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.