scholarly journals Endothelial sphingosine 1-phosphate receptors promote vascular normalization to influence tumor growth and metastasis

2019 ◽  
Author(s):  
Andreane Cartier ◽  
Tani Leigh ◽  
Catherine H. Liu ◽  
Timothy Hla
Keyword(s):  
Tumor Growth ◽  
Tumor Angiogenesis ◽  
Barrier Function ◽  
Vascular Normalization ◽  
Tumor Vessels ◽  
Sphingosine 1 Phosphate ◽  
Inflammatory Processes ◽  
Hand Tumor ◽  
Embryonic Vascular Development ◽  
Tumor Growth And Metastasis

AbstractSphingosine 1-phosphate receptor-1 (S1PR1) is essential for embryonic vascular development and maturation. In the adult, it is a key regulator of vascular barrier function and inflammatory processes. Its roles in tumor angiogenesis, tumor growth and metastasis are not well understood. In this report, we show that S1PR1 is expressed and active in tumor vessels. Tumor vessels that lack S1PR1 (S1pr1 ECKO) show excessive vascular sprouting and branching, decreased barrier function, and poor perfusion accompanied by loose attachment of pericytes. Compound knockout of S1pr1, 2 and 3 genes further exacerbated these phenotypes, suggesting compensatory function of endothelial S1PR2 and 3 in the absence of S1PR1. On the other hand, tumor vessels with high expression of S1PR1 (S1pr1 ECTG) show less branching, tortuosity and enhanced pericyte coverage. Larger tumors and enhanced lung metastasis were seen in S1pr1 ECKO whereas S1pr1 ECTG showed smaller tumors and reduced metastasis. Furthermore, anti-tumor activity of doxorubicin was more effective in S1pr1 ECTG than the wild-type counterparts. These data suggest that tumor endothelial S1PR1 induces vascular normalization and influences tumor growth, evolution and spread. Strategies to enhance S1PR1 signaling in tumor vessels may be an important adjunct to standard cancer therapy.SignificanceEndothelial sphingosine 1-phosphate receptors modulate tumor angiogenesis by inducing vascular normalization, which allows better blood circulation and enhanced anti-tumor therapeutic efficacy.

scholarly journals Endothelial sphingosine 1-phosphate receptors promote vascular normalization and antitumor therapy

2020 ◽  
Vol 117 (6) ◽  
pp. 3157-3166 ◽  
Author(s):  
Andreane Cartier ◽  
Tani Leigh ◽  
Catherine H. Liu ◽  
Timothy Hla
Keyword(s):  
Tumor Growth ◽  
Barrier Function ◽  
Vascular Normalization ◽  
Tumor Vessels ◽  
Sphingosine 1 Phosphate ◽  
In The Wild ◽  
Inflammatory Processes ◽  
Hand Tumor ◽  
Embryonic Vascular Development ◽  
Tumor Growth And Metastasis

Sphingosine 1-phosphate receptor-1 (S1PR1) is essential for embryonic vascular development and maturation. In the adult, it is a key regulator of vascular barrier function and inflammatory processes. Its roles in tumor angiogenesis, tumor growth, and metastasis are not well understood. In this paper, we show that S1PR1 is expressed and active in tumor vessels. Murine tumor vessels that lack S1PR1 in the vascular endothelium (S1pr1 ECKO) show excessive vascular sprouting and branching, decreased barrier function, and poor perfusion accompanied by loose attachment of pericytes. Compound knockout of S1pr1, 2, and 3 genes further exacerbated these phenotypes, suggesting compensatory function of endothelial S1PR2 and 3 in the absence of S1PR1. On the other hand, tumor vessels with high expression of S1PR1 (S1pr1 ECTG) show less branching, tortuosity, and enhanced pericyte coverage. Larger tumors and enhanced lung metastasis were seen in S1pr1 ECKO, whereas S1pr1 ECTG showed smaller tumors and reduced metastasis. Furthermore, antitumor activity of a chemotherapeutic agent (doxorubicin) and immune checkpoint inhibitor blocker (anti-PD-1 antibody) were more effective in S1pr1 ECTG than in the wild-type counterparts. These data suggest that tumor endothelial S1PR1 induces vascular normalization and influences tumor growth and metastasis, thus enhancing antitumor therapies in mouse models. Strategies to enhance S1PR1 signaling in tumor vessels may be an important adjunct to standard cancer therapy of solid tumors.

scholarly journals Inhibition of endothelial FAK activity prevents tumor metastasis by enhancing barrier function

