Harper Kelly, Brochu-Gaudreau Karine, Saucier Caroline, Dubois Claire M
Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, QC J1H 5N4, Canada.
Cancers (Basel). 2019 Sep 19;11(9):1403. doi: 10.3390/cancers11091403.
Hypoxia is a common characteristic of advanced solid tumors and a potent driver of tumor invasion and metastasis. Recent evidence suggests the involvement of autotaxin (ATX) and lysophosphatidic acid receptors (LPARs) in cancer cell invasion promoted by the hypoxic tumor microenvironment; however, the transcriptional and/or spatiotemporal control of this process remain unexplored. Herein, we investigated whether hypoxia promotes cell invasion by affecting the main enzymes involved in its production (ATX) and degradation (lipid phosphate phosphatases, LPP1 and LPP3). We report that hypoxia not only modulates the expression levels of lysophosphatidic acid (LPA) regulatory enzymes but also induces their significant spatial segregation in a variety of cancers. While LPP3 expression was downregulated by hypoxia, ATX and LPP1 were asymmetrically redistributed to the leading edge and to the trailing edge, respectively. This was associated with the opposing roles of ATX and LPPs in cell invasion. The regulated expression and compartmentalization of these enzymes of opposing function can provide an effective way to control the generation of an LPA gradient that drives cellular invasion and migration in the hypoxic zones of tumors.
缺氧是晚期实体瘤的一个常见特征，也是肿瘤侵袭和转移的一个强大驱动因素。最近的证据表明，自分泌运动因子（ATX）和溶血磷脂酸受体（LPARs）参与了缺氧肿瘤微环境促进的癌细胞侵袭；然而，这一过程的转录和/或时空控制仍未得到探索。在此，我们研究了缺氧是否通过影响其产生（ATX）和降解（脂质磷酸磷酸酶，LPP1和LPP3）所涉及的主要酶来促进细胞侵袭。我们报告，缺氧不仅调节溶血磷脂酸（LPA）调节酶的表达水平，还在多种癌症中诱导它们显著的空间分离。虽然缺氧使LPP3表达下调，但ATX和LPP1分别不对称地重新分布到前沿和后沿。这与ATX和LPPs在细胞侵袭中的相反作用有关。这些功能相反的酶的表达调控和区室化可以提供一种有效的方式来控制LPA梯度的产生，该梯度驱动肿瘤缺氧区域的细胞侵袭和迁移。
