title: 13-Hydroxyoctadecadienoic acid is the mitogenic signal for linoleic acid-dependent growth in rat hepatoma 7288CTC in vivo.
abstract: Growth of hepatoma 7288CTC in male Buffalo rats is directly dependent on uptake of linoleic acid (LA) from the arterial blood. One to 5% of the LA taken up is converted to 13-hydroxyoctadecadienoic acid (HODE), an agent that enhances epidermal growth factor-dependent mitogenesis. The role of 13-HODE in LA-dependent growth of solid tumors is not known. In this study, we examined LA uptake and 13-HODE formation on growth of tissue-isolated hepatoma 7288CTC in vivo and on [3H]thymidine incorporation and DNA content during perfusion in situ. Fatty acid uptake and metabolite release were determined from arteriovenous difference measurements. Tumor-bearing and blood donor rats were fed either LA-sufficient or -deficient diets. Hepatoma 7288CTC removed LA from the arterial blood and released 13-HODE [and a small amount of 13-ketooctadecadienoic acid (KODE)] into the venous blood both in vivo and during perfusion. Treatment with the lipoxygenase inhibitor nordihydroguaiaretic acid (10 microM) did not affect tumor LA uptake, but inhibited release of 13-HODE and 13-KODE in vivo and during perfusion, suppressed growth in vivo, and inhibited [3H]thymidine incorporation during perfusion. The addition of 13-HODE to the nordihydroguaiaretic acid-containing whole blood perfusate increased the rate of [3H]thymidine incorporation 10 times and nearly doubled tumor DNA content; the addition of 13-KODE or 9-HODE had no effect. 13-HODE and 13-KODE were not released from tumors growing in rats fed a LA-deficient diet, and the rates of tumor growth in vivo and [3H]thymidine incorporation during perfusion were decreased. The addition of 13-HODE to the LA-deficient blood perfusate promoted tumor 13-HODE uptake and a dose-dependent increase in [3H]thymidine incorporation and tumor DNA content. These results provide strong evidence that 13-HODE is the mitogenic signal responsible for LA-dependent growth in hepatoma 7288CTC in vivo.
authors.affiliation: Laboratory of Experimental Neuroendocrinology/Oncology, Bassett Research Institute, Cooperstown, New York 13326, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Sauer
authors.forename: R T
authors.initials: RT
authors.lastname: Dauchy
authors.forename: D E
authors.initials: DE
authors.lastname: Blask
authors.forename: B J
authors.initials: BJ
authors.lastname: Armstrong
authors.forename: S
authors.initials: S
authors.lastname: Scalici
mesh_terms: D000818:Animals; D001692:Biological Transport; D002455:Cell Division / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D019787:Linoleic Acid / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D008041:Linoleic Acids / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D051381:Rats; D011915:Rats, Inbred BUF; D013936:Thymidine / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; D008041:Linoleic Acids; C024348:13-hydroxy-9,11-octadecadienoic acid; D009637:Masoprocol; D019787:Linoleic Acid; D013936:Thymidine