13-hydroxyoctadecadienoic acid is the mitogenic signal for linoleic acid-dependent growth in rat hepatoma 7288CTC in vivo

Growth of hepatoma 7288CTC in male Buffalo rats is directly dependent on up take of linoleic acid (LA) from the arterial blood. One to 5% of the LA tak en 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, me exa mined LA uptake and 13-HODE formation on growth of tissue-isolated hepatoma 7288CTC in vivo and on [H-3]thymidine incorporation and DNA content during perfusion in situ, Fatty acid uptake and metabolite release mere determine d from arteriovenous difference measurements. Tumor-bearing and blood donor rats were fed either LA-sufficient or -deficient diets, Hepatoma 7288CTC r emoved 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 a nd during perfusion, Treatment with the lipoxygenase inhibitor nordihydrogu aiaretic acid (10 mu M) did not affect tumor LA uptake, but inhibited relea se of 13-MODE and 13-KODE in vivo and during perfusion, suppressed growth i n vivo and inhibited [H-3]thymidine incorporation during perfusion, The add ition of 13-HODE to the nordihydroguaiaretic acid-containing whole blood pe rfusate increased the rate of [H-3]thymidine incorporation 10 times and nea rly doubled tumor DNA content; the addition of 13-KODE or 9-MODE had no eff ect. 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]thymidin e incorporation during perfusion were decreased. The addition of 13-MODE to the LA-deficient blood perfusate promoted tumor 13-HODE uptake and a dose- dependent increase in [H-3]thymidine incorporation and tumor DNA content. T hese results provide strong evidence that 13-HODE is the mitogenic signal r esponsible for LA-dependent growth in hepatoma 7288CTC in vivo.