Elevated dietary linoleic acid increases gastric carcinoma cell invasion and metastasis in mice.
BACKGROUND
Dietary (n-6)-polyunsaturated fatty acids influence cancer development, but the mechanisms have not been well characterised in gastric carcinoma.


METHODS
We used two in vivo models to investigate the effects of these common dietary components on tumour metastasis. In a model of experimental metastasis, immunocompromised mice were fed diets containing linoleic acid (LA) at 2% (LLA), 8% (HLA) or 12% (VHLA) by weight and inoculated intraperitoneally (i.p.) with human gastric carcinoma cells (OCUM-2MD3). To model spontaneous metastasis, OCUM-2MD3 tumours were grafted onto the stomach walls of mice fed with the different diets. In in vitro assays, we investigated invasion and ERK phosphorylation of OCUM-2MD3 cells in the presence or absence of LA. Finally, we tested whether a cyclooxygenase (COX) inhibitor, indomethacin, could block peritoneal metastasis in vivo.


RESULTS
Both the HLA and VHLA groups showed increased incidence of tumour nodules (LA: 53%; HLA: 89%; VHLA: 100%; P<0.03); the VHLA group also displayed increased numbers of tumour nodules and higher total volume relative to LLA group in experimental metastasis model. Both liver invasion (78%) and metastasis to the peritoneal cavity (67%) were more frequent in VHLA group compared with the LLA group (22% and 11%, respectively; P<0.03) in spontaneous metastasis model. We also found that the invasive ability of these cells is greatly enhanced when exposed to LA in vitro. Linoleic acid also increased invasion of other scirrhous gastric carcinoma cells, OCUM-12, NUGC3 and MKN-45. Linoleic acid effect on OCUM-2MD3 cells seems to be dependent on phosphorylation of ERK. The data suggest that invasion and phosphorylation of ERK were dependent on COX. Indomethacin decreased the number of tumours and total tumour volume in both LLA and VHLA groups. Finally, COX-1, which is known to be an important enzyme in the generation of bioactive metabolites from dietary fatty acids, appears to be responsible for the increased metastatic behaviour of OCUM-2MD3 cells in the mouse model.


CONCLUSIONS
Dietary LA stimulates invasion and peritoneal metastasis of gastric carcinoma cells through COX-catalysed metabolism and activation of ERK, steps that compose pathway potentially amenable to therapeutic intervention.
Matsuoka
T
T
The Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Science, NIH, Research Triangle Park, NC 27709, USA. tskmtsk@aol.com
Adair
J E
JE
Lih
F B
FB
Hsi
L C
LC
Rubino
M
M
Eling
T E
TE
Tomer
K B
KB
Yashiro
M
M
Hirakawa
K
K
Olden
K
K
Roberts
J D
JD
D000818:Animals; D002277:Carcinoma / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects*; D004042:Dietary Fats, Unsaturated / Q000009:adverse effects / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D019787:Linoleic Acid / Q000009:adverse effects* / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D013274:Stomach Neoplasms / Q000473:pathology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D004042:Dietary Fats, Unsaturated; D019787:Linoleic Acid