Elevated dietary linoleic acid increases gastric carcinoma cell invasion and metastasis in mice.
Elevated dietary linoleic acid increases gastric carcinoma cell invasion and metastasis in mice.
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DOI：
10.1038/sj.bjc.6605881
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发表时间：
2010-10-12
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
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作者：
饮食中的（n-6）-多不饱和脂肪酸影响癌症的发展，但其机制尚未在胃癌中得到很好的表征。我们使用了两种体内模型来研究这些常见的饮食成分对肿瘤转移的影响。在实验性转移模型中，免疫受损的小鼠被喂食含有按重量计2%（LLA）、8%（HLA）或12%（VHLA）的亚油酸（LA）的饮食，并腹膜内（i. p.）人胃癌细胞株OCUM-2 MD 3。为了模拟自发转移，将OCUM-2 MD 3肿瘤移植到用不同饮食喂养的小鼠的胃壁上。在体外试验中，我们研究了在LA存在或不存在的情况下OCUM-2 MD 3细胞的侵袭和ERK磷酸化。最后，我们测试了环氧化酶（考克斯）抑制剂吲哚美辛是否可以阻断体内腹膜转移。HLA和VHLA组均显示肿瘤结节的发生率增加（LA：53%HLA：89%VHLA：100%P <0.03）;在实验转移模型中，VHLA组还显示相对于LLA组肿瘤结节数量增加和总体积更高。在自发转移模型中，VHLA组的肝转移率（78%）和腹腔转移率（67%）均高于LLA组（分别为22%和11%，P<0.03）。我们还发现，这些细胞的侵袭能力大大增强时，暴露于LA在体外。亚油酸还增加了其他硬癌细胞OCUM-12、NUGC 3和MKN-45的侵袭。亚油酸对OCUM-2 MD 3细胞的作用可能依赖于ERK的磷酸化。这些数据表明，侵袭和ERK的磷酸化依赖于考克斯。吲哚美辛降低了LLA和VHLA组的肿瘤数量和总肿瘤体积。最后，已知考克斯-1是从膳食脂肪酸产生生物活性代谢物的重要酶，似乎是小鼠模型中OCUM-2 MD 3细胞转移行为增加的原因。膳食LA通过COX-催化的代谢和ERK的激活刺激胃癌细胞的侵袭和腹膜转移，这些步骤构成可能适合于治疗干预的途径。
Dietary (n-6)-polyunsaturated fatty acids influence cancer development, but the mechanisms have not been well characterised in gastric carcinoma. 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. 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. 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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影响因子：
8.8
作者：
通讯作者：
--
影响因子：
4.8
作者：
Nony, PA;Kennett, SB;Roberts, JD
通讯作者：
Roberts, JD
影响因子：
5.3
作者：
Lee, MS;Kim, TY;Lee, JW
通讯作者：
Lee, JW
影响因子：
2.9
作者：
Funahashi, Hitoshi;Satake, Makoto;Eibl, Guido
通讯作者：
Eibl, Guido
影响因子：
4.2
作者：
Arab, L
通讯作者：
Arab, L