Tumor-induced inflammation in mammary adipose tissue stimulates a vicious cycle of autotaxin expression and breast cancer progression
Tumor-induced inflammation in mammary adipose tissue stimulates a vicious cycle of autotaxin expression and breast cancer progression
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DOI：
10.1096/fj.15-274480
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发表时间：
2015-09-01
期刊：
影响因子：
4.8
通讯作者：
Brindley, David N.
中科院分区：
文献类型：
--
作者：
Benesch, Matthew G. K.;Tang, Xiaoyun;Brindley, David N.
与正常组织相比，许多癌细胞过度表达自体趋化蛋白(ATX)。这种分泌的酶产生细胞外溶血磷脂酸盐，它通过6个GPCR发出信号来推动癌症的进展。我们以前的工作表明，ATX抑制BALB/c小鼠4T1乳腺肿瘤生长约11d，使其生长减少60%。然而，4T1细胞不产生显著的ATX。相反，ATX是由邻近的乳腺脂肪组织产生的。我们在人类和小鼠乳腺肿瘤中研究了这种相互作用的分子基础。乳腺癌细胞分泌的炎症介质增加了脂肪组织中ATX的产生。溶血磷脂酸信号的增加进一步增加了脂肪组织和肿瘤中炎症介质的产生。用10 mg/kg/d的ONO-8430506(一种竞争性的ATX抑制剂，IC_(90)=100 NM；日本大阪的小野制药有限公司)在荷4T1肿瘤的小鼠中阻断ATX活性，通过将癌症发炎的脂肪组织中的20种炎症介质减少1.5-8倍，打破了这一恶性炎症循环。没有携带肿瘤的脂肪垫中的炎症介质水平没有显著下降。ONO-8430506还使血浆肿瘤坏死因子-α和粒细胞集落刺激因子水平降低了70%，乳腺肿瘤和邻近脂肪组织中的白细胞浸润减少了50%。因此，通过抑制ATX来阻断肿瘤引起的炎症在减少乳腺癌肿瘤生长方面是有效的，因为在乳腺癌中癌细胞表达的ATX可以忽略不计。
Compared to normal tissues, many cancer cells overexpress autotaxin (ATX). This secreted enzyme produces extracellular lysophosphatidate, which signals through 6 GPCRs to drive cancer progression. Our previous work showed that ATX inhibition decreases 4T1 breast tumor growth in BALB/c mice by 60% for about 11 d. However, 4T1 cells do not produce significant ATX. Instead, the ATX is produced by adjacent mammary adipose tissue. We investigated the molecular basis of this interaction in human and mouse breast tumors. Inflammatory mediators secreted by breast cancer cells increased ATX production in adipose tissue. The increased lysophosphatidate signaling further increased inflammatory mediator production in adipose tissue and tumors. Blocking ATX activity in mice bearing 4T1 tumors with 10 mg/kg/d ONO-8430506 (a competitive ATX inhibitor, IC90 = 100 nM; Ono Pharma Co., Ltd., Osaka, Japan) broke this vicious inflammatory cycle by decreasing 20 inflammatory mediators by 1.5-8-fold in cancer-inflamed adipose tissue. There was no significant decrease in inflammatory mediator levels in fat pads that did not bear tumors. ONO-8430506 also decreased plasma TNF-alpha and G-CSF cytokine levels by >70% and leukocyte infiltration in breast tumors and adjacent adipose tissue by >50%. Hence, blocking tumor-driven inflammation by ATX inhibition is effective in decreasing tumor growth in breast cancers where the cancer cells express negligible ATX.