Tie-2 regulates the stemness and metastatic properties of prostate cancer cells

Tang, Kai-Dun; Holzapfel, Boris Michael; Liu, Ji; Lee, Terence; Ma, Stephanie; Jovanovic, Lidija; An, Jiyuan; Russell, Pamela J.; Clements, Judith A.; Hutmacher, Dietmar W.; Ling, Ming-Tat

doi:10.18632/oncotarget.3950

Cited by 23 publications

(21 citation statements)

References 47 publications

(41 reference statements)

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“…Osteoblast differentiation was assessed by measuring osteoblast differentiation markers by real‐time PCR, as described previously . The cell adhesion assay was undertaken as described previously . Briefly, 3 × 10 3 HARA‐B4 cells (containing GFP from the FG12 vector) were overlaid directly onto confluent MG‐63 cells in a dish and incubated for 30 minutes at 5% CO 2 and 37°C.…”

Section: Methodssupporting

confidence: 74%

Downregulation of CD24 suppresses bone metastasis of lung cancer

et al. 2017

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Suppression of bone metastasis can improve patient quality of life. Current drugs for bone metastasis have been shown to prolong progression‐free survival but not overall survival; therefore, other potential therapeutic targets for bone metastasis should be investigated. Cell‐surface antigens, such as CD24, have been recently shown to be involved in the metastasis of various cancers. However, whether CD24 plays a role in bone metastasis of lung cancer remains unknown. To observe metastasis of lung cancer cells by imaging technology, we introduced a near‐infrared fluorescent protein, iRFP720, into a bone‐seeking subclone established from lung cancer cells, HARA‐B4 cells. The anchorage‐independent growth of these cells was then evaluated by colony formation assays. We also compared cancer cell tropism to bone tissue with HARA‐B4 cells in the presence or absence of CD24 by cell adhesion assays. To clarify the role of CD24 in bone metastasis, we intracardially injected CD24‐knockdown HARA‐B4 cells into mice and monitored metastasis through detection of iRFP720 using an in vivo imaging system. CD24‐knockdown HARA‐B4 cells in vitro showed reduced anchorage‐independent growth and cancer cell tropism to bone. Bone metastasis was diminished in mice inoculated with CD24‐knockdown HARA‐B4 cells, which was rescued by add‐back of CD24 in cells. Our findings indicate that iRFP720 is effective for in vivo imaging analysis of bone metastasis and that downregulation of CD24 suppresses bone metastasis of lung cancer cells. These findings collectively indicate that CD24 may be considered a promising new therapeutic candidate for the prevention of bone metastasis of lung cancer.

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Section: Methodssupporting

confidence: 74%

Downregulation of CD24 suppresses bone metastasis of lung cancer

et al. 2017

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“…13), confirming the key role of endothelial Tie2 during embryonic development. Tie2 is, however, not exclusively expressed by EC1314151617181920. Based on the results of a systematic expression profiling screen of cultured pericytes isolated from different organs (Fig.…”

Section: Discussionmentioning

confidence: 99%

Pericyte-expressed Tie2 controls angiogenesis and vessel maturation

et al. 2017

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The Tie receptors with their Angiopoietin ligands act as regulators of angiogenesis and vessel maturation. Tie2 exerts its functions through its supposed endothelial-specific expression. Yet, Tie2 is also expressed at lower levels by pericytes and it has not been unravelled through which mechanisms pericyte Angiopoietin/Tie signalling affects angiogenesis. Here we show that human and murine pericytes express functional Tie2 receptor. Silencing of Tie2 in pericytes results in a pro-migratory phenotype. Pericyte Tie2 controls sprouting angiogenesis in in vitro sprouting and in vivo spheroid assays. Tie2 downstream signalling in pericytes involves Calpain, Akt and FOXO3A. Ng2-Cre-driven deletion of pericyte-expressed Tie2 in mice transiently delays postnatal retinal angiogenesis. Yet, Tie2 deletion in pericytes results in a pronounced pro-angiogenic effect leading to enhanced tumour growth. Together, the data expand and revise the current concepts on vascular Angiopoietin/Tie signalling and propose a bidirectional, reciprocal EC-pericyte model of Tie2 signalling.

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“…In addition to the extensive data on the role of the angiopoietin pathway in angiogenesis, several studies have demonstrated increased expression of Tie2 in cancer cells and in cancer-associated stromal cells. This, coupled with the expression of Ang1 and/or Ang2 by cancer cells and studies of cell lines and in vivo tumor models, suggests that Tie2 activation may contribute to cancer cell growth via additional autocrine mechanisms that promote a stem cell-like phenotype with enhanced adhesion, invasion, and metastatic potential (44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

A Phase I, First-in-Human Study of AMG 780, an Angiopoietin-1 and -2 Inhibitor, in Patients with Advanced Solid Tumors

Dowlati

Vlahović

Natale

et al. 2016

Clinical Cancer Research

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Purpose: To assess the toxicity, pharmacokinetics, tumor vascular response, tumor response, and pharmacodynamics of AMG 780, a mAb designed to inhibit the interaction between angiopoietin-1 and -2 and the Tie2 receptor.Experimental Design: This was a phase I dose-escalation study of patients with advanced solid tumors refractory to standard treatment without previous antiangiogenic treatment. AMG 780 was administered by intravenous infusion every 2 weeks in doses from 0.1 to 30 mg/kg. The primary endpoints were incidences of dose-limiting toxicity (DLT) and adverse events (AE), and pharmacokinetics. Secondary endpoints included tumor response, changes in tumor volume and vascularity, and anti-AMG 780 antibody formation.Results: Forty-five patients were enrolled across nine dose cohorts. Three patients had DLTs (0.6, 10, and 30 mg/kg), none of which prevented dose escalation. At 30 mg/kg, no MTD was reached. Pharmacokinetics of AMG 780 were dose proportional; median terminal elimination half-life was 8 to 13 days. No anti-AMG 780 antibodies were detected. At week 5, 6 of 16 evaluable patients had a >20% decrease in volume transfer constant (K trans ), suggesting reduced capillary blood flow/permeability. The most frequent AEs were hypoalbuminemia (33%), peripheral edema (29%), decreased appetite (27%), and fatigue (27%). Among 35 evaluable patients, none had an objective response; 8 achieved stable disease.Conclusions: AMG 780 could be administered at doses up to 30 mg/kg every 2 weeks in patients with advanced solid tumors. AMG 780 treatment resulted in tumor vascular effects in some patients. AEs were in line with toxicity associated with antiangiopoietin treatment.

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Tie-2 regulates the stemness and metastatic properties of prostate cancer cells

Abstract: AbstrAct

Cited by 23 publications

References 47 publications

Downregulation of CD24 suppresses bone metastasis of lung cancer

Downregulation of CD24 suppresses bone metastasis of lung cancer

Pericyte-expressed Tie2 controls angiogenesis and vessel maturation

A Phase I, First-in-Human Study of AMG 780, an Angiopoietin-1 and -2 Inhibitor, in Patients with Advanced Solid Tumors

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