L1CAM promotes vasculogenic mimicry formation by miR‐143‐3p‐induced expression of hexokinase 2 in glioma

Abstract

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.

HNRNPA2B1 stabilizes NFATC3 levels to potentiate its combined actions with FOSL1 to mediate vasculogenic mimicry in GBM cells

“…The cellular features of VM include the prominence of matrix protein-rich cells that do not express endothelial markers such as CD31 and CD34, while showing positive histochemical staining for periodic acid–Schiff (PAS) that detects the abundant carbohydrate stores (predominantly glycogen) in tumor cells, and the presence of blood components (Maniotis et al 1999 ; Xiang et al 2018 , Buccarelli et al 2022 ). VM also leads to the creation of a microenvironment that can deliver oxygen and nutrients to tumors, which is associated with the development and metastasis of a variety of tumors, including gliomas, and is ineffective against anti-angiogenic therapy (Huang, et al 2023 ). Indeed, patients with tumors that feature VM have worse clinical outcomes that those that do not feature VM (Luo et al 2020 ).…”

Down-regulated FTO and ALKBH5 co-operatively activates FOXO signaling through m6A methylation modification in HK2 mRNA mediated by IGF2BP2 to enhance glycolysis in colorectal cancer

“…The accumulation of glucose in tumor tissue provides a massive source of energy for tumor progression [ 10 ]. Glycolysis-related genes and transcriptional regulators have been found to correlate with the poor prognosis of various malignant tumors [ 11 ]. More interestingly, m6A modification is involved in regulating glycolysis in CRC [ 12 ], however, its role in glycolysis modification remains unclear.…”

SUMOylation of RALY promotes vasculogenic mimicry in glioma cells via the FOXD1/DKK1 pathway

“…VM represents a tumor microcirculation model that refers to the formation of non-endothelial blood vessels by tumor cells through extracellular matrix remodeling and deformation (Fernandez-Cortes et al 2019). The phenomenon of VM has been confirmed in a variety of tumors, including hepatocellular carcinoma (HCC), non-small-cell lung cancer (NSCLC), and glioma (Chu et al 2021;Huang et al 2023;Zhou et al 2021). It is associated with aggressive biological behavior, reduced anti-angiogenesis treatment efficacy, and enhanced tumor-related mortality (Dudley et al 2023).…”