Benesch Matthew G K, Tang Xiaoyun, Dewald Jay, Dong Wei-Feng, Mackey John R, Hemmings Denise G, McMullen Todd P W, Brindley David N
*Department of Biochemistry, Signal Transduction Research Group, and Department of Laboratory Medicine, Department of Oncology, Department of Obstetrics and Gynecology, Department of Medical Microbiology and Immunology, and Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
*Department of Biochemistry, Signal Transduction Research Group, and Department of Laboratory Medicine, Department of Oncology, Department of Obstetrics and Gynecology, Department of Medical Microbiology and Immunology, and Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
FASEB J. 2015 Sep;29(9):3990-4000. doi: 10.1096/fj.15-274480. Epub 2015 Jun 12.
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-α 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.
与正常组织相比，许多癌细胞中自分泌运动因子（ATX）过表达。这种分泌型酶产生细胞外溶血磷脂酸，其通过6种G蛋白偶联受体（GPCR）发出信号以驱动癌症进展。我们之前的研究表明，在BALB/c小鼠中，抑制ATX可使4T1乳腺肿瘤生长在约11天内降低60%。然而，4T1细胞不会产生大量的ATX。相反，ATX由相邻的乳腺脂肪组织产生。我们研究了人类和小鼠乳腺肿瘤中这种相互作用的分子基础。乳腺癌细胞分泌的炎症介质会增加脂肪组织中ATX的产生。溶血磷脂酸信号增强会进一步增加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ATX抑制剂，IC90 = 100 nM；日本大阪小野制药株式会社）阻断荷4T1肿瘤小鼠的ATX活性，可打破这种恶性炎症循环，使癌症炎症脂肪组织中的20种炎症介质减少1.5至8倍。未荷瘤的脂肪垫中炎症介质水平没有显著降低。ONO-8430506还使血浆肿瘤坏死因子-α（TNF-α）和粒细胞集落刺激因子（G-CSF）细胞因子水平降低>70%，并使乳腺肿瘤及相邻脂肪组织中的白细胞浸润减少>50%。因此，在癌细胞表达的ATX可忽略不计的乳腺癌中，通过抑制ATX阻断肿瘤驱动的炎症对减少肿瘤生长有效。
