Serum and tissue profile of VEGF and its receptors VGFR1/R2 in children with infantile hemangiomas on systemic propranolol treatment

Przewratil, Przemysław; Kobos, Józef; Wnęk, Aneta; Szemraj, Janusz; Wyrzykowski, Dariusz; Chrzanowska, B; Andrzejewska, Ewa; Taran, Katarzyna

doi:10.1016/j.imlet.2016.05.002

Cited by 18 publications

(15 citation statements)

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“…42,44 Although we have not yet identified the upstream regulatory mechanisms, we have established the downstream receptors of the PEDF/VEGF ratio adjustment. Consistent with previous studies, 34,41 our results showed that the expression levels of VEGF and VEGFR were upregulated in the EC of hemangiomas compared with the relatively quiescent EC. In contrast to previous studies, we found a major anti-angiogenic pathway in IH.…”

Section: Discussionsupporting

confidence: 93%

“…As observed in previous studies, all 3 receptors were overexpressed in IH (Figure ), and the majority of these receptors were merged with CD31 (Figure ). Many published articles have indicated that propranolol inhibits VEGF expression . However, the mechanism through which propranolol affects the most active anti‐angiogenesis factor, PEDF, has not been explored.…”

Section: Resultsmentioning

confidence: 99%

“…Many published articles have indicated that propranolol inhibits VEGF expression. 26,27,41 However, the mechanism through which propranolol affects the most active anti-angiogenesis factor, PEDF, has not been explored.…”

Section: Pedf and Propranolol Combination Achieves Greater Suppressmentioning

confidence: 99%

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Pigment epithelium‐derived factor/vascular endothelial growth factor ratio plays a crucial role in the spontaneous regression of infant hemangioma and in the therapeutic effect of propranolol

Zhu

Xie

Liu³

et al. 2018

Cancer Science

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Infantile hemangioma (IH) is a benign tumor that is formed by aberrant angiogenesis and that undergoes spontaneous regression over time. Propranolol, the first‐line therapy for IH, inhibits angiogenesis by downregulating activation of the vascular endothelial growth factor (VEGF) pathway, which is hyperactivated in IH. However, this treatment is reportedly ineffective for 10% of tumors, and 19% of patients relapse after propranolol treatment. Both pro‐angiogenic and anti‐angiogenic factors regulate angiogenesis, and pigment epithelium‐derived factor (PEDF) is the most effective endogenous anti‐angiogenic factor. PEDF/VEGF ratio controls many angiogenic processes, but its role in IH and the relationship between this ratio and propranolol remain unknown. Results of the present study showed that the PEDF/VEGF ratio increased during the involuting phase of IH compared with the proliferating phase. Similarly, in hemangioma‐derived endothelial cells (HemEC), which were isolated with magnetic beads, increasing the PEDF/VEGF ratio inhibited proliferation, migration, and tube formation and promoted apoptosis. Mechanistically, the VEGF receptors (VEGFR1 and VEGFR2) and PEDF receptor (laminin receptor, LR) were highly expressed in both IH tissues and HemEC, and PEDF inhibited HemEC function by binding to LR. Interestingly, we found that propranolol increased the PEDF/VEGF ratio but did so by lowering VEGF expression rather than by upregulating PEDF as expected. Furthermore, the combination of PEDF and propranolol had a more suppressive effect on HemEC. Consequently, our results suggested that the PEDF/VEGF ratio played a pivotal role in the spontaneous regression of IH and that the combination of PEDF and propranolol might be a promising treatment strategy for propranolol‐resistant IH.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Pigment epithelium‐derived factor/vascular endothelial growth factor ratio plays a crucial role in the spontaneous regression of infant hemangioma and in the therapeutic effect of propranolol

Zhu

Xie

Liu³

et al. 2018

Cancer Science

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“…There are many inconsistencies concerning the participation of VEGFR‐2 in IH pathogenesis. In our previous studies, no statistical difference was found in VEGFR‐2 serum levels between hemangioma patients and healthy controls or between hemangioma patients treated with propranolol and untreated . However, Jinnin et al .…”

