Abstract
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.
Highlights
Aberrant stromal cells, sustained neovascularization, dysfunctional angiogenic vasculature, and infiltrated immune cells contribute to a tumor microenvironment (TME) suitable for tumor growth and cancer metastasis [1]
circulating endothelial cells (CECs) derived from stromal cell transdifferentiation or cellular senescence were occasionally detected in healthy subjects [11], multinuclear fusogenic aneuploid endothelial cell (EC) clusters were observed only in the diagnosed cancer patients’ peripheral blood [11,12] or bone marrow (DTEC microemboli shown in Figure 2), not in healthy donors
In the depicted cascade of circulating tumor-derived endothelial cells (CTECs) formation, hypoxia acts as a pivotal trigger, epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndoMT) work as the crucial hubs, cancer stem cell (CSC) and mesenchymal stromal/stem cell (MSC) are the central nodes, ECs and tumor-derived ECs (TECs) in lymphatic and blood vessels are the essential contributors, and CTECs are the important players in tumor neovascularization and cancer metastasis
Summary
Aberrant stromal cells, sustained neovascularization, dysfunctional angiogenic vasculature, and infiltrated immune cells contribute to a tumor microenvironment (TME) suitable for tumor growth and cancer metastasis [1]. Hematogenous and lymphogenous cancer metastases are significantly impacted by tumor neovascularization [2], of which the latter is predominantly comprised of endothelium-dependent angiogenesis, vasculogenesis, lymphangiogenesis, and endothelium-independent vasculogenic mimicry (VM) Both epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndoMT) are involved in the neovascularization process [3,4]. A majority of ECs in the tumor vasculature are tumor-derived ECs (TECs) exhibiting cytogenetic abnormalities of aneuploid chromosomes [7,8] These aneuploid TECs [9,10], which could be directly derived from malignant cancer cells, harbor mixed properties of both endothelial vascularization ability and cancerous malignancy in the TME. This leads to an increase in vascular permeability and transendothelial intravasation as well as extravasation during tumor metastasis Following their shedding into peripheral blood, TECs turn into circulating tumor-derived endothelial cells (CTECs) [11]. The origin and clinical significance of CTECs are consecutively discussed along the axis of “formation mechanisms”, “hypoxia regulation”, and “therapeutic target potential” to provide new insights into CTECs’ impact on tumorigenesis, neovascularization, disease progression, and cancer metastasis
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