Mouse macrophage metalloelastase gene transfer into a murine melanoma suppresses primary tumor growth by halting angiogenesis.

Abstract

Mouse macrophage metalloelastase (MME) has been associated with the generation of angiostatin, an internal fragment of plasminogen, which inhibits angiogenesis. To clarify whether tumor cells that consistently generate MME can suppress angiogenesis and, therefore, inhibit the growth of primary tumors in vivo, we transfected a cDNA coding for MME into murine B16-BL6 melanoma cells that grow rapidly and are MME deficient. The generation of active MME in MME-transfected clones was confirmed by immunoprecipitation followed by in vitro cleavage of plasminogen. Subcutaneous implantation of these stable clones in C57BL/6 mice inhibited primary tumor growth by an average of 73% (P = 0.00002), which directly correlated with a significant reduction of blood vessel formation (approximately 76%) in such tumors. Microangiography revealed massive angiogenesis in control tumors (mock and vector); however, in MME-transfected primary tumors it demonstrated a decreased and disrupted vascular network. Western blot analysis using a specific anti-mouse angiostatin antibody demonstrated a strong 38-kDa immunoreactive band in MME-transfected tumors and in the serum of mice bearing those tumor cells. These results show that placing MME gene directly into B16-BL6 melanoma cells is an effective approach to suppress primary tumor growth in vivo because it halts angiogenesis. Our data provide a feasible and promising strategy for gene therapy of cancer by targeting tumor vasculature.

• Authors: M J Gorrin-Rivas, S Arii, M Furutani, M Mizumoto, A Mori, K Hanaki, M Maeda, H Furuyama, Y Kondo, M Imamura
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 6 Issue 5 Pg. 1647-54 (May 2000) ISSN: 1078-0432 [Print] United States
• PMID: 10815882 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Recombinant
• Peptide Fragments
• RNA, Messenger
• Angiostatins
• Plasminogen
• Metalloendopeptidases
• Matrix Metalloproteinase 12

Topics

• Angiostatins
• Animals
• Cell Division
• DNA, Recombinant (genetics)
• Gene Expression
• Gene Transfer Techniques
• Male
• Matrix Metalloproteinase 12
• Melanoma, Experimental (genetics, pathology, therapy)
• Metalloendopeptidases (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Neoplasm Transplantation (pathology)
• Neovascularization, Pathologic (prevention & control)
• Peptide Fragments (metabolism)
• Plasminogen (metabolism)
• RNA, Messenger (genetics, metabolism)
• Tumor Cells, Cultured