"Wolf in sheep's clothing" - CTEC's origins and veins.

Introduction: the special clinical significance of circulating tumor derived endothelial cell (CTEC) has attracted more and more attention in recent years. Both CTEC and CTC constitute a pair of "circulating tumor markers of cell type" in the blood.lung cancer, the highest incidence rate and mortality rate, poses a serious threat to public health worldwide.how to use non-invasive means to effectively distinguish benign and malignant pulmonary nodules in the early diagnosis of lung cancer has very urgent clinical significance.recently, a team of academicians, directors and Sun Nan from the National Cancer Center of China, the Chinese Academy of Medical Sciences and the Cancer Hospital of Peking Union Medical College, using the integrated technology of sete-i · fish, revealed that CD31 + CTEC and cd31-ctc were detected in situ and in combination There was a significant correlation between the specific subtype cells and the malignant pulmonary nodules in patients with early lung cancer. There were significant differences in cell size, ploidy and expression of tumor markers between CTC and CTEC in different stages of lung cancer. These two types of cells have different functions, but complement each other (Lei et al., 2020 Clin. Transl. Med. E128.the important achievements have important clinical and practical significance for the use of non-invasive means to effectively distinguish benign and malignant pulmonary nodules, and further improve the early diagnosis and screening of lung cancer.in addition, the breast surgery department of Jiangsu Provincial People's hospital recently reported the special clinical significance of dynamic monitoring of EpCAM + CTEC with SE-I · fish() in patients with locally advanced breast cancer receiving neoadjuvant chemotherapy (MA et al., 2020 then adv Med Oncol 12:1).this is the first time in the world that CET biology, tumor center of Shanghai First People's Hospital and medical center of Munich University of Germany jointly discovered the existence of CTEC in the world in 2017 (Lin et al., 2017 SCI Rep 7:9789), and Beijing chest hospital and Saite biology recently published the significance of PD-L1 + CTEC in the process of immunotherapy (Zhang et al, Since 2020 cancer lett 469:355), part of the latest progress in clinical research on CTEC has been made.in 2009, Li Longyun, director of the lung cancer center of Peking Union Medical College Hospital, and Saite biological Co., Ltd. jointly reported that Se enrichment technology can successfully isolate lung cancer CTC (Wu et al., 2009 J Thorac Oncol 4:30).with the clinical application of improved se, CTC and CTEC were detected Recently, the famous gynecological cancer center of Peking University People's Hospital, Peking University Cancer Center, National Cancer Center, Cancer Hospital of Chinese Academy of Medical Sciences and Saite biological team jointly classified rare circulating cells in blood and applied SE-I · fish for joint detection of CTC and CTEC in the Journal of clinical laboratory The clinical significance of Clin lab 14:43 was further introduced (Cheng et al., 2020 Clin lab 14:43).in recent years, more and more reports on clinical research of CTEC have been reported at home and abroad.people have realized that the detection and research of CTEC can not stop at the simple observation and counting in the past, and a series of important issues need to be comprehensively and clearly summarized, including what is the essence of aneuploid CTEC? What is their relationship with tumor cells? Where do these cells come from and where do they go? What is the clinical and biological significance of CTEC.recently, relevant articles published in the special issue of cells (Basel, Switzerland) have discussed these important issues of CTEC in depth (Lin, 2020 cells 9:1539).the author of this paper is Dr.Professor Dr. Olivier gires, a specially invited editor of this special issue, works in the famous Ludwig maximians University Medical Center in Munich, Germany. He is an internationally renowned expert in CTC, EpCAM, EGFR and other fields. He has published many works on nature cell biology, science advances, cancer research and other first-class miscellaneous records.tumor vascular system tumor vascular system is mainly composed of blood vessels and lymphatic vessels, which are closely related to the occurrence, progress and metastasis of tumor.tumor neovascularization mainly undergoes "angiogenesis", "vasculogenesis" and "lymphangiogenesis". Endothelial cells constitute the intima of the vascular system.in addition, tumor stem cells can directly form a special vascular system (VM channel) without intimal structure, which connects tumor cells and blood vessels, which is related to tumor metastasis.source of tumor endothelial cells (TEC) and CTEC, the intima of tumor vascular system is mainly composed of aneuploid "tumor derived endothelial cell (TEC)", which can be directly transformed from tumor cells. As the name suggests, Tec is a kind of special tumor cells expressing endothelial marker CD31. These cells shed into the blood and form circulating tumor endothelial cell CTEC.Tec can be produced through two pathways, namely "endothelial cell tumorigenesis" and "tumor cell endothelialization". Among them, tumor cell endothelialization can be divided into "transdifferentiation" and "cell fusion", which plays a major role.transdifferentiation (transd): tumor cells form CSCs with stem cell characteristics through "dedifferentiation" during EMT.after transdifferentiation, CSC can form aneuploid Tec in vivo or in vitro under hypoxic condition, and CTEC is formed after entering blood.stromal cells (including tumor associated fibroblasts CAF, pericutaneous cells, vascular endothelial cells, etc.) can form mesenchymal stem cells / stromal cells (MSc) through the process of "endothelial cell to mesenchymal cell transformation" (endomt), and then form Tec through "transdifferentiation".some of Tec and CTEC formed by transdifferentiation transd can express tumor markers, while those that do not express tumor markers are called null CTEC.the single aneuploid CD31 + naked cells in normal human body are called abnormal circulating endothelial cells (abnormal CEC), which are derived from the transdifferentiation of stromal cells (endomt pathway) or cell aging.these cells have nothing to do with tumors and have no clinical significance, and will eventually be eliminated by the homeostasis immune system.fusion: another major pathway of tumor cell endothelialization is "cell fusion".heterogeneous cell fusion refers to the fusion of two different kinds of cells, which can produce mononuclear or multinuclear fusion cells. Fusion cells play a very important role in the occurrence and progress of tumor.many tumor cells are fusible. Compared with the original tumor cells, the malignant degree and metastasis ability of the fusion cells are significantly improved due to mitotic changes.in addition, cell fusion is also one of the main causes of aneuploidy in tumor cells.it has been reported that inflammation is closely related to tumor (balkwill et al., 2001 lancet 357:539). In the inflammatory environment induced by TNF - α, tumor cells can fuse with normal endothelial cells to form a single aneuploid Tec or Tec cell cluster.compared with the above-mentioned "transdifferentiation", the fusion of tumor cells and EC plays a more important role in the production of tec.hypoxia is the most common phenomenon in tumor microenvironment.as shown in the figure, Tec is formed by "tumor cell endothelialization" and "endothelial cell tumorigenesis" based on "transdifferentiation" and xenogeneic cell fusion during tumor angiogenesis. hypoxia in tumor microenvironment is the inducing factor of all steps in the figure. EMT and endomt are the center of the whole process, CSC and MSC are important nodes, and cell fusion and dedifferentiation are the key steps, finally forming core products Tec and CTEC. hypoxic tumor microenvironment can activate HIF pathway, induce EMT / endomt, transd and cell fusion in the process of tumor angiogenesis, so as to promote the occurrence, progression, metastasis and new angiogenesis of tumor. during this process, a series of intracellular signal transduction pathways involving NFkB, Twist1, notch, Wnt / β - Catenin, MAPK, mTOR, snail, TGF - α / β, VCAM-1, PECAM-1 and other factors are activated, and new TECs and ctecs are continuously produced. in addition, hypoxia in vivo can also be simulated in vitro. For example, 1% O2 or CoCl2 can induce a variety of cultured CD31 tumor cell lines to directly transform into CD31 + tumor endothelial cells (TEC) in vitro, and form tubular structures in 3D culture system in vitro. the special clinical significance of CTEC and dtec, aneuploid Tec has the dual characteristics of tumor cells and endothelial cells. In addition to CTEC in peripheral blood, Tec in bone marrow, pleural effusion and cerebrospinal fluid was defined as disseminated tec (dtec). based on TEC, CTEC and dtec have obtained the mobile characteristics. these CTEC and dtec are closely related to tumor lymphatic metastasis, distal target organ metastasis, tumor progression, tumor microenvironment and neovascularization. compared with CTC, CTEC has the function of extra neovascularization on the basis of malignant tumor cell characteristics. in addition, clinical studies have shown that for lung cancer patients receiving immunotherapy, drug-resistant PD-L1 + CTEC is more closely related to tumor progression than CTC (Zhang et al., 2020 cancer lett 469:355). up to now, the modified SE-I · fish? Can effectively detect CTC and CTEC and dtec (Zhao et al., 2020 semi Oncol 60:334) in patients with solid tumors of different tumor types. They can be either interstitial (vimentin +) or non interstitial. the research on the clinical significance of CTEC and dtec, which express different tumor markers, is being actively carried out. conclusion the essence of alloploid tumor vascular endothelial cells (TEC) in tumor patients is tumor cells in the coat of CD31, which is vividly compared to "wolf in sheep's skin" (duelli et al., 2003 cancer cell 3:445). Tec is mainly produced by "endothelialization of endothelial cells" and "endothelialization of tumor cells", which involves EMT and endomt. Tec, CTEC and dtec are both malignant tumor cells and endothelial cells involved in tumor neovascularization. * CD31 + CTEC and CD31 CTC are two different types of cells with different clinical significance, so they should not be confused in the detection process. the specific detection technology based on the effective identification and differentiation of these two types of cells is an important premise and basis for accurate liquid biopsy of tumors 〉 CD31 + aneuploid circulating endothelial cells (single abnormality) occasionally appeared in normal blood Different from small fragments of ctDNA, CD31 CTC and CD31 + CTEC constitute a pair of "cellular circulating tumor markers" with biological activity, protein and complete nucleic acid information in one, and seeing as solid
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