Journal of inflammation research · 2025
ICAM1-Mediated Endothelial Cells and Macrophage Interactions in Modulating GBM Malignant Transformation.
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Li Junlin, Liang Tingyu, Liang Bo, Kang Xiaoman, Wu Wenbo, Wang Hai, Yang Huiyu, Wang Yu, Ma Wenbin
Аннотация
BACKGROUND: Glioblastoma (GBM) recurs frequently as the most common primary malignant brain tumor. Microvascular proliferation is a hallmark of GBM. Endothelial cells contribute to the tumor microenvironment (TME) in primary GBM and promote malignancy. However, their role in recurrent GBM (rGBM) remains unclear.
METHODS: An analysis was made of single-cell RNA data from GSE182109. Endothelial cells were isolated. Subclusters underwent differential expression and pseudotime trajectory analysis for the identification of signature genes. TCGA data confirmed the expression patterns and prognostic significance of signature genes. Immunofluorescence was performed on matched primary-recurrent GBM samples. Signature genes were knocked down in human umbilical vein endothelial cells (HUVECs). Co-culture experiments with THP-1 and U87 cells explored crosstalk mechanisms and their potential upstream and downstream pathways.
RESULTS: Two endothelial cell clusters were identified in single-cell analysis. Cluster 1 showed an elevation in rGBM and was associated with a poorer prognosis. Pseudotime analysis identified intercellular adhesion molecule-1 (ICAM1) as a signature gene. ICAM1 was up-regulated in rGBM, which was likely due to hypoxia. The knockdown of ICAM1 in endothelial cells reduced the adhesion of bone marrow-derived macrophages (BMDMs). Meanwhile, adrenomedullin (ADM) expression was decreased by lowering CCL2. Co-culture experiments demonstrated that macrophage-secreted ADM facilitated angiogenesis and the proliferation and migration of tumor cells.
CONCLUSION: This study suggests that hypoxia induces endothelial cells to upregulate the expression of ICAM1 during GBM recurrence and facilitates the recruitment of BMDMs. Concurrently, endothelial-derived CCL2 induces the expression of ADM in BMDMs. This macrophage-derived ADM, in turn, accelerates angiogenesis in endothelial cells while enhancing the proliferation and migration of tumor cells. These results elucidate a feedforward loop in the endothelial-BMDM-tumor cell axis, and provide mechanistic insights into the TME of rGBM.
METHODS: An analysis was made of single-cell RNA data from GSE182109. Endothelial cells were isolated. Subclusters underwent differential expression and pseudotime trajectory analysis for the identification of signature genes. TCGA data confirmed the expression patterns and prognostic significance of signature genes. Immunofluorescence was performed on matched primary-recurrent GBM samples. Signature genes were knocked down in human umbilical vein endothelial cells (HUVECs). Co-culture experiments with THP-1 and U87 cells explored crosstalk mechanisms and their potential upstream and downstream pathways.
RESULTS: Two endothelial cell clusters were identified in single-cell analysis. Cluster 1 showed an elevation in rGBM and was associated with a poorer prognosis. Pseudotime analysis identified intercellular adhesion molecule-1 (ICAM1) as a signature gene. ICAM1 was up-regulated in rGBM, which was likely due to hypoxia. The knockdown of ICAM1 in endothelial cells reduced the adhesion of bone marrow-derived macrophages (BMDMs). Meanwhile, adrenomedullin (ADM) expression was decreased by lowering CCL2. Co-culture experiments demonstrated that macrophage-secreted ADM facilitated angiogenesis and the proliferation and migration of tumor cells.
CONCLUSION: This study suggests that hypoxia induces endothelial cells to upregulate the expression of ICAM1 during GBM recurrence and facilitates the recruitment of BMDMs. Concurrently, endothelial-derived CCL2 induces the expression of ADM in BMDMs. This macrophage-derived ADM, in turn, accelerates angiogenesis in endothelial cells while enhancing the proliferation and migration of tumor cells. These results elucidate a feedforward loop in the endothelial-BMDM-tumor cell axis, and provide mechanistic insights into the TME of rGBM.