Tie2-Expressing Monocytes Are Associated with Identification and Prognoses of Hepatitis B Virus Related Hepatocellular Carcinoma after Resection

He, Yu; Wang, Chaoqun; Yu, Yao; Qian, Ji; Song, Kang; Sun, Qiqing; Zhou, Jian

doi:10.1371/journal.pone.0143657

Cited by 22 publications

(25 citation statements)

References 22 publications

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“…TEMs are a subgroup of circulating and tumor-infiltrating myeloid cells with potency to promote angiogenesis in xenotransplanted human tumors [ 6 ]. Previous studies [ 9 , 15 ] defined TEMs as CD14+CD16+Tie2+ cells and reported that they were increased in HCC patients.TEMs are generally considered as a novel biomarker and potential therapeutic target for the diagnosis of HCC. However, reports about TEMs in healthy individuals have been controversial [ 6 , 15 ].…”

Section: Discussionmentioning

confidence: 99%

TEMs but not DKK1 could serve as complementary biomarkers for AFP in diagnosing AFP-negative hepatocellular carcinoma

Mao

Wang

et al. 2017

PLoS ONE

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Background & aimsHepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is prevalent worldwide. Despite its limitations, serum alpha-fetoprotein (AFP) remains the most widely-used biomarker for the diagnosis of HCC. This study aimed to assess whether measurement of peripheral plasma Dickkopf-1 (DKK1) and Tie2-expressing monocytes (TEMs) could overcome the limitations of AFP and improve the diagnostic accuracy of HCC.MethodsPlasma DKK1 level and the percentage of TEMs in peripheral CD14+CD16+ monocytes from HCC patients (n = 82), HBV-related liver cirrhosis (LC) patients (n = 29), chronic hepatitis B (CHB) infected patients (n = 28) and healthy volunteers (n = 31) were analyzed by ELISA and flow cytometry. Receiver operating characteristic (ROC) curves were used to analyze a single biomarker, or a combination of two or three biomarkers. Univariate and multivariate analyses were performed to assess the significance of each marker in prediction of HCC and AFP-negative HCC from LC patients.ResultsThe percentage of TEMs in peripheral CD14+CD16+ monocytes and plasma level of DKK1 in HCC group were significantly higher than those in LC, CHB and healthy control groups (all P-values <0.05). The percentage of TEMs alone was also significantly higher in AFP-negative HCC group than that in LC, CHB and healthy control groups (all P-values <0.05). Plasma DKK1 level alone could not distinguish between AFP-negative HCC and LC patients. ROC curves showed that the optimal diagnostic cutoff value was 550.93 ng/L for DKK1 and 4.95% for TEMs. There was no significant difference in AUC of DKK1, TEMs and AFP in HCC diagnosis between the four groups (all P>0.05). A combination of DKK1, TEMs and AFP measurements increased the AUC for HCC diagnosis as compared with either marker alone (0.833; 95%CI 0.768–0.886). The AUC for TEMs was 0.692 (95% CI 0.564–0.819) in differentiating AFP-negative HCC from LC, with a sensitivity of 80.0% and a specificity of 65.52%. Only TEMs prevailed as a significant predictor for AFP-negative HCC differentiating from LC patients in univariate and multivariate analyses (P = 0.016, P = 0.023).ConclusionsTEMs and DKK1 may prove to be potential complementary biomarkers for AFP in the diagnosis of HCC. TEMs rather than DKK1 could serve as a complementary biomarker for AFP in the differential diagnosis of AFP-negative HCC versus LC patients.

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Section: Discussionmentioning

confidence: 99%

TEMs but not DKK1 could serve as complementary biomarkers for AFP in diagnosing AFP-negative hepatocellular carcinoma

Mao

Wang

et al. 2017

PLoS ONE

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“…Tie2 expression occurs, and is partially maintained, during differentiation in human neural stem cells (7), but not in mature neurons (8). Dysregulated Tie2 expression has also been observed in several tumor tissues, including oral squamous cell carcinoma, breast, gastric, leukemia and thyroid cancer (9)(10)(11)(12)(13). These studies revealed that Tie2 expression is associated with the identification and prognosis of these cancer types (12).…”

Section: Introductionmentioning

confidence: 99%

“…Dysregulated Tie2 expression has also been observed in several tumor tissues, including oral squamous cell carcinoma, breast, gastric, leukemia and thyroid cancer (9)(10)(11)(12)(13). These studies revealed that Tie2 expression is associated with the identification and prognosis of these cancer types (12). Ang1 is a secreted ligand for Tie2 that maintains vascular plasticity, perturbations in which can contribute to abnormal vascular growth (4).…”

Section: Introductionmentioning

confidence: 99%

Ang1/Tie2 induces cell proliferation and migration in human papillary thyroid carcinoma via the PI3K/AKT pathway

