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Background:
The endothelium is not a homogeneous organ. Endothelial cell heterogeneity has been described at the level of cell morphology, function, gene expression, and antigen composition. As a consequence of the genetic, transcriptome and surrounding environment diversity, endothelial cells from different vascular beds have differentiated funct...
Citations
... Besides lung tissue, GPR116 is abundantly expressed in endothelial cells involved in the vasculature development of the nervous system and in cardiovascular functions 27,28 . Moreover, several studies have described involvement of GPR116 in carcinogenesis and cancer metastasis [29][30][31][32] . Adipocyte-specific knock-out (ko) of GPR116 suggested a role in metabolic processes 33,34 . ...
Glucose homeostasis is maintained by hormones secreted from different cell types of the pancreatic islets and controlled by manifold input including signals mediated through G protein-coupled receptors (GPCRs). RNA-seq analyses revealed expression of numerous GPCRs in mouse and human pancreatic islets, among them Gpr116/Adgrf5. GPR116 is an adhesion GPCR mainly found in lung and required for surfactant secretion. Here, we demonstrate that GPR116 is involved in the somatostatin release from pancreatic delta cells using a whole-body as well as a cell-specific knock-out mouse model. Interestingly, the whole-body GPR116 deficiency causes further changes such as decreased beta-cell mass, lower number of small islets, and reduced pancreatic insulin content. Glucose homeostasis in global GPR116-deficient mice is maintained by counter-acting mechanisms modulating insulin degradation. Our data highlight an important function of GPR116 in controlling glucose homeostasis.
... Initially, we believed the CD34+ unclassified cluster to be common myeloid progenitors. Upon closer examination, we noted the population expressed endothelial cell markers (CD109) (44). Therefore, we state their CD34 positivity, but refrain from assigning a further identity due to the small representation of the cluster and conflicting gene signatures. ...
Translationally relevant animal models are essential for the successful translation of basic science findings into clinical medicine. While rodent models are widely accessible, there are numerous limitations that prevent the extrapolation of findings to human medicine. One approach to overcome these limitations is to use animal models that are genetically diverse and naturally develop disease. For example, pet dogs spontaneously develop diseases that recapitulate the natural progression seen in humans and live in similar environments alongside humans. Thus, dogs represent a useful animal model for many areas of research. Despite the value of the canine model, species specific reagent limitations have hampered in depth characterization of canine immune cells, which constrains the conclusions that can be drawn from canine immunotherapy studies. To address this need, we used single-cell RNA sequencing to characterize the heterogeneity of circulating leukocytes in healthy dogs (n = 7) and osteosarcoma (OS) affected dogs (n = 10). We present a cellular atlas of leukocytes in healthy dogs, then employ the dataset to investigate the impact of primary OS tumors on the transcriptome of circulating leukocytes. We identified 36 unique cell populations amongst dog circulating leukocytes, with a remarkable amount of heterogeneity in CD4 T cell subtypes. In our comparison of healthy dogs and dogs with OS, we identified relative increases in the abundances of polymorphonuclear (PMN-) and monocytic (M-) myeloid-derived suppressor cells (MDSCs), as well as aberrations in gene expression within myeloid cells. Overall, this study provides a detailed atlas of canine leukocytes and investigates how the presence of osteosarcoma alters the transcriptional profiles of circulating immune cells.
... It is a novel hypoxia-regulated tetramer adhesion junction protein, which regulates cell adhesion, cell bypass permeability, and angiogenesis [11]. The expression of TMEM204 in endothelial-specific transcripts in developing endothelial cells was higher than that in normal endothelial cells in the control group, indicating that TMEM204 plays an important role in adult angiogenesis [12]. In addition, meta array and methylationspecific PCR analysis showed that 95% of TMEM204 in three typical pancreatic cancer cell lines AsPC-1, Mia PaCa-2, and PANC-1, was methylated [13]. ...
TMEM204 (Transmembrane Protein 204) is a member of the TMEM family that regulates cell function and angiogenesis. Previous studies showed that TMEM204 is related to pancreatic cancer, but its roles in other cancers remain unknown. To reveal this relationship, we conducted a pan-cancer analysis by several online databases. The expression of TMEM204 was analyzed by Oncomine and Tumor Immune Estimation Resource2.0 (TIMER2.0). The prognostic potential of TMEM204 was evaluated by the GEPIA2, UALCAN, and Oncolnc. The methylation level of gene expression was analyzed by UALCAN, and the relationship between cancer and immune invasion was displayed by TIMER2.0. The Protein-Protein Interactions Network and functional analysis of TMEM204 and its related genes were conducted by STRING and Webgestalt. We found that TMEM204 expression was up-regulated and correlated with prognosis in multiple cancers. In liver hepatocellular carcinoma (LIHC), high TMEM204 expression was associated with a good prognosis, and with high infiltrating levels of CD8+ T and CD4+ T cells, macrophages, neutrophils, and myeloid dendritic cells. In addition, the methylation level in LIHC was higher than in normal tissues. p53 signaling pathway and Fanconi anemia pathway were implicated by KEGG pathway analysis. These results indicate that TMEM204 is associated with the prognosis, methylation, and immune invasion of cancers, especially LIHC. TMEM204 may act as a prognostic marker of LIHC and its role in other cancers should be studied.
... Additionally, CD109 + and EGFR + EVs could discriminate NPC patients from healthy controls, and CD109 + EVs in combination with EGFR + EVs were a highly sensitive and specific biomarker for NPC patients. It has been reported that CD109 is a GPI-anchored glycoprotein overexpressing in a wide variety of tumors [45][46][47]. CD109 may promote tumor initiation and metastasis by enhancing the EGF or the JAK-STAT3 pathway [48]. Importantly, CD109 + EVs have not been previously reported in NPC as a diagnostic marker. ...
Tumor-derived extracellular vesicles (TEVs) have emerged as promising sources of diagnostic and prognostic biomarkers for nasopharyngeal carcinoma (NPC). However, the lack of high-sensitivity analytic methods for ultratrace membrane proteins on TEVs hamper their clinical application of TEVs. Herein, by combining aptamers that specifically bind to protein targets on TEVs, PCR-based exponential amplification and CRISPR/Cas12a real-time DNA detection, we developed a novel technique, termed the aptamer-CRISPR/Cas12a assay, to detect CD109+ and EGFR+ TEVs from cell lines and complex biofluids. The platform enables highly sensitive detection of CD109+ and EGFR+ TEVs at as low as 100 particles/mL with a linear range spanning 6 orders of magnitude (102-108 particles/mL), which was found to be sufficient to effectively detect TEV proteins directly in low-volume (50 μl) samples. Furthermore, clinical serum sample analysis verified that the combination of serum CD109+ and EGFR+ TEV levels yielded high diagnostic accuracy, with an AUC of 0.934 (95% CI: 0.868-1.000), a sensitivity of 84.1% and a specificity of 85.0%, in discriminating NPC from healthy controls. Moreover, the dramatic decrease in both biomarkers in responders after radiotherapy indicated their potential roles in radiotherapy surveillance. Given that the aptamer-CRISPR/Cas12a assay rapidly and conveniently detects ultralow concentrations of CD109+ and EGFR+ TEVs directly in serum, it could be useful in NPC diagnosis and prognosis.
... CECs serve as the specific and direct indicators for vascular injury in the body, and large numbers of studies have demonstrated that the content of peripheral blood is correlated with the growth of tumors to some extent. Mancuso et al found that the level of CECs in the peripheral blood in patients with breast cancer and lymphoma is higher than in normal people [19]. Monestiroli et al [20] researched the correlation between CECs and tumors through animal experiments and discovered that CECs are associated with tumor volume, indicating that the increase in CECs is correlated with tumor progression. ...
Purpose:
To explore the efficacy and safety of thoracic hyperthermia perfusion with recombinant human endostatin plus nedaplatin in the treatment of pleural effusion in patients with advanced non-small cell lung cancer (NSCLC).
Methods:
A retrospective analysis was conducted on the clinical data of 122 advanced NSCLC patients with pleural effusion, and among them, 61 received thoracic hyperthermic perfusion with recombinant human endostatin (ES) plus nedaplatin (Endostatin group), while the other 61 underwent thoracic hyperthermic perfusion with cisplatin alone (Cisplatin group). The short-term efficacy, changes in the pleural effusion and serum immunological indicators before and after treatment, quality of life, and incidence of adverse reactions were compared between the two groups of patients. Finally, the progression of pleural effusion in patients were followed up and recorded.
Results:
After treatment, the overall response rate of patients in Endostatin group was considerably higher than that in Cisplatin group (p=0.030). At 2 weeks after treatment, the level of alanine transferase (ALT) rose notably, while that of carcinoembryonic antigen (CEA) declined dramatically in both groups of patients, and the patients in Endostatin group had markedly lower levels of ALT and CEA than those in Cisplatin group (p=0.007, p=0.003). After treatment, the Karnofsky Performance status (KPS) score of patients was prominently raised in the two groups, and Endostatin group exhibited considerably higher KPS scores than Cisplatin group (p=0.045). The incidence rates of nausea and vomiting as well as diarrhea in Endostatin group were prominently lower than those in Cisplatin group (p=0.039, p=0.048). According to the follow-up results, the median time to the progression of pleural effusion in Endostatin group was markedly longer than that in Cisplatin group (p=0.008).
