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Elevated dietary linoleic acid increases gastric carcinoma cell invasion and metastasis in mice.

Matsuoka T, Adair JE, Lih FB, Hsi LC, Rubino M, Eling TE, Tomer KB, Yashiro M, Hirakawa K, Olden K, Roberts JD - Br. J. Cancer (2010)

Bottom Line: We also found that the invasive ability of these cells is greatly enhanced when exposed to LA in vitro.Linoleic acid effect on OCUM-2MD3 cells seems to be dependent on phosphorylation of ERK.Indomethacin decreased the number of tumours and total tumour volume in both LLA and VHLA groups.

View Article: PubMed Central - PubMed

Affiliation: The Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Science, NIH, Research Triangle Park, NC 27709, USA. tskmtsk@aol.com

ABSTRACT

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.

Conclusion: 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.

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The effect of LA on the metastasis of a human gastric cancer cell line. (A) Typical views of the abdominal space in a euthanised mouse fed the 12% LA diet are shown. Left panel: metastatic lymph nodes around stomach (black arrows) in the model of orthotopic implantation. Middle panel: primary gastric implanted tumour (grey arrow). Right panel: metastatic peritoneal tumour (white arrows) in the experimental metastasis model. (B) Number of metastatic nodules per mouse, counted 4 weeks after i.p. injection of OCUM-2MD3 cells. Bars indicate the mean. a: Different from LLA group (P<0.03). b: Different from HLA group (P<0.03 by the Jonckheere–Terpstra test). Points at the abscissa indicate mice with no detectable tumour. Bars represent the mean for each group.
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fig1: The effect of LA on the metastasis of a human gastric cancer cell line. (A) Typical views of the abdominal space in a euthanised mouse fed the 12% LA diet are shown. Left panel: metastatic lymph nodes around stomach (black arrows) in the model of orthotopic implantation. Middle panel: primary gastric implanted tumour (grey arrow). Right panel: metastatic peritoneal tumour (white arrows) in the experimental metastasis model. (B) Number of metastatic nodules per mouse, counted 4 weeks after i.p. injection of OCUM-2MD3 cells. Bars indicate the mean. a: Different from LLA group (P<0.03). b: Different from HLA group (P<0.03 by the Jonckheere–Terpstra test). Points at the abscissa indicate mice with no detectable tumour. Bars represent the mean for each group.

Mentions: To determine whether LA would stimulate metastasis of gastric carcinoma cells, OCUM-2MD3 human gastric carcinoma cells were injected into the peritoneal cavities of Balb/c nude mice, which were fed high-fat diets containing 2% (LLA), 8% (HLA) or 12% (VHLA) LA. Mean per mouse body weights did not differ between the three dietary groups at either the beginning or the end of the study (Table 1). Both the HLA and VHLA groups showed a higher incidence of metastasis compared with the LLA group (Table 1), despite identical total fat and energy intakes (Supplementary Table 1). Interestingly, the mean number of metastatic nodules per mouse and the mean total tumour volumes in the VHLA group increased over those in either the LLA or HLA groups (Table 1 and Figure 1B). Metastatic colonies, identified as white nodules in the peritoneal cavity (Figure 1A, right panel), were primarily located at the omentum and occasionally at the lesser curvature of stomach, mesentery and parietal peritoneum. Tumour location did not vary between dietary groups.


Elevated dietary linoleic acid increases gastric carcinoma cell invasion and metastasis in mice.

Matsuoka T, Adair JE, Lih FB, Hsi LC, Rubino M, Eling TE, Tomer KB, Yashiro M, Hirakawa K, Olden K, Roberts JD - Br. J. Cancer (2010)

The effect of LA on the metastasis of a human gastric cancer cell line. (A) Typical views of the abdominal space in a euthanised mouse fed the 12% LA diet are shown. Left panel: metastatic lymph nodes around stomach (black arrows) in the model of orthotopic implantation. Middle panel: primary gastric implanted tumour (grey arrow). Right panel: metastatic peritoneal tumour (white arrows) in the experimental metastasis model. (B) Number of metastatic nodules per mouse, counted 4 weeks after i.p. injection of OCUM-2MD3 cells. Bars indicate the mean. a: Different from LLA group (P<0.03). b: Different from HLA group (P<0.03 by the Jonckheere–Terpstra test). Points at the abscissa indicate mice with no detectable tumour. Bars represent the mean for each group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2967057&req=5

fig1: The effect of LA on the metastasis of a human gastric cancer cell line. (A) Typical views of the abdominal space in a euthanised mouse fed the 12% LA diet are shown. Left panel: metastatic lymph nodes around stomach (black arrows) in the model of orthotopic implantation. Middle panel: primary gastric implanted tumour (grey arrow). Right panel: metastatic peritoneal tumour (white arrows) in the experimental metastasis model. (B) Number of metastatic nodules per mouse, counted 4 weeks after i.p. injection of OCUM-2MD3 cells. Bars indicate the mean. a: Different from LLA group (P<0.03). b: Different from HLA group (P<0.03 by the Jonckheere–Terpstra test). Points at the abscissa indicate mice with no detectable tumour. Bars represent the mean for each group.
Mentions: To determine whether LA would stimulate metastasis of gastric carcinoma cells, OCUM-2MD3 human gastric carcinoma cells were injected into the peritoneal cavities of Balb/c nude mice, which were fed high-fat diets containing 2% (LLA), 8% (HLA) or 12% (VHLA) LA. Mean per mouse body weights did not differ between the three dietary groups at either the beginning or the end of the study (Table 1). Both the HLA and VHLA groups showed a higher incidence of metastasis compared with the LLA group (Table 1), despite identical total fat and energy intakes (Supplementary Table 1). Interestingly, the mean number of metastatic nodules per mouse and the mean total tumour volumes in the VHLA group increased over those in either the LLA or HLA groups (Table 1 and Figure 1B). Metastatic colonies, identified as white nodules in the peritoneal cavity (Figure 1A, right panel), were primarily located at the omentum and occasionally at the lesser curvature of stomach, mesentery and parietal peritoneum. Tumour location did not vary between dietary groups.

Bottom Line: We also found that the invasive ability of these cells is greatly enhanced when exposed to LA in vitro.Linoleic acid effect on OCUM-2MD3 cells seems to be dependent on phosphorylation of ERK.Indomethacin decreased the number of tumours and total tumour volume in both LLA and VHLA groups.

View Article: PubMed Central - PubMed

Affiliation: The Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Science, NIH, Research Triangle Park, NC 27709, USA. tskmtsk@aol.com

ABSTRACT

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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus