Cell
Volume 79, Issue 2, 21 October 1994, Pages 315-328
Journal home page for Cell

Article
Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a lewis lung carcinoma

https://doi.org/10.1016/0092-8674(94)90200-3Get rights and content

Abstract

The phenomenon of inhibition of tumor growth by tumor mass has been repeatedly studied, but without elucidation of a satisfactory mechanism. In our animal model, a primary tumor inhibits its remote metastases. After tumor removal, metastases neovascularize and grow. When the primary tumor is present, metastatic growth is suppressed by a circulating angiogenesis inhibitor. Serum and urine from tumor-bearing mice, but not from controls, specifically inhibit endothelial cell proliferation. The activity copurifies with a 38 kDa plasminogen fragment that we have sequenced and named angiostatin. A corresponding fragment of human plasminogen has similar activity. Systemic administration of angiostatin, but not intact plasminogen, potently blocks neovascularization and growth of metastases. We here show that the inhibition of metastases by a primary mouse tumor is mediated, at least in part, by angiostatin.

References (77)

  • A. Brunschwig et al.

    Clinical experiments by homotransplants, autotransplants and admixture of autologous leucocytes

    Ann. Surgery

    (1965)
  • W. Bursch et al.

    Determination of the length of the histological stages of apoptosis in normal liver and in altered hepatic foci of rats

    Carcinogenesis

    (1990)
  • V. Castle et al.

    Antisense-mediated reduction in thrombospondin reverses the malignant phenotype of a human squamous carcinoma

    J. Clin. Invest.

    (1991)
  • C. Clapp et al.

    The 16-kilodalton N-terminal fragment of human prolactin is a potent inhibitor of angiogenesis

    Endocrinology

    (1993)
  • W.H. Clark et al.

    Model predicting survival in stage I melanoma based on tumor progression

    J. Natl. Cancer Inst.

    (1989)
  • D.G. Deutsch et al.

    Plasminogen: purification from human plasma by affinity chromatography

    Science

    (1970)
  • W.D. DeWys

    Studies correlating the growth rate of a tumor and its metastases and providing evidence for tumor-related systemic growth-retarding factors

    Cancer Res.

    (1972)
  • P. Ehrlich et al.

    Beobachtungen über maligne Mäusetumoren

    Berl. klin. Wschr.

    (1905)
  • C.J. Elleman et al.

    Suppressive factors in ascitic fluids and sera of mice bearing ascites tumors

    J. Natl. Cancer Inst.

    (1977)
  • I.J. Fidler

    Cancer metastasis

    Br. Med. Bull.

    (1991)
  • B. Fisher et al.

    Influence of the interval between primary tumor removal and chemotherapy on kinetics and growth of metastases

    Cancer Res.

    (1983)
  • B. Fisher et al.

    Presence of a growth-stimulating factor in serum following primary tumor removal in mice

    Cancer Res.

    (1989)
  • J. Folkman

    Tumor angiogenesis: therapeutic implications

    N. Engl. J. Med.

    (1971)
  • J. Folkman

    What is the evidence that tumors are angiogenesis dependent?

    J. Natl. Cancer Inst.

    (1989)
  • J. Folkman

    Angiogenesis and breast cancer

    J. Clin. Oncol.

    (1994)
  • J. Folkman et al.

    Long-term culture of capillary endothelial cells

  • Y. Gavrieli et al.

    Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation

    J. Cell Biol.

    (1992)
  • R.K. Gershon et al.

    On concomitant immunity in tumor-bearing hamsters

    Nature

    (1967)
  • D.J. Good et al.

    A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin

  • E. Gorelik

    Resistance of tumor-bearing mice to a second tumor challenge

    Cancer Res.

    (1983)
  • E. Gorelik et al.

    Growth of a local tumor exerts a specific inhibitory effect on progression of lung metastases

    Int. J. Cancer.

    (1978)
  • E. Gorelik et al.

    Control of lung metastasis progression in mice: role of growth kinetics of 3LL Lewis lung carcinoma and host immune reactivity

    J. Natl. Cancer Inst.

    (1980)
  • E. Gorelik et al.

    On the mechanism of tumor “concomitant immunity”

    Int. J. Cancer

    (1981)
  • H.S.N. Greene et al.

    The inhibitory influence of a transplanted hamster lymphoma on metastasis

    Cancer Res.

    (1960)
  • N. Gunduz et al.

    Effect of surgical removal on the growth and kinetics of residual tumor

    Cancer Res.

    (1979)
  • J.C. Himmele et al.

    Inhibition of Lewis lung tumor growth and metastasis by Ehrlich ascites tumor growing in the same host

    J. Cancer Res. Clin. Oncol.

    (1986)
  • G.A. Homandberg et al.

    Heparin-binding fragments of fibronectin are potent inhibitors of endothelial cell growth

    Am. J. Pathol.

    (1985)
  • A. Hori et al.

    Suppression of solid tumor growth by immunoneutralizing monoclonal antibody against human basic fibroblast growth factor

    Cancer Res.

    (1991)
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