2014 ◽  
Vol 204 (2) ◽  
pp. 247-263 ◽  
Author(s):  
Christine Jean ◽  
Xiao Lei Chen ◽  
Ju-Ock Nam ◽  
Isabelle Tancioni ◽  
Sean Uryu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Stromal Cells ◽  
Barrier Function ◽  
Tumor Metastasis ◽  
Vascular Endothelial ◽  
Vascular Endothelial Cadherin ◽  
Tumor Growth And Metastasis ◽  
Endothelial Growth Factor

Pharmacological focal adhesion kinase (FAK) inhibition prevents tumor growth and metastasis, via actions on both tumor and stromal cells. In this paper, we show that vascular endothelial cadherin (VEC) tyrosine (Y) 658 is a target of FAK in tumor-associated endothelial cells (ECs). Conditional kinase-dead FAK knockin within ECs inhibited recombinant vascular endothelial growth factor (VEGF-A) and tumor-induced VEC-Y658 phosphorylation in vivo. Adherence of VEGF-expressing tumor cells to ECs triggered FAK-dependent VEC-Y658 phosphorylation. Both FAK inhibition and VEC-Y658F mutation within ECs prevented VEGF-initiated paracellular permeability and tumor cell transmigration across EC barriers. In mice, EC FAK inhibition prevented VEGF-dependent tumor cell extravasation and melanoma dermal to lung metastasis without affecting primary tumor growth. As pharmacological c-Src or FAK inhibition prevents VEGF-stimulated c-Src and FAK translocation to EC adherens junctions, but FAK inhibition does not alter c-Src activation, our experiments identify EC FAK as a key intermediate between c-Src and the regulation of EC barrier function controlling tumor metastasis.

scholarly journals COUP-TFII regulates tumor growth and metastasis by modulating tumor angiogenesis

2010 ◽  
Vol 107 (8) ◽  
pp. 3687-3692 ◽  
Author(s):  
Jun Qin ◽  
Xinpu Chen ◽  
Xin Xie ◽  
Ming-Jer Tsai ◽  
Sophia Y. Tsai
Keyword(s):  
Tumor Growth ◽  
Tumor Angiogenesis ◽  
Tumor Growth And Metastasis

scholarly journals Hypoxia Regulated Inhibin Promotes Tumor Growth and Vascular Permeability By ACVRL1 and CD105 Dependent VE-Cadherin Internalization

2021 ◽  
Author(s):  
Karthikeyan Mythreye ◽  
Ben Horst ◽  
Shrikant Pradhan ◽  
Roohi Chaudhary ◽  
Eduardo Listik ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Ovarian Cancer Cell ◽  
Vascular Normalization ◽  
Cancer Management ◽  
Vessel Normalization ◽  
Ovarian Cancer Cell Lines ◽  
Tumor Growth And Metastasis ◽  
Early Tumor

Abstract Hypoxia, a driver of tumor growth and metastasis, regulates angiogenic pathways that are targets for vessel normalization and ovarian cancer management. However, toxicities and resistance to anti-angiogenics limits their use making identification of new targets vital. Inhibin, a heteromeric TGFb ligand, is a contextual regulator of tumor progression acting as an early tumor suppressor, yet also an established biomarker for ovarian cancers. Here, we demonstrate a previously unknown role for inhibins and find that hypoxia increases inhibin levels in ovarian cancer cell lines, xenograft tumors, and patients. Inhibin is regulated specifically through HIF-1, shifting the balance from activins to inhibins. Hypoxia regulated inhibin promotes tumor growth, endothelial cell invasion and permeability. Targeting inhibin in vivo through knockdown and anti-inhibin strategies robustly reduces permeability in vivo and alters the balance of pro and anti-angiogenic mechanisms resulting in vascular normalization. Mechanistically, inhibin regulates permeability by increasing VE-cadherin internalization via ACVRL1 and CD105, a receptor complex that we find stabilized directly by inhibin. Our findings are the first to demonstrate direct roles for inhibins in vascular normalization via TGF-b receptors providing new insights into the therapeutic significance of inhibins as a strategy to normalize the tumor vasculature in ovarian cancer.

