Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma

MS O'Reilly, L Holmgren, Y Shing, C Chen… - cell, 1994 - cell.com
MS O'Reilly, L Holmgren, Y Shing, C Chen, RA Rosenthal, M Moses, WS Lane, Y Cao
cell, 1994cell.com
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 neovascularire 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 copurlfles with a 38 kDa …
Summary
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 neovascularire 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 copurlfles 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 angiostatln.
The inhibition of tumor growth by tumor mass is observed in some clinical and experimental malignancies. In cancer patients, the removal of a carcinoma, alone or in combination with other therapies, may be curative. However, the removal of certain tumors, eg, breast carcinomas, colon carcinomas, and osteogenic sarcomas, can be followed by the rapid growth of distant metastases (Warren et al., 1977; Sugarbaker et al., 1977; Clark et al., 1989; Woodruff, 1980, 1990). Several studies in terminally ill cancer patients demonstrate the suppression of a secondary tumor by a primary tumor (Koike et al., 1983; Brunschwig et al., 1965; Howard, 1963; Southam and Brunschwig, 1961). The inhibition of metastases of one tumor can be seen with a different type of primary tumor; eg, a breast carcinoma can inhibit metastases of a melanoma. In melanoma, partial spontaneous regression of the primary tu-
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