Conclusions:
Compared with the thoracic hyperthermic perfusion with cisplatin alone, the thoracic hyperthermic perfusion with recombinant human endostatin plus nedaplatin showed dramatically potential efficacy, decrease of the incidence rate of adverse reactions in the digestive system, improvement of quality of life of patients, and prolongation of progression of pleural effusion.
... 24 TGF-β1 plays an important role in chemoresistance in breast cancer and squamous cell carcinoma. 25,26 During TGF-β1 expression, cancer cells proliferate slowly in the early tumor stage and lead to chemoresistance because they can be protected against DNA-damaging chemotherapeutic agents. 26 In myxofibrosarcomas, tumors with high CD109 expression level showed decreased expression of TGF-β1 with a good effect of treatment. ...
... 25,26 During TGF-β1 expression, cancer cells proliferate slowly in the early tumor stage and lead to chemoresistance because they can be protected against DNA-damaging chemotherapeutic agents. 26 In myxofibrosarcomas, tumors with high CD109 expression level showed decreased expression of TGF-β1 with a good effect of treatment. 27 However, tumors with low CD109 expression and high TGF-β1 expression showed chemoresistance. ...
Background:
Ovarian epithelial cancer (OEC) is the second-most common gynecologic malignancy. CD109 expression is elevated in human tumor cell lines and carcinomas. A previous study showed that CD109 expression is elevated in human tumor cell lines and CD109 plays a role in cancer progression. Therefore, this study aimed to determine whether CD109 is expressed in OEC and can be useful in predicting the prognosis.
Methods:
Immunohistochemical staining for CD109 and reverse transcription-quantitative polymerase chain reaction was performed. Then we compared CD109 expression and chemoresistance, overall survival, and recurrence-free survival of OEC patients. Chemoresistance was evaluated by dividing into good-response group and poor-response group by the time to recurrence after chemotherapy.
Results:
CD109 expression was associated with overall survival (p = .020), but not recurrence-free survival (p = .290). CD109 expression was not an independent risk factor for overall survival due to its reliability (hazard ratio, 1.58; p = .160; 95% confidence interval, 0.82 to 3.05), although we found that CD109 positivity was related to chemoresistance. The poor-response group showed higher rates of CD109 expression than the good-response group (93.8% vs 66.7%, p = .047). Also, the CD109 mRNA expression level was 2.88 times higher in the poor-response group as compared to the good-response group (p = .001).
Conclusions:
Examining the CD109 expression in patients with OEC may be helpful in predicting survival and chemotherapeutic effect.
... CD109 functions by binding to both transforming growth factor b1 (TGF-b1) and TGF-b re- ceptor 1 (TGFBR1), thereby forming a macromolecular complex sequestered in caveolae and lipid raft compartments and even- tually degrading the receptor complex and inhibiting SMAD signaling (Bizet et al., 2012). High levels of CD109 have been re- ported in multiple cancers, including GBM ( Chuang et al., 2017;Hashimoto et al., 2004;Shiraki et al., 2017;Tao et al., 2014;Zhang et al., 2005Zhang et al., , 2015; notably, CD109 + circulating endothe- lial cells in recurrent GBM have been reported to be prognostic ( Mancuso et al., 2014). However, the nature of the activation of CD109 in response to extrinsic signals and the modes by which it promotes tumorigenesis in GBM remain unknown. ...
Unresectable glioblastoma (GBM) cells in the invading
tumor edge can act as seeds for recurrence. The
molecular and phenotypic properties of these cells
remain elusive. Here, we report that the invading
edge and tumor core have two distinct types of glioma
stem-like cells (GSCs) that resemble proneural (PN)
and mesenchymal (MES) subtypes, respectively.
Upon exposure to ionizing radiation (IR), GSCs, initially
enriched for a CD133+ PN signature, transition to
a CD109+ MES subtype in a C/EBP-b-dependent
manner. Our gene expression analysis of paired cohorts
of patients with primary and recurrent GBMs
identified a CD133-to-CD109 shift in tumors with an
MES recurrence. Patient-derived CD133�/CD109+
cells are highly enriched with clonogenic, tumor-initiating,
and radiation-resistant properties, and silencing
CD109 significantly inhibits these phenotypes. We
also report a conserved regulation of YAP/TAZ pathways
by CD109 that could be a therapeutic target in
GBM.
