Endothelial Tie1–mediated angiogenesis and vascular abnormalization promote tumor progression and metastasis

Porta, Silvia La; Roth, Lise; Singhal, Mahak; Mogler, Carolin; Spegg, Carleen; Schieb, Benjamin; Qu, Xiaomei; Adams, Ralf H.; Baldwin, H. Scott; Savant, Soniya; Augustin, Hellmut G.

doi:10.1172/jci94674

Cited by 75 publications

(58 citation statements)

References 48 publications

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“…LIGHT-mediated vessel normalization is predominantly effected through pericyte maturation but also upregulates endothelial adherens junctions (He et al, 2018;Johansson-Percival et al, 2015). Our findings are consistent with other studies, which have shown that improving endothelial cell barrier function, for instance by genetic targeting of VE-cadherin, tie2/angiopoietin2 (Ang2), or tie1, increases tumor perfusion and oxygenation, leading to reduced metastatic tumor dissemination (Cantelmo et al, 2016;La Porta et al, 2018;Mazzone et al, 2009;Park et al, 2016). In contrast, endothelial cell death induced by VEGF inhibitors or experimental pericyte depletion increases hypoxia in solid tumors, which in turn accelerates metastases (Keskin et al, 2015;Pà ez-Ribes et al, 2009).…”

Section: Discussionsupporting

confidence: 88%

Remodeling of Metastatic Vasculature Reduces Lung Colonization and Sensitizes Overt Metastases to Immunotherapy

Johansson

Backhouse

et al. 2020

Cell Reports

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Section: Discussionsupporting

confidence: 88%

Remodeling of Metastatic Vasculature Reduces Lung Colonization and Sensitizes Overt Metastases to Immunotherapy

Johansson

Backhouse

et al. 2020

Cell Reports

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“…In the present study, we found that the expression of Tie1 was signi cantly elevated in response to hypoxia and that the down-regulation of Tie1 by shRNA could render cells more sensitive to cisplatin and reduce the stemness characteristics of cells. The involvement of Tie1 in the stemness of cancer cells has also been noted in a recent study [30]. La Porta et al [30] studied Tie1 in tumor progression and found that the deletion of Tie1 in a mouse metastasis model prevented the extravasation of tumor cells into the lungs and reduced metastatic foci.…”

Section: Discussionmentioning

confidence: 72%

“…The involvement of Tie1 in the stemness of cancer cells has also been noted in a recent study [30]. La Porta et al [30] studied Tie1 in tumor progression and found that the deletion of Tie1 in a mouse metastasis model prevented the extravasation of tumor cells into the lungs and reduced metastatic foci. In our study, hypoxia gave rise to increased drug resistance and an elevated level of genetic markers associated with stemness.…”

Section: Discussionmentioning

confidence: 72%

Hypoxia-induced Tie1 Drives Stemness and Cisplatin Resistance in Non-small Cell Lung Carcinoma Cells

Yang

Chen

et al. 2020

Preprint

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Background: Drug resistance and metastasis involving hypoxic tumor environment and persistent stem cell populations are detrimental to the survival of patients with non-small cell lung carcinoma (NSCLC). Tie1 is upregulated in hypoxia and is believed to counteract the effectiveness of platinum agents, by promoting the stemness properties in cells. We have investigated the association of Tie1 with HIF-1α and cisplatin resistance in NSCLC cell lines. Methods: Expression of Tie1 in a pulmonary microvascular endothelial cell line (HPMEC) and in NSCLC cell lines was detected using qRT-PCR and western blot. The effect of Tie1 on cell stemness and migration was examined by sphere-forming assay and transwell assay in NSCLC cells with Tie1 silenced. The regulation of Tie1 by HIF-1α was evaluated by a dual-luciferase reporter assay and chromatinImmune precipitation (ChIP) analysis.Results: We found that hypoxia could induce stemness and cisplatin resistance in vitro. Tie1 was expressed at low levels in NSCLC cells when compared with human pulmonary microvascular endothelial cells, however, its expression was increased by hypoxia. Additionally, Tie1 knockdown could reduce the stemness properties and increase sensitivity to cisplatin in vitro and in a xenograft mouse model. The promoter of Tie1 contains two predicted hypoxia-response elements (HREs). We mutated both HRE sites and conducted chromatin immune-precipitation and promoter luciferase reporter assays and were able to conclude that the induction of Tie1 by hypoxia was HIF-1α-dependent. Conclusions: Our findings indicated that Tie1 is upregulated in a hypoxic environment by HIF-1α and contributes to tumorigenesis and cisplatin resistance through the promotion of stemness in NSCLC cells.

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“…For instance, gene expression of Tie1 in valvular endothelial cells may be essential for ECM remodeling in valve tissues (107), as Tie1 is found to be necessary for endothelial cell proliferation (108). However, due to its orphan receptor status, Tie1 is still poorly characterized (109).…”

Section: Biomechanical Contextmentioning

confidence: 99%

Oscillatory fluid-induced mechanobiology in heart valves with parallels to the vasculature

2020

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Forces generated by blood flow are known to contribute to cardiovascular development and remodeling. These hemodynamic forces induce molecular signals that are communicated from the endothelium to various cell types. The cardiovascular system consists of the heart and the vasculature, and together they deliver nutrients throughout the body. While heart valves and blood vessels experience different environmental forces and differ in morphology as well as cell types, they both can undergo pathological remodeling and become susceptible to calcification. In addition, while the plaque morphology is similar in valvular and vascular diseases, therapeutic targets available for the latter condition are not effective in the management of heart valve calcification. Therefore, research in valvular and vascular pathologies and treatments have largely remained independent. Nonetheless, understanding the similarities and differences in development, calcific/fibrous pathologies and healthy remodeling events between the valvular and vascular systems can help us better identify future treatments for both types of tissues, particularly for heart valve pathologies which have been understudied in comparison to arterial diseases.

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Endothelial Tie1–mediated angiogenesis and vascular abnormalization promote tumor progression and metastasis

Cited by 75 publications

References 48 publications

Remodeling of Metastatic Vasculature Reduces Lung Colonization and Sensitizes Overt Metastases to Immunotherapy

Remodeling of Metastatic Vasculature Reduces Lung Colonization and Sensitizes Overt Metastases to Immunotherapy

Hypoxia-induced Tie1 Drives Stemness and Cisplatin Resistance in Non-small Cell Lung Carcinoma Cells

Oscillatory fluid-induced mechanobiology in heart valves with parallels to the vasculature

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