PD-L1+ aneuploid circulating tumor endothelial cells (CTECs) exhibit resistance to the checkpoint blockade immunotherapy in advanced NSCLC patients

Zhang, Lina; Zhang, Xinyong; Liu, Yanxia; Zhang, Tongmei; Wang, Ziyu; Gu, Meng; Li, Yilin; Wang, Daisy Dandan; Li, Weiying; Lin, Peter Ping

doi:10.1016/j.canlet.2019.10.041

Cited by 62 publications

(87 citation statements)

References 51 publications

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“…CSCs, therefore, are the central nodes of transdifferentiation. Among the transdifferentiated TECs in carcinoma patients, some express TMs as either shown in this review or demonstrated previously by us [ 11 , 12 , 13 ].…”

Section: Mechanism Of Tumor-derived Ec and Ctec Formation: Endothesupporting

confidence: 79%

“…Compared to transdifferentiation, cell fusion principally accounts for the observed cell identity changes [ 75 ]. Among individual non-hematologic CTECs [ 12 , 13 ] and their clusters [ 11 , 12 ] obtained from either transdifferentiation or cell fusion, those harboring a mixed phenotype of both endothelial lineage and various tumor markers (TMs) are either aneuploid or infrequently diploid.…”

Section: Mechanism Of Tumor-derived Ec and Ctec Formation: Endothementioning

confidence: 99%

“…As discussed above, although some non-clustered, mononuclear, polyploid, abnormal null CECs derived from stromal cell transdifferentiation or cellular senescence were occasionally detected in healthy subjects [ 11 ], multinuclear fusogenic aneuploid EC clusters were observed only in the diagnosed cancer patients’ peripheral blood (termed as CTEC microemboli) [ 11 , 12 ] or bone marrow (DTEC microemboli shown in Figure 2 ), not in healthy donors. It is interesting to point out that in cancer patients, besides those expressing TMs, many aneuploid CD31 + CTECs have no TM expression, namely the null CTECs.…”

Section: Mechanism Of Tumor-derived Ec and Ctec Formation: Endothementioning

confidence: 99%

“…Following their shedding into peripheral blood, TECs turn into circulating tumor-derived endothelial cells (CTECs) [ 11 ]. Some CTECs in different types of carcinoma patients were found to express a variety of tumor and mesenchymal markers, such as HER2, PD-L1, EpCAM, CD44v6 and Vimentin [ 11 , 12 , 13 ]. Aneuploid CD31 + CTECs and their counterpart CD31 – CTCs compose a unique pair of cellular circulating tumor biomarkers in cancer patients [ 12 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Aneuploid Circulating Tumor-Derived Endothelial Cell (CTEC): A Novel Versatile Player in Tumor Neovascularization and Cancer Metastasis

Lin

2020

Cells

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Hematogenous and lymphogenous cancer metastases are significantly impacted by tumor neovascularization, which predominantly consists of blood vessel-relevant angiogenesis, vasculogenesis, vasculogenic mimicry, and lymphatic vessel-related lymphangiogenesis. Among the endothelial cells that make up the lining of tumor vasculature, a majority of them are tumor-derived endothelial cells (TECs), exhibiting cytogenetic abnormalities of aneuploid chromosomes. Aneuploid TECs are generated from “cancerization of stromal endothelial cells” and “endothelialization of carcinoma cells” in the hypoxic tumor microenvironment. Both processes crucially engage the hypoxia-triggered epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndoMT). Compared to the cancerization process, endothelialization of cancer cells, which comprises the fusion of tumor cells with endothelial cells and transdifferentiation of cancer cells into TECs, is the dominant pathway. Tumor-derived endothelial cells, possessing the dual properties of cancerous malignancy and endothelial vascularization ability, are thus the endothelialized cancer cells. Circulating tumor-derived endothelial cells (CTECs) are TECs shed into the peripheral circulation. Aneuploid CD31+ CTECs, together with their counterpart CD31- circulating tumor cells (CTCs), constitute a unique pair of cellular circulating tumor biomarkers. This review discusses a proposed cascaded framework that focuses on the origins of TECs and CTECs in the hypoxic tumor microenvironment and their clinical implications for tumorigenesis, neovascularization, disease progression, and cancer metastasis. Aneuploid CTECs, harboring hybridized properties of malignancy, vascularization and motility, may serve as a unique target for developing a novel metastasis blockade cancer therapy.

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Section: Mechanism Of Tumor-derived Ec and Ctec Formation: Endothesupporting

confidence: 79%

Section: Mechanism Of Tumor-derived Ec and Ctec Formation: Endothementioning

confidence: 99%

Section: Mechanism Of Tumor-derived Ec and Ctec Formation: Endothementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Aneuploid Circulating Tumor-Derived Endothelial Cell (CTEC): A Novel Versatile Player in Tumor Neovascularization and Cancer Metastasis

Lin

2020

Cells

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“…After all, in congruence with other works, a decrease in both circulating EnC and EPC correlated with a longer PFS or OS in the majority of studies, before and after effective anti-angiogenic therapy and/or chemotherapy [85,86] Polyploidy is a common cellular cancer marker and has been included into investigations on circulating EnC [34,87,88]. Latest work on the topic may come from Zhang et al [88], employing Cytelligen's SE-iFISH to identify PD-L1 positive, aneuploid circulating EnC (multiploidy in chromosme 8) assumed to be tumor-associated and investigating their usefulness as companion diagnostic as to predict resistance to checkpoint blockade immunotherapy in advanced NSCLC patient [88]. The authors reported that patients with multiploid PD-L1+ tumor-associated circulating EnC were found to have a statistically significant shorter PFS when compared to the subjects without.…”

Section: Endothelial Cell Clinical Usesupporting

confidence: 77%

The Blood Circulating Rare Cell Population. What Is It and What Is It Good for?

