Transactivation of the Receptor-tyrosine Kinase Ephrin Receptor A2 Is Required for the Low Molecular Weight Hyaluronan-mediated Angiogenesis That Is implicated in Tumor Progression

Lennon, Frances E.; Mirzapoiazova, Tamara; Mambetsariev, Nurbek; Mambetsariev, Bolot; Salgia, Ravi; Singleton, Patrick A.

doi:10.1074/jbc.m114.554766

Cited by 35 publications

(30 citation statements)

References 74 publications

(84 reference statements)

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“…For example, degradation of high-molecular-weight hyaluronan results in accumulation of excess amounts of LMW-HA, which is proangiogenic. 19 Studies have indicated that impairment of blood vascular barrier could be mediated by LMW-HA and an accelerating vascular metastasis of cancer cells was followed. 20,21 To date, there are no reports regarding how LMW-HA modulates lymphatic endothelial cell junctions or facilitates cancer cell metastasis through lymph vessels.…”

Section: Introductionmentioning

confidence: 99%

Low-molecular-weight hyaluronan (LMW-HA) accelerates lymph node metastasis of melanoma cells by inducing disruption of lymphatic intercellular adhesion

Cao

Liu

et al. 2016

OncoImmunology

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Endothelial integrity defects initiate lymphatic metastasis of tumor cells. Low-molecular-weight hyaluronan (LMW-HA) derived from plasma and interstitial fluid was reported to be associated with tumor lymphatic metastasis. In addition, LMW-HA was proved to disrupt lymphatic vessel endothelium integrity, thus promoting lymphatic metastasis of tumor cells. Until now, there are few reports on how LMW-HA modulates lymphatic endothelial cells adhesion junctions and affects cancer cells metastasizing into lymph vessels. The aim of our study is to unravel the novel mechanism of LMW-HA in mediating tumor lymphatic metastasis. Here, we employed a melanoma metastasis model to investigate whether LMW-HA facilitates tumor cells transferring from foci to remote lymph nodes by disrupting the lymphatic endothelial integrity. Our data indicate that LMW-HA significantly induces metastasis of melanoma cells to lymph nodes and accelerates interstitial-lymphatic flow in vivo. Further experiments show that increased migration of melanoma cells across human dermal lymphatic endothelial cell (HDLEC) monolayers is accompanied by impaired lymphatic endothelial barrier function and increased permeability. The mechanism study reveals that VE-cadherin-b-catenin pathway and relevant signals are involved in modulating the interactions between endothelial cells and that a significant inhibition of lymphatic endothelium disruption is observed when antibodies to the LMW-HA receptor (LYVE-1) are present. Thus, our findings demonstrate a disruptive effect of LMW-HA on lymphatic endothelium continuity which leads to a promotion on melanoma lymphatic metastasis and also suggest a cellular signaling mechanism associated with VE-cadherin-mediated lymphatic intercellular junctions.

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Section: Introductionmentioning

confidence: 99%

Low-molecular-weight hyaluronan (LMW-HA) accelerates lymph node metastasis of melanoma cells by inducing disruption of lymphatic intercellular adhesion

Cao

Liu

et al. 2016

OncoImmunology

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“…(e) The defect in the transmigration of the cps1Δ strain is not due to growth inhibition in the endothelial cell culture medium. * p < 0.05, ** p < 0.01, *** p < 0.0001, n/s = not significant the endothelial cell barrier and angiogenesis (Lennon et al, 2014). A recent study found that treating endothelial cells with low molecular weight hyaluronan induced the association of CD44v10 (a variant of CD44) with EphA2 and the concomitant activation of EphA2 via phosphorylation, thus suggesting a cross-talk between EphA2 and CD44 (Lennon et al, 2014).…”

Section: Discussionmentioning

confidence: 98%

“…The roles of EphA2 and CD44 in promoting the transcellular migration of C. neoformans across the BBB may not be incongruous because it is conceivable that both receptors may work in unison. Indeed, both CD44 and EphA2 have been implicated in regulating the endothelial cell barrier and angiogenesis (Lennon et al, ). A recent study found that treating endothelial cells with low molecular weight hyaluronan induced the association of CD44v10 (a variant of CD44) with EphA2 and the concomitant activation of EphA2 via phosphorylation, thus suggesting a cross‐talk between EphA2 and CD44 (Lennon et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, both CD44 and EphA2 have been implicated in regulating the endothelial cell barrier and angiogenesis (Lennon et al, ). A recent study found that treating endothelial cells with low molecular weight hyaluronan induced the association of CD44v10 (a variant of CD44) with EphA2 and the concomitant activation of EphA2 via phosphorylation, thus suggesting a cross‐talk between EphA2 and CD44 (Lennon et al, ). Furthermore, the CD44‐EphA2 complex facilitated recruitment of several proteins needed to induce RhoA activation during angiogenesis (Lennon et al, ).…”

