Role of pigment epithelium-derived factor in the involution of hemangioma: Autocrine growth inhibition of hemangioma-derived endothelial cells

Kim, Kyung Jin; Yun, Jeong‐Ho; Heo, Jeongyun; Lee, Eun Hui; Min, Hye Sook; Choi, Tae Hyun; Cho, Chung–Hyun

doi:10.1016/j.bbrc.2014.10.052

Cited by 8 publications

(10 citation statements)

References 30 publications

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“…13,42 Until now, PEDF has been regarded as a suppressor of ischemia-induced retinal neovascularization, VEGF-induced migration and growth, 43 and EC migration and proliferation. 13 Consistent with studies published in 2014 and 2017, 14,15 we found that the increased PEDF/VEGF ratio during the involuting phase of IH may be caused by both a decrease in VEGF and an increase in PEDF and that this increase is accompanied by a lower microvascular density and expanded blood vessel structures ( Figure 1). Furthermore, our results indicated that an increased PEDF/VEGF ratio could impact IH progression by inhibiting HemEC processes, including proliferation, apoptosis, migration, and tube formation (Figures 2 and 3).…”

Section: Discussionsupporting

confidence: 91%

“…In addition, PEDF is the most active endogenous anti‐angiogenic factor and can directly target EC to inhibit EC proliferation and promote cell apoptosis . Recent studies have found that PEDF is highly expressed in the involuting phases of IH . Previous investigations, including ours, have confirmed that the balance between PEDF and VEGF plays a crucial role in the processes of vascular development and angiogenesis .…”

Section: Introductionsupporting

confidence: 57%

“…12,13 Recent studies have found that PEDF is highly expressed in the involuting phases of IH. 14,15 Previous investigations, including ours, have confirmed that the balance between PEDF and VEGF plays a crucial role in the processes of vascular development and angiogenesis. 13,[16][17][18][19][20][21] Nevertheless, whether and how the PEDF/ VEGF ratio plays a role in IH is unclear.…”

Section: Introductionsupporting

confidence: 53%

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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: 91%

Section: Introductionsupporting

confidence: 57%

Section: Introductionsupporting

confidence: 53%

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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“…Many researchers have found that lymph node metastases are significantly correlated with decreased survival in several solid tumors (31), and reduced PEDF levels in lung cancer tissues significantly correlated with lymph node metastasis (32). In addition to the anti-angiogenesis effect, PEDF plays a role in apoptosis, autophagy, and many other antitumor processes in various malignancies (14,15). All of these suggest that PEDF may decrease lymph node metastasis in cancers.…”

Section: Discussionmentioning

confidence: 99%

“…Many observations have shown that PEDF is implicated in several biological processes, such as neurogenesis, neuroprotection, anti-angiogenesis, retina protection, stem cell renewal, and inflammation (11). PEDF expresses in various kinds of cancers, such as lung cancer, pancreatic cancer, and breast cancer (12)(13)(14), and some research suggests that PEDF could be a new treatment to benefit cancer patients (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Prognostic value of pigment epithelium-derived factor for neoadjuvant radiation therapy in patients with locally advanced rectal carcinoma

Zhan

et al. 2016

International Journal of Oncology

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The aim of the study was to investigate the prognostic value of pigment epithelium-derived factor (PEDF) in locally advanced rectal carcinoma (LARC) treated with neoadjuvant radiation therapy (nRT). The level of PEDF expressing was examined in LARC tissues treated with nRT by immunohistochemistry and the prognostic significance of PEDF was analysed by univariate and multivariate survival analyses. We forced expression of PEDF in highly metastatic LoVo cells. The clonogenic survival assay was used to test the cellular sensitivity to radiation. Wound healing and Boyden chamber assays were used to detect cell migration and invasion. To assess the contribution of PEDF in vivo, we established tumor xenografts. The mechanisms of PEDF on cancer cells was analysed by bioinformatics. Our immunohistochemical staining of tissue samples revealed that prolonged DFS (77.1 vs 49.0%) and OS (87.1 vs 56.3%) was observed in PEDF-positive cases (P<0.001) following nRT. PEDF could be an independent factor for DFS [P=0.001; HR, 0.422 (95% CI, 0.249-0.717)] and OS [P=0.003; HR, 0.418 (95% CI, 0.234-0.749)]. Positive-expression of PEDF was negatively correlated with tumor differentiation (P<0.016), ypT stage (P<0.037), ypTNM stage (P<0.033), and ypN stage (P=0.006). Overexpression of PEDF in high metastatic cells enhanced radiosensitivity and, suppressed migration and invasion in vitro. In tumor xenografts, PEDF significantly suppressed tumor growth. Furthermore, by bioinformatics analysis, we found PEDF performs functions via activating P53 to regulate double-strand break repair pathway and activate the G protein activation pathway. Our findings indicate that PEDF was identified as a predictive candidate for nRT responsiveness. These findings may be used to stratify LARC patients and make alternative strategies for adjuvant treatment.

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Retinal pigment epithelium‐derived transforming growth factor‐β2 inhibits the angiogenic response of endothelial cells by decreasing vascular endothelial growth factor receptor‐2 expression

Jeong

Yun

Lee

et al. 2018

Journal Cellular Physiology

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Transforming growth factor-β (TGF-β) is a multifunctional cytokine that is known to modulate various aspects of endothelial cell (EC) biology. Retinal pigment epithelium (RPE) is important for regulating angiogenesis of choriocapillaris and one of the main cell sources of TGF-β secretion, particularly TGF-β2. However, it is largely unclear whether and how TGF-β2 affects angiogenic responses of ECs. In the current study, we demonstrated that TGF-β2 reduces vascular endothelial growth factor receptor-2 (VEGFR-2) expression in ECs and thereby inhibits vascular endothelial growth factor (VEGF) signaling and VEGF-induced angiogenic responses such as EC migration and tube formation. We also demonstrated that the reduction of VEGFR-2 expression by TGF-β2 is due to the suppression of JNK signaling. In coculture of RPE cells and ECs, RPE cells decreased VEGFR-2 levels in ECs and EC migration. In addition, we showed that TGF-β2 derived from RPE cells is involved in the reduction of VEGFR-2 expression and inhibition of EC migration. These results suggest that TGF-β2 plays an important role in inhibiting the angiogenic responses of ECs during the interaction between RPE cells and ECs and that angiogenic responses of ECs may be amplified by a decrease in TGF-β2 expression in RPE cells under pathologic conditions.

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Role of pigment epithelium-derived factor in the involution of hemangioma: Autocrine growth inhibition of hemangioma-derived endothelial cells

Cited by 8 publications

References 30 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

Prognostic value of pigment epithelium-derived factor for neoadjuvant radiation therapy in patients with locally advanced rectal carcinoma

Retinal pigment epithelium‐derived transforming growth factor‐β2 inhibits the angiogenic response of endothelial cells by decreasing vascular endothelial growth factor receptor‐2 expression

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