Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma

Cell. 1997 Mar 21;88(6):801-10. doi: 10.1016/s0092-8674(00)81926-1.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angiostatins
  • Animals
  • Antineoplastic Agents / metabolism*
  • Carcinoma, Lewis Lung / metabolism*
  • Carcinoma, Lewis Lung / secondary
  • Carcinoma, Lewis Lung / surgery
  • Collagenases / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / physiology
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Macrophages, Alveolar / cytology
  • Macrophages, Alveolar / enzymology*
  • Matrix Metalloproteinase 12
  • Matrix Metalloproteinase 9
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Peptide Fragments / metabolism*
  • Plasminogen / metabolism*
  • RNA, Messenger / metabolism
  • Specific Pathogen-Free Organisms
  • Tumor Cells, Cultured / enzymology


  • Antineoplastic Agents
  • Peptide Fragments
  • RNA, Messenger
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Angiostatins
  • Plasminogen
  • Collagenases
  • Metalloendopeptidases
  • Matrix Metalloproteinase 9
  • Matrix Metalloproteinase 12