Endothelial TRPV4 channels prevent tumor growth and metastasis via modulation of tumor angiogenesis and vascular integrity

Angiogenesis ◽  
2021 ◽  
Author(s):  
Anantha K. Kanugula ◽  
Ravi K. Adapala ◽  
Anurag Jamaiyar ◽  
Nina Lenkey ◽  
Brianna D. Guarino ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Angiogenesis ◽  
Vascular Integrity ◽  
Tumor Growth And Metastasis ◽  
Prevent Tumor Growth

scholarly journals Endothelial deletion of SHP2 suppresses tumor angiogenesis and promotes vascular normalization

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhiyong Xu ◽  
Chunyi Guo ◽  
Qiaoli Ye ◽  
Yueli Shi ◽  
Yihui Sun ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Angiogenesis ◽  
Endothelial Cell Proliferation ◽  
Mouse Tumor ◽  
Vascular Normalization ◽  
Genetic Studies ◽  
Tyrosine Kinase Signaling ◽  
Reduce Tumor Growth ◽  
Multiple Receptor

AbstractSHP2 mediates the activities of multiple receptor tyrosine kinase signaling and its function in endothelial processes has been explored extensively. However, genetic studies on the role of SHP2 in tumor angiogenesis have not been conducted. Here, we show that SHP2 is activated in tumor endothelia. Shp2 deletion and pharmacological inhibition reduce tumor growth and microvascular density in multiple mouse tumor models. Shp2 deletion also leads to tumor vascular normalization, indicated by increased pericyte coverage and vessel perfusion. SHP2 inefficiency impairs endothelial cell proliferation, migration, and tubulogenesis through downregulating the expression of proangiogenic SRY-Box transcription factor 7 (SOX7), whose re-expression restores endothelial function in SHP2-knockdown cells and tumor growth, angiogenesis, and vascular abnormalization in Shp2-deleted mice. SHP2 stabilizes apoptosis signal-regulating kinase 1 (ASK1), which regulates SOX7 expression mediated by c-Jun. Our studies suggest SHP2 in tumor associated endothelial cells is a promising anti-angiogenic target for cancer therapy.

scholarly journals S1P Provokes Tumor Lymphangiogenesis via Macrophage-Derived Mediators Such as IL-1β or Lipocalin-2

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Shahzad N. Syed ◽  
Michaela Jung ◽  
Andreas Weigert ◽  
Bernhard Brüne
Keyword(s):  
Tumor Growth ◽  
Apoptotic Cell ◽  
Interleukin 1 ◽  
Macrophage Phenotype ◽  
Lipocalin 2 ◽  
Tumor Lymphangiogenesis ◽  
Sphingosine 1 Phosphate ◽  
Tumor Growth And Metastasis ◽  
Factor C

A pleiotropic signaling lipid, sphingosine-1-phosphate (S1P), has been implicated in various pathophysiological processes supporting tumor growth and metastasis. However, there are only a few descriptive studies suggesting a role of S1P in tumor lymphangiogenesis, which is critical for tumor growth and dissemination. Corroborating own data, the literature suggests that apoptotic tumor cell-derived S1P alters the phenotype of tumor-associated macrophages (TAMs) to gain protumor functions. However, mechanistically, the role of TAM-induced lymphangiogenesis has only been poorly described, mostly linked to the production of lymphangiogenic factors such as vascular endothelial growth factor C (VEGF-C) and VEGF-D, or transdifferentiation into lymphatic endothelial cells. Recent findings highlight a rather underappreciated role of S1P in tumor lymphangiogenesis, referring to the production of interleukin-1β (IL-1β) and lipocalin-2 (LCN2) by a tumor-promoting macrophage phenotype. In this review, we aim to provide to the readers with the current understanding of the molecular mechanism how apoptotic cell-derived S1P triggers TAMs to promote lymphangiogenesis.

scholarly journals Vascular Normalization Induced by Sinomenine Hydrochloride Results in Suppressed Mammary Tumor Growth and Metastasis

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Huimin Zhang ◽  
Yu Ren ◽  
Xiaojiang Tang ◽  
Ke Wang ◽  
Yang Liu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Mammary Tumor ◽  
Vascular Normalization ◽  
Mammary Tumor Growth ◽  
Tumor Growth And Metastasis ◽  
Sinomenine Hydrochloride

scholarly journals S1P2, the G Protein–Coupled Receptor for Sphingosine-1-Phosphate, Negatively Regulates Tumor Angiogenesis and Tumor Growth In vivo in Mice

2010 ◽  
Vol 70 (2) ◽  
pp. 772-781 ◽  
Author(s):  
Wa Du ◽  
Noriko Takuwa ◽  
Kazuaki Yoshioka ◽  
Yasuo Okamoto ◽  
Koichi Gonda ◽  
...  
Keyword(s):  
Tumor Growth ◽  
G Protein ◽  
Tumor Angiogenesis ◽  
G Protein Coupled Receptor ◽  
Sphingosine 1 Phosphate ◽  
G Protein Coupled
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