... Mancuso et al identified a subpopulation of CECs that expressed CD109, which was implicated as a potential prognostic factor for glioblastoma patients. 41 More importantly, many tumor endothelial markers have been identified through genomic studies that distinguished antigens enriched in tumors from nonmalignant endothelia, thereby making it possible to identify CEC subpopulations that more closely reflect the pathological state of angiogenesis. 42,43 For example, Kraan et al identified a tumor-associated endothelial marker, CD276, by comparing the antigen expression of normal and tumor tissue-derived endothelial cells, and CD276+ CECs were significantly higher in patients with advanced cancers. ...
Background
Circulating endothelial cells (CECs) and their subpopulations could be potential novel biomarkers for various malignancies. However, reliable enumerable methods are warranted to further improve their clinical utility. This study aimed to optimize a flow cytometric method (FCM) assay for CECs and subpopulations in peripheral blood for patients with solid cancers.
Patients and methods
An FCM assay was used to detect and identify CECs. A panel of 60 blood samples, including 44 metastatic cancer patients and 16 healthy controls, were used in this study. Some key issues of CEC enumeration, including sample material and anticoagulant selection, optimal titration of antibodies, lysis/wash procedures of blood sample preparation, conditions of sample storage, sufficient cell events to enhance the signal, fluorescence-minus-one controls instead of isotype controls to reduce background noise, optimal selection of cell surface markers, and evaluating the reproducibility of our method, were integrated and investigated. Wilcoxon and Mann–Whitney U tests were used to determine statistically significant differences.
Results
In this validation study, we refined a five-color FCM method to detect CECs and their subpopulations in peripheral blood of patients with solid tumors. Several key technical issues regarding preanalytical elements, FCM data acquisition, and analysis were addressed. Furthermore, we clinically validated the utility of our method. The baseline levels of mature CECs, endothelial progenitor cells, and activated CECs were higher in cancer patients than healthy subjects (P<0.01). However, there was no significant difference in resting CEC levels between healthy subjects and cancer patients (P=0.193).
Conclusion
We integrated and comprehensively addressed significant technical issues found in previously published assays and validated the reproducibility and sensitivity of our proposed method. Future work is required to explore the potential of our optimized method in clinical oncologic applications.
... CD109 is expressed in angiogenic vessels of hepatocellular carcinoma, and is associated with the regulation of tumor progression (22). In addition, CD109 expression was observed in the circulating endothelial cells of patients with blood cancer and glioblastomas (24,25). In the present study, CD109 was not detected in the blood vessels of normal penile or PSCC tissue. ...
Cluster of differentiation (CD) 109 is a glycosylphosphatidylinositol-anchored cell surface glycoprotein and a co-receptor for transforming growth factor β. The expression of CD109 has been detected in squamous cell carcinoma of the lung, esophagus, skin and gallbladder. The aim of the present study was to evaluate CD109 expression in penile squamous cell carcinoma (PSCC). CD109 expression in PSCC tumor and adjacent tissues from 45 specimens in tissue microarrays was examined by immunohistochemical analyses. In addition, 3 fresh surgical samples of PSCC were collected and examined for their CD109 mRNA and protein levels by reverse transcription-quantitative polymerase chain reaction, western blotting and immunofluorescence staining. CD109 transcription and expression were significantly higher in the PSCC tissues compared with adjacent normal penile tissues, and its expression was restricted to squamous cells. However, CD109 expression level was not associated with the PSCC differentiation grade. These results suggest that CD109 may be associated with the pathogenesis of PSCC, and may therefore be a potential therapeutic target.
... Interestingly, CLEC14a is also highly expressed on blood vessels in RIP-Tag2 insulinoma and HPV16/E2-induced invasive cervical cancer [209]. In addition, CLEC14A mRNA is highly upregulated in CD109+ circulating endothelial cells in breast cancer and glioblastoma patients [210]. Recently, Noy et al. reported that tumor growth and vascularity was reduced in a CLEC14a-knockout syngeneic tumor mouse model, compared to wild-type mice [207]. ...
Tumor angiogenesis is a key event that governs tumor progression and metastasis. It is controlled by the complicated and coordinated actions of pro-angiogenic factors and their receptors that become upregulated during tumorigenesis. Over the past several decades, vascular endothelial growth factor (VEGF) signaling has been identified as a central axis in tumor angiogenesis. The remarkable advent of recombinant antibody technology has led to the development of bevacizumab, a humanized antibody that targets VEGF and is a leading clinical therapy to suppress tumor angiogenesis. However, despite the clinical efficacy of bevacizumab, its significant side effects and drug resistance have raised concerns necessitating the identification of novel drug targets and development of novel therapeutics to combat tumor angiogenesis. This review will highlight the role and relevance of VEGF and other potential therapeutic targets and their receptors in angiogenesis. Simultaneously, we will also cover the current status of monoclonal antibodies being developed to target these candidates for cancer therapy.
