Leukotriene B4 Creates a Favorable Microenvironment for Murine Melanoma Growth
Leukotriene B4 Creates a Favorable Microenvironment for Murine Melanoma Growth
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DOI：
10.1158/1541-7786.mcr-09-0038
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发表时间：
2009-09-01
影响因子：
5.2
通讯作者：
Correa, Mariangela
中科院分区：
文献类型：
--
作者：
Lacerda Bachi, Andre Luis;Kyung Kim, Fabiana Jin;Correa, Mariangela
长期以来，慢性炎症与肿瘤进展有关。我们的研究小组最近表明，在肿瘤微环境中加入大量凋亡肿瘤细胞会诱导一种能够促进黑色素瘤生长的有效急性炎症反应;然而，主要是坏死细胞不会引起这种反应。在这里，我们表明，有效的炎症因子，如脂多糖（LPS）和角叉菜胶，也促进生长的亚致瘤剂量的黑色素瘤细胞，在体外对黑色素瘤增殖没有影响。5-脂氧合酶（5-LOX）的抑制似乎在该模型中具有关键作用，因为咖啡酸和MK 886，一种FLAP（5-LOX激活蛋白）抑制剂，部分阻碍了凋亡细胞或LIPS诱导的肿瘤生长。花生四烯酸途径的其他酶，环氧合酶-1和环氧合酶-2，似乎没有参与这种肿瘤促进作用，因为这两种酶的抑制剂（吲哚美辛）没有改变黑色素瘤的生长。白三烯B4（LTB 4），5-LOX途径的主要产物，能够诱导黑色素瘤细胞的亚致瘤性接种物的生长，并且LTB 4受体拮抗剂抑制急性炎症相关的肿瘤生长。在肿瘤炎症微环境中添加二十碳五烯酸（一种具有抗炎特性的ω 3-多不饱和脂肪酸）或白三烯B5（一种二十碳五烯酸衍生的白三烯）可显著抑制肿瘤发展。这些结果为炎症可能导致肿瘤进展的机制提供了新的见解，并表明LOX在存在细胞凋亡的情况下与炎症状态相关的肿瘤进展中具有重要作用，这可能是诱导凋亡治疗（如化疗和放疗）的考虑因素。(Mol Cancer Res 2009; 7（9）：1417-24）
Chronic inflammation has long been associated with neoplastic progression. Our group had recently shown that the addition of a large number of apoptotic tumor cells to the tumor microenvironment induces a potent acute inflammatory reaction capable of promoting melanoma growth; however, primarily necrotizing cells do not cause such a reaction. Here, we show that potent inflammatory agents, such as lipopolysaccharide (LPS) and carrageenan, also promote growth of subtumorigenic doses of melanoma cells, having no effect on melanoma proliferation in vitro. Inhibition of 5-lipoxygenase (5-LOX) seems to have a pivotal role in this model because caffeic acid and MK886, a FLAP (5-LOX-activating protein) inhibitor, partially hindered tumor growth induced by apoptotic cells or LIPS. Other enzymes of the arachidonic acid pathway, cyclooxygenase-1 and cyclooxygenase-2, seem to have no participation in this tumor promoter effect, as the inhibitor of both enzymes (Indomethacin) did not alter melanoma growth. Leukotriene B4 (LTB4), the main product of the 5-LOX pathway, was able to induce growth of subtumorigenic inocula of melanoma cells, and a LTB4 receptor antagonist inhibited acute Inflammation-associated tumor growth. Addition to the tumor inflammatory microenvironment of eicosapentaenoic acid, an omega 3-polyunsaturated fatty acid with anti-inflammatory properties, or leukotriene B5, an eicosapentaenoic acid-derived leukotriene, significantly inhibited tumor development. These results give new insights to the mechanisms through which inflammation may contribute to tumor progression and suggest that LOX has an important role in tumor progression associated with an inflammatory state in the presence of apoptosis, which may be a consideration for apoptosis-inducing treatments, such as chemotherapy and radiotherapy. (Mol Cancer Res 2009; 7(9):1417-24)