Guangdong Provincial Key Laboratory of Infectious Disease and Molecular Immunopathology, Shantou University Medical College, China.
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Mol Oncol. 2023 Apr;17(4):664-685. doi: 10.1002/1878-0261.13384. Epub 2023 Feb 8.
In recent decades, antiangiogenic therapy, which blocks the supply of oxygen and nutrition to tumor cells, has become a promising clinical strategy for the treatment of patients with tumors. However, recent studies revealed that vasculogenic mimicry (VM), which is the process by which vascular morphological structures are formed by highly invasive tumor cells, has been considered a potential factor for the failure of antiangiogenic therapy in patients with tumors. Thus, inhibition of VM formation might be a potential target for improving the outcome of antiangiogenic strategies. However, the mechanism underlying VM formation is still incompletely elucidated. Herein, we report that L1CAM might be a critical regulator of VM formation in glioma, and might be associated with the resistance of glioma to antiangiogenic therapy. We found that the tumor-invasion and tube-formation capabilities of L1CAM-overexpressing cells were significantly enhanced in vitro and in vivo. In addition, the results indicated that miR-143-3p, which might directly target the 3'UTR of the hexokinase 2 (HK2) gene to regulate its protein expression, was subsequently involved in L1CAM-mediated VM formation by glioma cells. Further study revealed that the regulation of MMP2, MMP9, and VEGFA expression was involved in this process. Moreover, we identified that activation of the downstream PI3K/AKT signaling pathway of the L1CAM/HK2 cascade is critical for VM formation by glioma cells. Furthermore, we found that the combined treatment of anti-L1CAM neutralizing monoclonal antibody and bevacizumab increases efficacy beyond that of bevacizumab alone, and suppresses glioma growth in vivo, indicating that the inhibition of L1CAM-mediated VM formation might efficiently improve the effect of antiangiogenic treatment for glioma patients. Together, our findings demonstrated a critical role of L1CAM in regulating VM formation in glioma, and that L1CAM might be a potential target for ameliorating tumor resistance to antiangiogenic therapy in glioma patients.
在最近几十年中，抗血管生成治疗（通过阻断肿瘤细胞的氧气和营养供应来治疗肿瘤）已成为治疗肿瘤患者的一种有前途的临床策略。然而，最近的研究表明，血管生成拟态（VM），即高度侵袭性肿瘤细胞形成血管形态结构的过程，已被认为是肿瘤患者抗血管生成治疗失败的潜在因素。因此，抑制 VM 形成可能是改善抗血管生成策略效果的潜在目标。然而，VM 形成的机制仍不完全清楚。在这里，我们报告 L1CAM 可能是胶质瘤中 VM 形成的关键调节因子，并且可能与胶质瘤对抗血管生成治疗的耐药性有关。我们发现，L1CAM 过表达细胞的肿瘤侵袭和管形成能力在体外和体内均显著增强。此外，结果表明，miR-143-3p 可能通过直接靶向己糖激酶 2（HK2）基因的 3'UTR 来调节其蛋白表达，从而参与 L1CAM 介导的胶质瘤细胞 VM 形成。进一步的研究表明，该过程涉及 MMP2、MMP9 和 VEGFA 表达的调节。此外，我们确定了 L1CAM/HK2 级联的下游 PI3K/AKT 信号通路的激活对于胶质瘤细胞的 VM 形成至关重要。此外，我们发现抗 L1CAM 中和单克隆抗体与贝伐单抗联合治疗的效果优于贝伐单抗单独治疗，并且抑制了体内胶质瘤的生长，表明抑制 L1CAM 介导的 VM 形成可能有效地改善抗血管生成治疗对胶质瘤患者的效果。总之，我们的研究结果表明 L1CAM 在调节胶质瘤中 VM 形成中起关键作用，并且 L1CAM 可能是改善胶质瘤患者对抗血管生成治疗耐药性的潜在靶点。
