Exosome-associated lysophosphatidic acid signaling contributes to cancer pain.
Exosome-associated lysophosphatidic acid signaling contributes to cancer pain.
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DOI：
10.1097/j.pain.0000000000002967
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发表时间：
2023-12-01
期刊：
影响因子：
7.4
通讯作者：
中科院分区：
文献类型：
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作者：
癌细胞分泌的外泌体通过启动痛觉感觉神经元中的溶血磷脂酸信号传导来促进癌痛。与骨癌相关的疼痛仍然管理不善，用于治疗癌症的化疗药物通常会增加疼痛。发现既能减少癌症又能产生镇痛作用的双效药物是最佳途径。骨癌疼痛的机制涉及癌细胞和伤害神经元之间的相互作用。我们证明了纤维肉瘤细胞表达高水平的autotaxin (ATX)，一种合成溶血磷脂酸（LPA）的酶。溶血磷脂酸促进体外纤维肉瘤细胞增殖。溶血磷脂酸也是一种疼痛信号分子，可激活位于背根神经节痛觉神经元和卫星细胞上的LPA受体（LPARs）。因此，我们在骨癌疼痛的小鼠模型中研究了ATX-LPA-LPAR信号对疼痛的贡献，在骨癌疼痛模型中，纤维肉瘤细胞被植入跟骨及其周围，导致肿瘤生长和过敏。荷瘤小鼠血清中的LPA升高，阻断ATX或LPAR可减少肿瘤引起的过敏反应。由于癌细胞分泌的外泌体有助于过敏，而ATX与外泌体结合，我们确定了外泌体相关的ATX - lpa - lpar信号在癌症外泌体产生的过敏中的作用。将癌外泌体足底注射到幼稚小鼠体内，通过致敏c纤维伤害感受器产生超敏反应。抑制ATX或阻断LPAR以ATX - lpa - LPAR依赖的方式减弱癌症外泌体诱发的超敏反应。平行的体外研究表明，ATX-LPA-LPAR信号参与了癌症外泌体对背根神经节神经元的直接致敏。因此，我们的研究确定了一种癌症外泌体介导的途径，它可能代表了治疗骨癌患者肿瘤生长和疼痛的治疗靶点。
Exosomes secreted by cancer cells contribute to cancer pain by initiating lysophosphatidic acid signaling in nociceptive sensory neurons. Pain associated with bone cancer remains poorly managed, and chemotherapeutic drugs used to treat cancer usually increase pain. The discovery of dual-acting drugs that reduce cancer and produce analgesia is an optimal approach. The mechanisms underlying bone cancer pain involve interactions between cancer cells and nociceptive neurons. We demonstrated that fibrosarcoma cells express high levels of autotaxin (ATX), the enzyme synthetizing lysophosphatidic acid (LPA). Lysophosphatidic acid increased proliferation of fibrosarcoma cells in vitro. Lysophosphatidic acid is also a pain-signaling molecule, which activates LPA receptors (LPARs) located on nociceptive neurons and satellite cells in dorsal root ganglia. We therefore investigated the contribution of the ATX–LPA–LPAR signaling to pain in a mouse model of bone cancer pain in which fibrosarcoma cells are implanted into and around the calcaneus bone, resulting in tumor growth and hypersensitivity. LPA was elevated in serum of tumor-bearing mice, and blockade of ATX or LPAR reduced tumor-evoked hypersensitivity. Because cancer cell–secreted exosomes contribute to hypersensitivity and ATX is bound to exosomes, we determined the role of exosome-associated ATX–LPA–LPAR signaling in hypersensitivity produced by cancer exosomes. Intraplantar injection of cancer exosomes into naive mice produced hypersensitivity by sensitizing C-fiber nociceptors. Inhibition of ATX or blockade of LPAR attenuated cancer exosome-evoked hypersensitivity in an ATX–LPA–LPAR-dependent manner. Parallel in vitro studies revealed the involvement of ATX–LPA–LPAR signaling in direct sensitization of dorsal root ganglion neurons by cancer exosomes. Thus, our study identified a cancer exosome-mediated pathway, which may represent a therapeutic target for treating tumor growth and pain in patients with bone cancer.
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DOI：
10.1111/tra.12803
发表时间：
2021-07
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
--
作者：
Donoso-Quezada J;Ayala-Mar S;González-Valdez J
通讯作者：
González-Valdez J
影响因子：
3.7
作者：
Dubeykovskaya, Zinaida A.;Tu, Nguyen Huu;Garcia, Paulina D. Ramirez;Schmidt, Brian L.;Albertson, Donna G.
通讯作者：
Albertson, Donna G.
DOI：
10.1073/pnas.1521230113
发表时间：
2016-02-23
影响因子：
11.1
作者：
Kowal, Joanna;Arras, Guillaume;Thery, Clotilde
通讯作者：
Thery, Clotilde
影响因子：
1.9
作者：
Brose SA;Golovko SA;Golovko MY
通讯作者：
Golovko MY
癌细胞中的溶血磷脂酸信号传导：是什么使LPA如此特别？
影响因子：
6
作者：
Balijepalli P;Sitton CC;Meier KE
通讯作者：
Meier KE