Section: Discussionmentioning

confidence: 99%

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The blood-brain barrier internalisesCryptococcus neoformansvia the EphA2-tyrosine kinase receptor

Aaron

Jamklang

Uhrig

et al. 2018

Cellular Microbiology

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Cryptococcus neoformans is an opportunistic fungal pathogen that causes life-threatening meningitis most commonly in populations with impaired immunity. Here, we resolved the transcriptome of the human brain endothelium challenged with C. neoformans to establish whether C. neoformans invades the CNS by co-opting particular signalling pathways as a means to promote its own entry. Among the 5 major pathways targeted by C. neoformans, the EPH-EphrinA1 (EphA2) tyrosine kinase receptor-signalling pathway was examined further. Silencing the EphA2 receptor transcript in a human brain endothelial cell line or blocking EphA2 activity with an antibody or chemical inhibitor prevented transmigration of C. neoformans in an in vitro model of the blood-brain barrier (BBB). In contrast, treating brain endothelial cells with an EphA2 chemical agonist or an EphA2 ligand promoted greater migration of fungal cells across the BBB. C. neoformans activated the EPH-tyrosine kinase pathway through a CD44-dependent phosphorylation of EphA2, promoting clustering and internalisation of EphA2 receptors. Moreover, HEK293T cells expressing EphA2 revealed an association between EphA2 and C. neoformans that boosted internalisation of C. neoformans. Collectively, the results suggest that C. neoformans promotes EphA2 activity via CD44, and this in turn creates a permeable barrier that facilitates the migration of C. neoformans across the BBB.

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“…EphA2 belongs to the EphA subclass, and is expressed at a minimal level in epithelial cells (33). There is evidence that high levels of EphA2 promote various aspects of the malignant phenotype, including cell growth, angiogenesis, migration, invasion and survival of cancer cells (34,35). A previous study reported that there is a correlation between EphA2 and high levels of angiogenesis markers, in particular, VEGF expression and MVD counts, in HCC tumorigenesis (36,37).…”

Section: Discussionmentioning

confidence: 99%

Overexpression and correlation of HIF-2α, VEGFA and EphA2 in residual hepatocellular carcinoma following high-intensity focused ultrasound treatment: Implications for tumor recurrence and progression

Youshun

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Rapid growth of residual tumors can occur as a result of their recurrence and progression. The present study aimed to investigate the expression of hypoxia inducible factor-2 subunit α (HIF-2α), vascular endothelial growth factor A (VEGFA), erythropoietin-producing hepatocellular A2 (EphA2) and angiogenesis in residual hepatocellular carcinoma (HCC), following treatment with high-intensity focused ultrasound (HIFU) ablation, in order to investigate the association between protein expression and tumor recurrence and growth. Athymic BALB/c (nu/nu) mice were subcutaneously inoculated with the HCC cell line HepG2, in order to create xenograft tumors. Approximately 30 days post-inoculation, eight mice were treated with HIFU, whereas eight mice received no treatment and acted as the control group. Residual tumor tissues were obtained from the experimental groups after one month. Levels of HIF-2α, VEGFA, EphA2 and cluster of differentiation 31 (CD31) expression was measured by immunohistochemical staining. CD31-positive vascular endothelial cells were counted to calculate microvascular density (MVD), and western blot analysis was performed to determine levels of HIF-2α, VEGFA, and EphA2 protein. It was found that the expression levels of HIF-2α, VEGFA, EphA2, and MVD proteins in residual HCC tissues were significantly higher than in the control group tissues (P<0.05). Tumor MVD was strongly correlated with VEGFA (R=0.957, P<0.01) and EphA2 (R=0.993, P<0.01) protein expression levels. Furthermore, there was a significant positive correlation between HIF-2α and EphA2 expression (R=0.991, P<0.01). The correlation between VEGFA and EphA2 expression was also positive (R=0.985, P<0.01). These data suggest that overexpression of HIF-2α, VEGFA and EphA2 is related to angiogenesis in residual HCC following HIFU ablation, potentially via their association with key mediators of recurrence.

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Transactivation of the Receptor-tyrosine Kinase Ephrin Receptor A2 Is Required for the Low Molecular Weight Hyaluronan-mediated Angiogenesis That Is implicated in Tumor Progression

Cited by 35 publications

References 74 publications

Low-molecular-weight hyaluronan (LMW-HA) accelerates lymph node metastasis of melanoma cells by inducing disruption of lymphatic intercellular adhesion

Low-molecular-weight hyaluronan (LMW-HA) accelerates lymph node metastasis of melanoma cells by inducing disruption of lymphatic intercellular adhesion

The blood-brain barrier internalisesCryptococcus neoformansvia the EphA2-tyrosine kinase receptor

Overexpression and correlation of HIF-2α, VEGFA and EphA2 in residual hepatocellular carcinoma following high-intensity focused ultrasound treatment: Implications for tumor recurrence and progression

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