La. Sauer et al., 13-hydroxyoctadecadienoic acid is the mitogenic signal for linoleic acid-dependent growth in rat hepatoma 7288CTC in vivo, CANCER RES, 59(18), 1999, pp. 4688-4692
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.