Schreier

Triampo

2020

Cells

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Blood contains a diverse cell population of low concentration hematopoietic as well as non-hematopoietic cells. The majority of such rare cells may be bone marrow-derived progenitor and stem cells. This paucity of circulating rare cells, in particular in the peripheral circulation, has led many to believe that bone marrow as well as other organ-related cell egress into the circulation is a response to pathological conditions. Little is known about this, though an increasing body of literature can be found suggesting commonness of certain rare cell types in the peripheral blood under physiological conditions. Thus, the isolation and detection of circulating rare cells appears to be merely a technological problem. Knowledge about rare cell types that may circulate the blood stream will help to advance the field of cell-based liquid biopsy by supporting inter-platform comparability, making use of biological correct cutoffs and “mining” new biomarkers and combinations thereof in clinical diagnosis and therapy. Therefore, this review intends to lay ground for a comprehensive analysis of the peripheral blood rare cell population given the necessity to target a broader range of cell types for improved biomarker performance in cell-based liquid biopsy.

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Role of aneuploid circulating tumor cells and CD31⁺ circulating tumor endothelial cells in predicting and monitoring anti‐angiogenic therapy efficacy in advanced NSCLC

Zhang

Gao

et al. 2021

Molecular Oncology

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Prognosticating the efficacy of anti‐angiogenic therapy through longitudinal monitoring and early detection of treatment resistance in cancer patients remain highly challenging. In this study, co‐detection and comprehensive phenotypic and karyotypic molecular characterization of aneuploid circulating tumor cells (CTCs) and circulating tumor endothelial cells (CTECs) were conducted on non‐small cell lung cancer (NSCLC) patients receiving bevacizumab plus chemotherapy. Prognostic values of the cell‐based significant univariate risk factors identified by Cox regression analyses were progressively investigated. Subjects showing an increase in total post‐therapeutic platelet endothelial cell adhesion molecule‐1 (CD31)– CTCs and CD31+ CTECs exhibited a significantly reduced median progression‐free survival (mPFS) and overall survival. Further stratification analyses indicated that pretherapeutic patients bearing vimentin (Vim)+ CTECs (mesenchymal M‐type) at baseline revealed a significantly shortened mPFS compared with patients with Vim– CTECs. Post‐therapeutic patients harboring epithelial cell adhesion molecule (EpCAM)+ CTCs and CTECs (epithelial E‐type), regardless of Vim expression or not, showed a significantly reduced mPFS. Post‐therapeutic patients possessing de novo EpCAM+/Vim+ (hybrid E/M‐type) CTECs displayed the shortest mPFS. Patients harboring either pre‐ or post‐therapeutic EpCAM–/Vim– null CTECs (N‐type) exhibited a better response to therapy compared to patients harboring EpCAM+ and/or Vim+ CTECs. The presented results support the notion that baseline Vim+ CTECs and post‐therapeutic EpCAM+ CTCs and CTECs are predictive biomarkers for longitudinal monitoring of response to anti‐angiogenesis combination regimens in NSCLC patients.

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PD-L1+ aneuploid circulating tumor endothelial cells (CTECs) exhibit resistance to the checkpoint blockade immunotherapy in advanced NSCLC patients

Cited by 62 publications

References 51 publications

Aneuploid Circulating Tumor-Derived Endothelial Cell (CTEC): A Novel Versatile Player in Tumor Neovascularization and Cancer Metastasis

Aneuploid Circulating Tumor-Derived Endothelial Cell (CTEC): A Novel Versatile Player in Tumor Neovascularization and Cancer Metastasis

The Blood Circulating Rare Cell Population. What Is It and What Is It Good for?

Role of aneuploid circulating tumor cells and CD31⁺ circulating tumor endothelial cells in predicting and monitoring anti‐angiogenic therapy efficacy in advanced NSCLC

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PD-L1+ aneuploid circulating tumor endothelial cells (CTECs) exhibit resistance to the checkpoint blockade immunotherapy in advanced NSCLC patients

Cited by 62 publications

References 51 publications

Aneuploid Circulating Tumor-Derived Endothelial Cell (CTEC): A Novel Versatile Player in Tumor Neovascularization and Cancer Metastasis

Aneuploid Circulating Tumor-Derived Endothelial Cell (CTEC): A Novel Versatile Player in Tumor Neovascularization and Cancer Metastasis

The Blood Circulating Rare Cell Population. What Is It and What Is It Good for?

Role of aneuploid circulating tumor cells and CD31+ circulating tumor endothelial cells in predicting and monitoring anti‐angiogenic therapy efficacy in advanced NSCLC

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Product

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Role of aneuploid circulating tumor cells and CD31⁺ circulating tumor endothelial cells in predicting and monitoring anti‐angiogenic therapy efficacy in advanced NSCLC