Autotaxin is an inflammatory mediator and therapeutic target in thyroid cancer
Autotaxin is an inflammatory mediator and therapeutic target in thyroid cancer
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DOI：
10.1530/erc-15-0045
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发表时间：
2015-08-01
影响因子：
3.9
通讯作者：
McMullen, Todd P. W.
中科院分区：
文献类型：
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作者：
Benesch, Matthew G. K.;Ko, Yi M.;McMullen, Todd P. W.
自分泌运动因子是将细胞外溶血磷脂酰胆碱转化为溶血磷脂酸（LPA）的分泌酶。在癌症中，LPA通过激活六种G蛋白偶联受体来增加肿瘤生长、转移和化学抗性。我们检查了超过200例人类甲状腺活检。自分泌运动因子在转移性沉积物和原发性癌中的表达是良性肿瘤或正常甲状腺组织的4 - 10倍。自分泌运动因子免疫组化染色也增加了良性肿瘤与白细胞浸润。恶性肿瘤与良性肿瘤的区别在于高肿瘤自分泌运动因子、LPA水平和炎症介质，包括IL 1 β、IL 6、IL 8、GMCSF、TNF α、CCL 2、CXCL 10和血小板衍生生长因子（PDGF）-AA。我们确定了这些结果的机制解释，并揭示了一个恶性调节循环，其中LPA增加了乳头状甲状腺癌培养物中16种炎症调节剂的分泌。相反，用十种炎性细胞因子和趋化因子或PDGF-AA和PDGF-BB处理癌细胞增加了自分泌运动因子的分泌。我们证实，这种自分泌运动因子/炎症循环发生在两个SCID小鼠模型的乳头状甲状腺癌通过阻断LPA信号转导使用自分泌运动因子抑制剂ONO-8430506。这降低了肿瘤中16种炎症介质的水平，并伴随着肿瘤体积减少50-60%。这是由于癌细胞的有丝分裂指数降低以及肿瘤中血管内皮生长因子和血管生成水平降低所致。我们的结果表明，自分泌运动因子/炎症循环是驱动恶性甲状腺肿瘤进展和可能的治疗耐药性的焦点。抑制autotaxin活性为减少甲状腺癌的炎症表型提供了一种有效的新策略，这应该是对其他治疗方式的补充。
Autotaxin is a secreted enzyme that converts extracellular lysophosphatidylcholine to lysophosphatidate (LPA). In cancers, LPA increases tumour growth, metastasis and chemoresistance by activating six G-protein coupled receptors. We examined >200 human thyroid biopsies. Autotaxin expression in metastatic deposits and primary carcinomas was four-to tenfold higher than in benign neoplasms or normal thyroid tissue. Autotaxin immunohistochemical staining was also increased in benign neoplasms with leukocytic infiltrations. Malignant tumours were distinguished from benign tumours by high tumour autotaxin, LPA levels and inflammatory mediators including IL1 beta, IL6, IL8, GMCSF, TNF alpha, CCL2, CXCL10 and platelet-derived growth factor (PDGF)-AA. We determined the mechanistic explanation for these results and revealed a vicious regulatory cycle in which LPA increased the secretion of 16 inflammatory modulators in papillary thyroid cancer cultures. Conversely, treating cancer cells with ten inflammatory cytokines and chemokines or PDGF-AA and PDGF-BB increased autotaxin secretion. We confirmed that this autotaxin/inflammatory cycle occurs in two SCID mouse models of papillary thyroid cancer by blocking LPA signalling using the autotaxin inhibitor ONO-8430506. This decreased the levels of 16 inflammatory mediators in the tumours and was accompanied by a 50-60% decrease in tumour volume. This resulted from a decreased mitotic index for the cancer cells and decreased levels of vascular endothelial growth factor and angiogenesis in the tumours. Our results demonstrate that the autotaxin/inflammatory cycle is a focal point for driving malignant thyroid tumour progression and possibly treatment resistance. Inhibiting autotaxin activity provides an effective and novel strategy for decreasing the inflammatory phenotype in thyroid carcinomas, which should complement other treatment modalities.