Identification of arachidonic acid pathways required for the invasive and metastatic activity of malignant tumor cells.
Metastasis is a complex process, almost a cascade, involving multiple steps and activities. However, an important factor is that malignant cells are able to penetrate through the multiple basement membrane barriers surrounding tissues, blood vessels, nerves and muscle that would otherwise block their dissemination. Penetration of malignant tumor cells through basement membrane is an active process requiring proteolysis. We report here that inhibitors of both the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism convert mouse melanoma and human fibrosarcoma cells to a non invasive state by reducing the production of MMP-2, an enzyme required for the degradation of basement membranes. Specific metabolites of each pathway, i.e. PGF2 alpha and 5-HPETE, are able to transcend the block and restore collagenase production, invasiveness in vitro and metastatic activity in vivo. These studies indicate a key role for arachidonic acid metabolites in metastasis and suggest novel therapeutic approaches for inhibiting the spread of cancer.
Department of Pharmacology, Hebrew University of Jerusalem, Israel.
R
R
Reich
G R
GR
Martin
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002110:Caffeine / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015237:Dinoprost / Q000494:pharmacology; D004338:Drug Combinations; D005109:Extracellular Matrix / Q000378:metabolism; D005354:Fibrosarcoma / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007797:Laminin / Q000378:metabolism; D015289:Leukotrienes / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009637:Masoprocol / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2; D008545:Melanoma; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis; D011509:Proteoglycans / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014468:Umbelliferones / Q000494:pharmacology; D002722:Chlorobenzenes
D016718:Arachidonic Acid; D002110:Caffeine; D003094:Collagen; D016861:Cyclooxygenase Inhibitors; D015237:Dinoprost; D004338:Drug Combinations; D018093:Gelatinases; D007211:Indoles; D007213:Indomethacin; D007797:Laminin; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D009637:Masoprocol; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases; D011509:Proteoglycans; D014468:Umbelliferones; C060893:MK-886; D002722:Chlorobenzenes; C059485:matrigel; C025348:arachidonic acid 5-hydroperoxide; C007628:esculetin