, Sukhatme VP, Ramakrishnan S: Synergy between angiostatin and endostatin: inhibition of ovarian cancer growth. Cancer Res 60: 2190-2196, 2000

    Google Scholar 

  80. Yoon SS, Eto H, Lin CM, Nakamura H, Pawlik TM, Song SU, Tanabe KK: Mouse endostatin inhibits the formation of lung and liver metastases. Cancer Res 59: 6251-6256, 1999

    Google Scholar 

  81. Yung WK, Tepper SJ, Young DF: Diffuse bone marrow metastasis by glioblastoma: premortem diagnosis by peroxidase-antiperoxidase staining for glial fibrillary acidic protein. Ann Neurol 14: 581-585, 1983

    Google Scholar 

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  1. Klinik und Poliklinik für Neurochirurgie, Technische Universität Dresden, Germany

    Matthias Kirsch & Gabriele Schackert

  2. Neurosurgery, Children's Hospital, Boston, MA, USA

    Peter McL. Black

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  1. Matthias Kirsch
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Kirsch, M., Schackert, G. & Black, P.M. Angiogenesis, Metastasis, and Endogenous Inhibition. J Neurooncol 50, 173–180 (2000). https://doi.org/10.1023/A:1006453428013

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