Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma.
To determine the mechanism responsible for the in vivo production of angiostatin that inhibits growth and metastasis in Lewis lung carcinoma (3LL), we implanted 3LL variant cells into the subcutis of syngeneic C57BL/6 mice. The tumors were infiltrated by macrophages and expressed high levels of steady-state mRNA for metalloelastase (MME). Successive passages (more than three) of cultures established from the tumors resulted in complete depletion of macrophages; steady-state MME mRNA, elastinolytic activity, and production of angiostatin (in the presence of plasminogen) were correspondingly reduced. Coculture of macrophages with either 3LL cells or their conditioned media containing granulocyte-macrophage colony-stimulating factor resulted in secretion of MME and production of angiostatin by the macrophages, suggesting that angiostatin is produced by tumor-infiltrating macrophages whose MME expression is stimulated by tumor cell-derived granulocyte-macrophage colony-stimulating factor.
Dong
Z
Z
Department of Cell Biology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Kumar
R
R
Yang
X
X
Fidler
I J
IJ
D043168:Angiostatins; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D018827:Carcinoma, Lewis Lung / Q000378:metabolism* / Q000556:secondary / Q000601:surgery; D017364:Collagenases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000166:cytology / Q000201:enzymology*; D053508:Matrix Metalloproteinase 12; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000378:metabolism*; D010958:Plasminogen / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D014407:Tumor Cells, Cultured / Q000201:enzymology
D000970:Antineoplastic Agents; D010446:Peptide Fragments; D012333:RNA, Messenger; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D043168:Angiostatins; D010958:Plasminogen; D017364:Collagenases; D008666:Metalloendopeptidases; D020780:Matrix Metalloproteinase 9; D053508:Matrix Metalloproteinase 12