Section: Discussionmentioning

confidence: 77%

“…In our previous studies, no statistical difference was found in VEGFR-2 serum levels between hemangioma patients and healthy controls or between hemangioma patients treated with propranolol and untreated. 37 However, Jinnin et al 14 T/A polymorphism has been found to reduce the affinity of VEGF for its receptor 2 39 and A/A genotype of À271 G/A polymorphism has been shown to correlate with lower VEGFR-2 protein levels. 40 In the result, this may dysregulate the VEGF/ VEGFR-2 signaling pathway.…”

Section: Analysis Of Gene Expressionmentioning

confidence: 98%

Single‐nucleotide polymorphisms of VEGF‐A and VEGFR‐2 genes and risk of infantile hemangioma

et al. 2018

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Propranolol Suppresses the Growth of Colorectal Cancer Through Simultaneously Activating Autologous CD8⁺ T Cells and Inhibiting Tumor AKT/MAPK Pathway

Liao

Song

Zhu

et al. 2020

Clin Pharma and Therapeutics

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Propranolol suppresses tumor growth in a variety of preclinical solid tumor models, with a number of proposed cell signaling and immunological mechanisms. We want to confirm the potential mechanisms, including reduced phosphorylation of AKT/MAPK pathways, as well as enhanced CD8+ T‐cell–mediated antitumor immune response. To clarify the mechanism of propranolol activity in colorectal cancer, the therapeutic activity of propranolol was then assessed in CT26WT tumors engrafted in BALB/C mice. Then the effect of propranolol treatment was also examined by randomizing patients undergoing surgical resection of a previously untreated colorectal cancer to propranolol or placebo group and treated for 1 week prior to surgery. CT26WT tumor size was smaller after propranolol than vehicle control. Propranolol downregulated the expression of p‐AKT/p‐ERK/p‐MEK in tumor tissue. The frequency of tumor CD8+ T cells was significantly elevated in propranolol‐treated mice. The expression of GzmB/IFN‐γ/T‐bet in the CD8+ T‐cell population was significantly increased in propranolol treated mice tumor tissue. In propranolol‐treated surgical specimens, the expression of p‐ERK was decreased and the frequency of CD8+ was significantly elevated. The expression of GzmB in the CD8+ T‐cell population was significantly increased in propranolol‐treated subjects. Together, these data show propranolol simultaneously activating autologous CD8+ T cells and decreasing the expression of p‐AKT/p‐ERK/p‐MEK in mouse tumor models, while inhibiting the expression of p‐ERK in clinical colorectal cancer. Effort is now needed to further dissect whether both pathways are required for antitumor effect, as the activity of this old drug is moved forward.

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Serum and tissue profile of VEGF and its receptors VGFR1/R2 in children with infantile hemangiomas on systemic propranolol treatment

Cited by 18 publications

References 29 publications

Pigment epithelium‐derived factor/vascular endothelial growth factor ratio plays a crucial role in the spontaneous regression of infant hemangioma and in the therapeutic effect of propranolol

Pigment epithelium‐derived factor/vascular endothelial growth factor ratio plays a crucial role in the spontaneous regression of infant hemangioma and in the therapeutic effect of propranolol

Single‐nucleotide polymorphisms of VEGF‐A and VEGFR‐2 genes and risk of infantile hemangioma

Propranolol Suppresses the Growth of Colorectal Cancer Through Simultaneously Activating Autologous CD8⁺ T Cells and Inhibiting Tumor AKT/MAPK Pathway

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Serum and tissue profile of VEGF and its receptors VGFR1/R2 in children with infantile hemangiomas on systemic propranolol treatment

Cited by 18 publications

References 29 publications

Pigment epithelium‐derived factor/vascular endothelial growth factor ratio plays a crucial role in the spontaneous regression of infant hemangioma and in the therapeutic effect of propranolol

Pigment epithelium‐derived factor/vascular endothelial growth factor ratio plays a crucial role in the spontaneous regression of infant hemangioma and in the therapeutic effect of propranolol

Single‐nucleotide polymorphisms of VEGF‐A and VEGFR‐2 genes and risk of infantile hemangioma

Propranolol Suppresses the Growth of Colorectal Cancer Through Simultaneously Activating Autologous CD8+ T Cells and Inhibiting Tumor AKT/MAPK Pathway

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Product

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Propranolol Suppresses the Growth of Colorectal Cancer Through Simultaneously Activating Autologous CD8⁺ T Cells and Inhibiting Tumor AKT/MAPK Pathway