Interaction with CD68 and Regulation of GAS6 Expression by Endosialin in Fibroblasts Drives Recruitment and Polarization of Macrophages in Hepatocellular Carcinoma

Fa, Yang; Yan, Wei; Han, Donghui; Yu, Li; Shi, Shengjia; Jiao, Dian; Wu, Jieheng; Zhang, Qiang; Shi, Changhong; Yang, Lijun; Song, Wei; Zhang, Jingliang; Han, Yueheng; Zhang, Rui; Yang, An; Dimitrov, Dimiter S.; Zhao, Aizhi; Qin, Weijun; Wen, Weihong

doi:10.1158/0008-5472.can-19-2691

Cited by 72 publications

(76 citation statements)

References 47 publications

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“…In our previous study, we found that PSMA and CD248 were both expressed specifically in the vasculature in hepatocellular carcinoma (HCC), and vascular-expressed PSMA and CD248 might be used as prognostic markers and vascular therapeutic targets for HCC ( 30 , 31 ). We also found that overexpression of CD248 in renal cell carcinoma (RCC) was related to poor prognosis ( 32 ).…”

Section: Introductionmentioning

confidence: 99%

Prognostic Value of Vascular-Expressed PSMA and CD248 in Urothelial Carcinoma of the Bladder

Liu

Zhang

et al. 2021

Front. Oncol.

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BackgroundUrothelial carcinoma of the bladder (UCB) is a common cancer of the urinary system. Despite substantial improvements in available treatment options, the survival outcome of patients with advanced UCB is unsatisfactory. Therefore, it is necessary to identify new prognostic biomarkers for monitoring and therapy guidance of UCB. In recent years, prostate-specific membrane antigen (PSMA) and CD248 have been identified promising candidate bio7markers.MethodsIn this study, we first examined PSMA and CD248 expression in tissues from 124 patients with UCB using immunohistochemical and immunofluorescent staining. We then analyzed the association between the expression of the two biomarkers and other clinicopathological features and prognosis. Finally, we performed bioinformatic analysis of CD248 and FOLH 1 (PSMA) using the TCGA-BLCA dataset to explore the underlying mechanism of PSMA and CD248 in the progression of UCB.ResultsAmong the 124 cases, PSMA and CD248 were confirmed to be expressed in tumor-associated vessels. Vascular PSMA and CD248 expression levels were associated significantly with several deteriorated clinicopathological features. Furthermore, using univariate and multivariate Cox analyses, high vascular PSMA and CD248 expression levels were observed to be associated significantly with poor prognosis in patients with UCB. As risk factors, both PSMA and CD248 expression showed good performance to predict prognosis. Furthermore, combining these vascular molecules with other clinical risk factors generated a risk score that could promote predictive performance. Bioinformatic analysis showed that both PSMA and CD248 might contribute to angiogenesis and promote further progression of UCB.ConclusionBoth PSMA and CD248 are specifically expressed in the tumor-associated vasculature of UCB. These two molecules might be used as novel prognostic biomarkers and vascular therapeutic targets for UCB.

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Section: Introductionmentioning

confidence: 99%

Prognostic Value of Vascular-Expressed PSMA and CD248 in Urothelial Carcinoma of the Bladder

Liu

Zhang

et al. 2021

Front. Oncol.

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“…9 CD248 was initially identified on blood vessels of various human tumors and was subsequently defined as an abnormally expressed marker of tumor endothelial cells, 9 involving in the reorganization of tumor blood vessels. 10 Recently, emerging observations indicate that CD248 is also expressed in non-endothelial perivascular cells, such as pericytes, 11 fibroblasts, 12 mesenchymal cells, 13 and CD8+ T cells, 14 arguing that CD248-mediated actions are not confined to vascular endothelial cells but rather may extend to vascular remodeling/inflammation process. So far, the functions of CD248 in human vascular pathologies remain unexplored.…”

Section: Introductionmentioning

confidence: 99%

CD248+CD8+ T lymphocytes suppress pathological vascular remodeling in human thoracic aortic aneurysms

Wu²,

Wang

et al. 2020

Exp Biol Med (Maywood)

