The omega-3 polyunsaturated fatty acid eicosapentaenoic acid inhibits mouse MC-26 colorectal cancer cell liver metastasis via inhibition of PGE2-dependent cell motility
The omega-3 polyunsaturated fatty acid eicosapentaenoic acid inhibits mouse MC-26 colorectal cancer cell liver metastasis via inhibition of PGE2-dependent cell motility
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DOI：
10.1111/j.1476-5381.2012.01882.x
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发表时间：
2012-07-01
影响因子：
7.3
通讯作者：
Hull, M. A.
中科院分区：
文献类型：
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作者：
Hawcroft, G.;Volpato, M.;Hull, M. A.
背景和目的ω-3多不饱和脂肪酸（PUFA）二十碳五烯酸（EPA）在结直肠癌发生的早期阶段具有抗肿瘤活性，与结直肠癌（CRC）的化学预防有关。我们测试了这样一个假设，即EPA在结直肠癌发生的后期阶段也具有抗CRC活性，与转移性CRC的治疗相关，通过调节E型PG合成。实验方法使用BALB/c小鼠模型，其中脾内注射同基因MC-26小鼠CRC细胞导致肝转移的发展。在超声引导脾内注射1 × 106个MC-26细胞之前和之后，以游离脂肪酸（FFA）形式给予膳食EPA 2周（每组n= 16）。与对照动物相比，用5%（w w-1）EPA-FFA治疗与MC-26小鼠CRC细胞肝脏肿瘤负荷降低相关（中位肝脏重量1.03 g对1.62 g; P < 0.034）。施用5% EPA-FFA还与肿瘤EPA掺入的显著增加和肿瘤内PGE 2水平的降低（伴随PGE 3产生的增加）相关。来自5% EPA-FFA处理的小鼠的肝肿瘤表现出5-溴-2-脱氧尿苷阳性CRC细胞增殖减少，并且在肿瘤的侵袭性边缘处磷酸化ERK 1/2表达减少。体外EPA-FFA处理（50 - 200 μ M）后MC-26 CRC细胞Transwell（R）迁移的浓度依赖性降低被外源性PGE 2（10 μ M）和PGE 1-醇（1 μ M）挽救。结论EPA-FFA可抑制MC-26结直肠癌细胞的肝转移。EPA掺入与肝脏肿瘤中PGE 2至PGE 3的转换相关。PGE 2-EP 4受体依赖性CRC细胞运动的抑制可能有助于EPA的抑制活性。
BACKGROUND AND PURPOSE The omega-3 polyunsaturated fatty acid (PUFA) eicosapentaenoic acid (EPA) has antineoplastic activity at early stages of colorectal carcinogenesis, relevant to chemoprevention of colorectal cancer (CRC). We tested the hypothesis that EPA also has anti-CRC activity at later stages of colorectal carcinogenesis, relevant to treatment of metastatic CRC, via modulation of E-type PG synthesis. EXPERIMENTAL APPROACH A BALB/c mouse model, in which intrasplenic injection of syngeneic MC-26 mouse CRC cells leads to development of liver metastases, was used. Dietary EPA was administered in the free fatty acid (FFA) form for 2 weeks before and after ultrasound-guided intrasplenic injection of 1 x 106 MC-26 cells (n= 16 each group). KEY RESULTS Treatment with 5% (w w-1) EPA-FFA was associated with a reduced MC-26 mouse CRC cell liver tumour burden compared with control animals (median liver weight 1.03 g vs. 1.62 g; P < 0.034). Administration of 5% EPA-FFA was also linked to a significant increase in tumour EPA incorporation and lower intratumoural PGE2 levels (with concomitant increased production of PGE3). Liver tumours from 5% EPA-FFA- treated mice demonstrated decreased 5-bromo-2-deoxyuridine-positive CRC cell proliferation and reduced phosphorylated ERK 1/2 expression at the invasive edge of tumours. A concentration-dependent reduction in MC-26 CRC cell Transwell (R) migration following EPA-FFA treatment (50200 mu M) in vitro was rescued by exogenous PGE2 (10 mu M) and PGE1-alcohol (1 mu M). CONCLUSIONS AND IMPLICATIONS EPA-FFA inhibits MC-26 CRC cell liver metastasis. EPA incorporation is associated with a PGE2 to PGE3 switch in liver tumours. Inhibition of PGE2-EP4 receptor-dependent CRC cell motility probably contributes to the antineoplastic activity of EPA.