Yao

et al. 2017

Oncol Lett

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Abstract. The angiopoietin 1 (Ang1)/angiopoietin receptor (Tie2) signaling pathway may have a notable role in the pathogenesis of inflammatory diseases. The abnormal expression of angiopoietin 1 and Tie2 has also been reported in various malignant tumors, including papillary thyroid carcinoma (PTC). However, the role and mechanism of the Ang1/Tie2 pathway in the progression of PTC remains unclear. Therefore, the aims of the present study were to clarify this. Significantly high expression levels of Ang1 and Tie2 were observed in PTC tissues and cell lines. Furthermore, MTT and wound-healing assays revealed that the Ang1-mediated stimulation of human PTC cells resulted in increased proliferation and migration. Conversely, the downregulation of Tie2 levels using short hairpin RNA targeted at Tie2 abrogated the Ang1-mediated effect on cell proliferation and migration. In studying the expression of phosphoinositide-3 kinase (PI3K)/RAC serine/threonine-protein kinase (Akt) pathway, the upregulation of Ang1/Tie2 was found to be associated with the activation of the PI3K/Akt pathway in PTC. In conclusion, the data from the present study indicated that the Ang1/Tie2 induces PTC oncogenesis via the PI3K/Akt pathway, providing novel insights into human PTC therapy. IntroductionPapillary thyroid carcinoma (PTC) is the most prevalent histological thyroid carcinoma subtype, accounting for ~80% of cases (1,2). Although recent advances in diagnosis and treatment strategies have been made in clinical and experimental oncology, ≤30% of patients present with local/regional recurrence or distant metastasis within 10 years (2,3). Thus, the elucidation of the molecular mechanisms underlying PTC progression is urgently required in order to develop effective diagnostic, prognostic and therapeutic strategies.Receptor tyrosine kinases are cell surface proteins that transduce signals from extracellular growth factors intracellularly, to elicit biological responses (4). Receptor tyrosine kinases act as potent oncoproteins and are abnormally expressed in a number of cancer types, including gliomas (5). Angiopoietin-1 (Ang1) receptor (TEK, also known as Tie2) is a receptor tyrosine kinase that was identified as an endothelial-cell-specific receptor with a critical role in the modulation of vasculogenesis and remodeling (6). Tie2 expression occurs, and is partially maintained, during differentiation in human neural stem cells (7), but not in mature neurons (8). Dysregulated Tie2 expression has also been observed in several tumor tissues, including oral squamous cell carcinoma, breast, gastric, leukemia and thyroid cancer (9-13). These studies revealed that Tie2 expression is associated with the identification and prognosis of these cancer types (12). Ang1 is a secreted ligand for Tie2 that maintains vascular plasticity, perturbations in which can contribute to abnormal vascular growth (4). Daly et al (6) revealed that Ang2 functions as a Tie2 agonist in tumor models, limiting the effects of VEGF inhibition (6). Mitsutake et al (13) revealed ...

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“…Chemotaxis may be a driving force for Ang-2 induced monocyte migration. However, as described earlier, Ang-2 directly interacts with monocytes and TEMs through both Tie-2 and integrin signaling [170][171][172]. These myeloid cells, once present in a KSHV infection microenvironment, rapidly differentiated into TAMs [157,173], which, as described earlier, are well known to promote tumor growth and progression [171,174,175].…”

Section: Ang-2 Promotes Angiogenesis Inflammation and Ks Tumor Growthmentioning

confidence: 72%

Role of Angiopoietins in Development of Cancer and Neoplasia Associated with Viral Infection

2020

Cells

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Angiopoietin/tyrosine protein kinase receptor Tie-2 signaling in endothelial cells plays an essential role in angiogenesis and wound healing. Angiopoietin-1 (Ang-1) is crucial for blood vessel maturation while angiopoietin-2 (Ang-2), in collaboration with vascular endothelial growth factor (VEGF), initiates angiogenesis by destabilizing existing blood vessels. In healthy people, the Ang-1 level is sustained while Ang-2 expression is restricted. In cancer patients, Ang-2 level is elevated, which correlates with poor prognosis. Ang-2 not only drives tumor angiogenesis but also attracts infiltration of myeloid cells. The latter rapidly differentiate into tumor stromal cells that foster tumor angiogenesis and progression, and weaken the host’s anti-tumor immunity. Moreover, through integrin signaling, Ang-2 induces expression of matrix metallopeptidases (MMPs) to promote tumor cell invasion and metastasis. Many oncogenic viruses induce expression of Ang-2 to promote development of neoplasia associated with viral infection. Multiple Ang-2 inhibitors exhibit remarkable anti-tumor activities, further highlighting the importance of Ang-2 in cancer development.

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Tie2-Expressing Monocytes Are Associated with Identification and Prognoses of Hepatitis B Virus Related Hepatocellular Carcinoma after Resection

Cited by 22 publications

References 22 publications

TEMs but not DKK1 could serve as complementary biomarkers for AFP in diagnosing AFP-negative hepatocellular carcinoma

TEMs but not DKK1 could serve as complementary biomarkers for AFP in diagnosing AFP-negative hepatocellular carcinoma

Ang1/Tie2 induces cell proliferation and migration in human papillary thyroid carcinoma via the PI3K/AKT pathway

Role of Angiopoietins in Development of Cancer and Neoplasia Associated with Viral Infection

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