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Aortic aneurysms are characterized by vascular inflammation, neovascularization, and extracellular matrix destruction of the aortic wall. Although experimental studies indicate a potential role of CD248 in microvessel remodeling, the functions of CD248 in human vascular pathologies remain unexplored. Here we aimed to study how CD248 interferes with pathological vascular remodeling of human aortic aneurysms. Immunofluorescent staining showed that CD248 expression was mainly localized in the CD8+ T cells infiltrating in the adventitia and media of aortic walls of patients with ascending thoracic aortic aneurysms. qPCR and immunofluorescent staining analyses revealed increased aortic CD248 expression and infiltrating CD248+CD8+ T cells in aortic aneurysms than in nonaneurysmal aortas. Flow cytometry analysis of human peripheral blood further identified a fraction of circulating CD248+ cells which was confined in the CD8+ T-cell compartment. The increased infiltrating of CD248+CD8+ T cells was coincident with reduced circulating CD248+CD8+ T cells in patients with ascending TAA when compared with patients with coronary artery diseases and healthy donors. The CD248+CD8+ T cells were characterized by upregulated IL-10 and downregulated IL-1β/INF-γ expression when compared with CD248-CD8+ T cells. Moreover, when co-cultured with human aortic endothelial cells, the CD248+CD8+ T cells not only downregulated endothelial expression of ICAM1/VCAM1 and MMP2/3 but also suppressed endothelial migration. This study shows that CD248 reduces pathological vascular remodeling via anti-inflammatory CD248+CD8+ T cells, revealing a CD248-mediated cellular mechanism against human aortic aneurysms. Impact statement In spite of recent evidence indicating that CD248 is linked to microvasculature remodeling, immune response, and MMP activity, the functions of CD248 in human TAA remain unexplored. In this work, by analyzing cellular components of in situ as well as of blood circulation of human TAA, we have identified a novel T cell subset, the CD248+CD8+ T cells, which exhibits anti-inflammatory properties, and that we have also provided the first evidence that these cells not only suppress endothelial expression of ICAM1/VCAM1 and MMP2/3, but also inhibit endothelial migration, thus uncovering a CD248-mediated cellular mechanism against pathological vascular remodeling in human aortic aneurysms.

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“…As such, the activation of MERTK increased the production of antiinflammatory cytokines [151]. It is worth noting that Gas6 is produced and released from cancer-associated fibroblasts and M2 macrophages, suggesting a positive feedback loop that drastically reinforces the immunosuppressive environment in tumors [153].…”

Section: The Role Of Mertk In Efferocytosismentioning

confidence: 95%

MERTK Inhibition: Potential as a Treatment Strategy in EGFR Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer

Chen

Liu

2021

Pharmaceuticals

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Epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) are currently the most effective treatment for non-small cell lung cancer (NSCLC) patients, who carry primary EGFR mutations. However, the patients eventually develop drug resistance to EGFR-TKIs after approximately one year. In addition to the acquisition of the EGFR T790M mutation, the activation of alternative receptor-mediated signaling pathways is a common mechanism for conferring the insensitivity of EGFR-TKI in NSCLC. Upregulation of the Mer receptor tyrosine kinase (MERTK), which is a member of the Tyro3-Axl-MERTK (TAM) family, is associated with a poor prognosis of many cancers. The binding of specific ligands, such as Gas6 and PROS1, to MERTK activates phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) cascades, which are the signaling pathways shared by EGFR. Therefore, the inhibition of MERTK can be considered a new therapeutic strategy for overcoming the resistance of NSCLC to EGFR-targeted agents. Although several small molecules and monoclonal antibodies targeting the TAM family are being developed and have been described to enhance the chemosensitivity and converse the resistance of EGFR-TKI, few have specifically been developed as MERTK inhibitors. The further development and investigation of biomarkers which can accurately predict MERTK activity and the response to MERTK inhibitors and MERTK-specific drugs are vitally important for obtaining appropriate patient stratification and increased benefits in clinical applications.

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Interaction with CD68 and Regulation of GAS6 Expression by Endosialin in Fibroblasts Drives Recruitment and Polarization of Macrophages in Hepatocellular Carcinoma

Cited by 72 publications

References 47 publications

Prognostic Value of Vascular-Expressed PSMA and CD248 in Urothelial Carcinoma of the Bladder

Prognostic Value of Vascular-Expressed PSMA and CD248 in Urothelial Carcinoma of the Bladder

CD248+CD8+ T lymphocytes suppress pathological vascular remodeling in human thoracic aortic aneurysms

MERTK Inhibition: Potential as a Treatment Strategy in EGFR Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer

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