primary tumor angiostatin suppresses remote tumor growth

[malernee]

O'Reilly MS. Angiostatin: an endogenous inhibitor of angiogenesis and
of tumor growth. EXS. 79:273-94, 1997.

Abstract:
Angiostatin, an internal fragment of plasminogen, is a potent
inhibitor of angiogenesis, which selectively inhibits endothelial
cell proliferation. When given systemically, angiostatin potently
inhibits tumor growth and can maintain metastatic and primary tumors
in a dormant state defined by a balance of proliferation and
apoptosis of the tumor cells. We identified angiostatin while
studying the phenomenon of inhibition of tumor growth by tumor mass
and have elucidated one mechanism for this phenomenon. In our animal
model, a primary tumor almost completely suppresses the growth of its
remote metastases. However, after tumor removal, the previously
dormant 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 kD plasminogen
fragment which we have sequenced and named angiostatin. Human
angiostatin, obtained from a limited proteolytic digest of human
plasminogen, has similar activities. Systemic administration of
angiostatin, but not intact plasminogen, potently blocks
neovascularization and growth of metastases and primary tumors. We
here show that the inhibition of metastases by a primary mouse tumor
is mediated, at least in part, by the angiogenesis inhibitor
angiostatin.

[malernee]

Boston Neurosurgical Foundation

http://www.boston-neurosurg.org/blacklab/w-angio.html

Anti-angiogenesis as a novel treatment modality for human malignant gliomas.

Numerous animal studies have provided substantial direct and indirect evidence that tumor growth is angiogenesis dependent. Additional studies have demonstrated that partial removal of some primary tumors may result in an increased growth rate of the residual tumor or proliferation of metastatic cells. This phenomenon is frequently encountered by the neurosurgeon in the case of malignant gliomas. Numerous studies have clearly indicated an association between angiogenesis and malignant brain tumors.

The goal of the project is to study the effect of angiostatin as a therapeutic agent in the treatment of glioblastoma multiforme and to investigate whether brain tumors express endogenous angiogenesis inhibitors similar to angiostatin, which may be therapeutically useful for the treatment of brain tumors.

Previously published findings have demonstrated that a growing primary tumor that has become neovascularized, can stimulate angiogenesis in its own tumor bed but inhibit angiogenesis in the vascular bed of its distant metastases. Subsequent removal of the primary tumor increases angiogenesis in the metastasis and this leads to a decreased rate of apoptosis and rapid proliferation of the metastatic cells. O'Reilly et al. found that the suppression of angiogenesis in a remote metastasis is mediated by a circulating angiogenesis inhibitor "angiostatin" in the case of Lewis lung carcinoma. Angiostatin is one the negative regulators of angiogenesis which are decreased during the switch to the angiogenic phenotype by a primary tumor. It is a specific inhibitor of endothelial cell proliferation. Angiostatin which has been purified and sequenced, is a 38 kD protein with 98% homology to an internal fragment of plasminogen, having an N-terminus at amino acid 98 and a approximate C-terminus at amino acid 440. Full length plasminogen has no endothelial cell inhibitory activity. Human angiostatin when given systemically to mice bearing Lewis lung metastases can virtually shut-down angiogenesis and produce dormancy in metastases restricting their size to <200 mm radius.

[malernee]

UNIQUE IDENTIFIER
1392512
AUTHORS
Katenkamp D. Kosmehl H. Neupert G.
INSTITUTION
Institute of Pathology, Friedrich Schiller University, Jena, Germany.
TITLE
Metastasis induction by incomplete tumor resection. A new metastasis
model using inoculation sarcomas in adult nude mice after long-term
cultivation of sarcoma cells.
SOURCE
Experimental & Toxicologic Pathology. 44(1):25-8, 1992 Mar.
ABSTRACT
In searching an animal model to study metastasis formation we used
cultured cells of experimental rhabdomyosarcomas and their inoculation
tumors in adult nude mice. Supplementing earlier observations (Katenkamp
et al. 1987) we found that long-term cultured sarcoma cells induce
tumors in adult nude mice which do not metastasize spontaneously but
produce lung metastases after repeated incomplete tumor removal. Possible
factors and mechanisms responsible for metastasis emergence are discussed.
The metastasis model introduced may be apt to study cellular changes at
cytogenetic and molecular biological level that occur during tumor
progression and metastatic dissemination.