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已发表论文
ICAM1 介导的内皮细胞与巨噬细胞相互作用在调节胶质母细胞瘤恶性转化中的作用
Authors Li J, Liang T, Liang B, Kang X, Wu W, Wang H, Yang H, Wang Y, Ma W
Received 4 June 2025
Accepted for publication 21 October 2025
Published 5 November 2025 Volume 2025:18 Pages 15409—15427
DOI https://doi.org/10.2147/JIR.S544632
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Felix Marsh-Wakefield
Junlin Li,1,2,* Tingyu Liang,1,* Bo Liang,3,4,* Xiaoman Kang,1 Wenbo Wu,1 Hai Wang,1 Huiyu Yang,1 Yu Wang,1,5 Wenbin Ma1,5
1Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 2Eight-Year Medical Doctor Program, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People’s Republic of China; 3Department of Neurosurgery, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4National Center for Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 5China Anti-Cancer Association Specialty Committee of Glioma, Beijing, 100730, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Yu Wang, Department of Neurosurgery, Peking Union Medical College Hospital, Dongcheng District, Beijing, People’s Republic of China, Email ywang@pumch.cn Wenbin Ma, Department of Neurosurgery, Peking Union Medical College Hospital, Dongcheng District, Beijing, People’s Republic of China, Email mawb2001@hotmail.com
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.
Plain Language Summary: GBM, the most aggressive brain tumor, often relapses after treatment. Microvascular proliferation is an important feature of GBM. These endothelial cells play a key role in shaping the tumor environment. Nevertheless, the changes in these cells during tumor recurrence are not fully understood.
In this study, single-cell data from GBM patients were analyzed to explore the behavior of endothelial cells. It was found that two main types of endothelial cells exist in GBM, and the type that increases during tumor recurrence is linked to a worse outcome for patients. It was identified that a gene called ICAM1 is up-regulated in this group of endothelial cells. This result was also found in patient samples. It was confirmed that ICAM1 is also elevated in rGBM, and its higher levels are associated with poorer patient prognosis. Moreover, hypoxia may lead to an increase of ICAM1.
Research was also conducted on how endothelial cells interact with other cells, particularly macrophages, which are the most immune cells. It was discovered that ICAM1 attracts macrophages. In the meantime, these endothelial cells secrete CCL2, which promotes the expression of ADM in macrophages. In turn, macrophages release ADM to promote blood vessel growth and also facilitate the growth and movement of cancer cells.
The findings show that a complex feedback loop, where endothelial cells, macrophages and tumor cells work together to support tumor growth, exists in rGBM. This understanding could bring about new ways to target these interactions and improve treatment for patients with rGBM.
Keywords: glioblastoma, endothelial cells, intercellular adhesion molecule 1, adrenomedullin
1Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 2Eight-Year Medical Doctor Program, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People’s Republic of China; 3Department of Neurosurgery, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4National Center for Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 5China Anti-Cancer Association Specialty Committee of Glioma, Beijing, 100730, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Yu Wang, Department of Neurosurgery, Peking Union Medical College Hospital, Dongcheng District, Beijing, People’s Republic of China, Email ywang@pumch.cn Wenbin Ma, Department of Neurosurgery, Peking Union Medical College Hospital, Dongcheng District, Beijing, People’s Republic of China, Email mawb2001@hotmail.com
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.
Plain Language Summary: GBM, the most aggressive brain tumor, often relapses after treatment. Microvascular proliferation is an important feature of GBM. These endothelial cells play a key role in shaping the tumor environment. Nevertheless, the changes in these cells during tumor recurrence are not fully understood.
In this study, single-cell data from GBM patients were analyzed to explore the behavior of endothelial cells. It was found that two main types of endothelial cells exist in GBM, and the type that increases during tumor recurrence is linked to a worse outcome for patients. It was identified that a gene called ICAM1 is up-regulated in this group of endothelial cells. This result was also found in patient samples. It was confirmed that ICAM1 is also elevated in rGBM, and its higher levels are associated with poorer patient prognosis. Moreover, hypoxia may lead to an increase of ICAM1.
Research was also conducted on how endothelial cells interact with other cells, particularly macrophages, which are the most immune cells. It was discovered that ICAM1 attracts macrophages. In the meantime, these endothelial cells secrete CCL2, which promotes the expression of ADM in macrophages. In turn, macrophages release ADM to promote blood vessel growth and also facilitate the growth and movement of cancer cells.
The findings show that a complex feedback loop, where endothelial cells, macrophages and tumor cells work together to support tumor growth, exists in rGBM. This understanding could bring about new ways to target these interactions and improve treatment for patients with rGBM.
Keywords: glioblastoma, endothelial cells, intercellular adhesion molecule 1, adrenomedullin