Benesch Matthew G K, MacIntyre Iain T K, McMullen Todd P W, Brindley David N
Discipline of Surgery, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL AlB 3V6, Canada.
Signal Transduction Research Group, Cancer Research Institute of Northern Alberta, Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2S2, Canada.
Cancers (Basel). 2018 Mar 15;10(3):73. doi: 10.3390/cancers10030073.
A quarter-century after the discovery of autotaxin in cell culture, the autotaxin-lysophosphatidate (LPA)-lipid phosphate phosphatase axis is now a promising clinical target for treating chronic inflammatory conditions, mitigating fibrosis progression, and improving the efficacy of existing cancer chemotherapies and radiotherapy. Nearly half of the literature on this axis has been published during the last five years. In cancer biology, LPA signaling is increasingly being recognized as a central mediator of the progression of chronic inflammation in the establishment of a tumor microenvironment which promotes cancer growth, immune evasion, metastasis, and treatment resistance. In this review, we will summarize recent advances made in understanding LPA signaling with respect to chronic inflammation and cancer. We will also provide perspectives on the applications of inhibitors of LPA signaling in preventing cancer initiation, as adjuncts extending the efficacy of current cancer treatments by blocking inflammation caused by either the cancer or the cancer therapy itself, and by disruption of the tumor microenvironment. Overall, LPA, a simple molecule that mediates a plethora of biological effects, can be targeted at its levels of production by autotaxin, LPA receptors or through LPA degradation by lipid phosphate phosphatases. Drugs for these applications will soon be entering clinical practice.
在细胞培养中发现自分泌运动因子25年后，自分泌运动因子-溶血磷脂酸（LPA）-脂质磷酸酶轴如今已成为一个有前景的临床靶点，可用于治疗慢性炎症性疾病、减轻纤维化进展以及提高现有癌症化疗和放疗的疗效。关于该轴的文献近一半是在过去五年发表的。在癌症生物学中，LPA信号传导越来越被认为是肿瘤微环境建立过程中慢性炎症进展的核心介质，而肿瘤微环境会促进癌症生长、免疫逃逸、转移和治疗抵抗。在本综述中，我们将总结在理解LPA信号传导与慢性炎症和癌症方面的最新进展。我们还将探讨LPA信号传导抑制剂在预防癌症发生方面的应用前景，作为通过阻断癌症或癌症治疗本身引起的炎症以及破坏肿瘤微环境来延长当前癌症治疗疗效的辅助手段。总体而言，LPA是一种介导多种生物学效应的简单分子，可以通过自分泌运动因子的产生水平、LPA受体或通过脂质磷酸酶对LPA的降解来靶向作用。用于这些应用的药物很快将进入临床实践。
