Differential Effects of EGFL6 on Tumor versus Wound Angiogenesis

Noh, Kyunghee; Mangala, Lingegowda S.; Han, Hee Dong; Zhang, Ningyan; Pradeep, Sunila; Wu, Sherry Y.; Ma, Shaolin; Mora, Edna; Rupaimoole, Rajesha; Jiang, Dahai; Wen, Yunfei; Shahzad, Mian M.K.; Lyons, Yasmin; Cho, Min Soon; Hu, Wei; Nagaraja, Archana S.; Haemmerle, Monika; Mak, C. H.; Chen, Xiuhui; Gharpure, Kshipra M.; Deng, Hui; Xiong, Wei; Kingsley, Charles V.; Liu, Jinsong; Jennings, Nicholas B.; Birrer, Michael J.; Bouchard, Richard R.; López-Berestein, Gabriel; Coleman, Robert L.; An, Zhiqiang; Sood, Anil K.

doi:10.1016/j.celrep.2017.11.020

Cited by 37 publications

(47 citation statements)

References 33 publications

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“…Since then, EGFL6 was reported to be overexpressed in tumors and in abnormal microenvironments such as the bone local environment and ovarian cancer [12,13]. Recently, EGFL6 was found to be significantly upregulated in tumor tissues versus wound tissues or normal endothelial cells, which in turn enhances tumor angiogenesis by mediating Tie2/PI3K/AKT signaling in hypoxic environments, thereby suggesting that the targeting of EGFL6 could be an effective treatment target [14]. Moreover, although EGFL6 expression has been shown to be correlated with tumorigenesis, angiogenesis, and vasculogenesis, its unique role in SBVM remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Thalidomide targets EGFL6 to inhibit EGFL6/PAX6 axis-driven angiogenesis in small bowel vascular malformation

Tang

Zhang

et al. 2020

Cell. Mol. Life Sci.

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Background Small bowel vascular malformation disease (SBVM) is the most common cause of obscure gastrointestinal bleeding (OGIB). Several studies suggested that EGFL6 was able to promote the growth of tumor endothelial cells by forming tumor vessels. To date, it remains unclear how EGFL6 promotes pathological angiogenesis in SBVM and whether EGFL6 is a target of thalidomide. Methods We took advantage of SBVM plasma and tissue samples and compared the expression of EGFL6 between SBVM patients and healthy people via ELISA and Immunohistochemistry. We elucidated the underlying function of EGFL6 in SBVM in vitro and by generating a zebrafish model that overexpresses EGFL6, The cycloheximide (CHX)-chase experiment and CoIP assays were conducted to demonstrate that thalidomide can promote the degradation of EGFL6 by targeting CRBN. Results The analysis of SBVM plasma and tissue samples revealed that EGFL6 was overexpressed in the patients compared to healthy people. Using in vitro and in vivo assays, we demonstrated that an EMT pathway triggered by the EGFL6/PAX6 axis is involved in the pathogenesis of SBVM. Furthermore, through in vitro and in vivo assays, we elucidated that thalidomide can function as anti-angiogenesis medicine through the regulation of EGFL6 in a proteasome-dependent manner. Finally, we found that CRBN can mediate the effect of thalidomide on EGFL6 expression and that the CRBN protein interacts with EGFL6 via a Lon N-terminal peptide. Conclusion Our findings revealed a key role for EGFL6 in SBVM pathogenesis and provided a mechanism explaining why thalidomide can cure small bowel bleeding resulting from SBVM.

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Section: Introductionmentioning

confidence: 99%

Thalidomide targets EGFL6 to inhibit EGFL6/PAX6 axis-driven angiogenesis in small bowel vascular malformation

Tang

Zhang

et al. 2020

Cell. Mol. Life Sci.

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“…EGFL6 is involved in the regulation of the cell cycle, cell proliferation, and development [4] . Further, EGFL6 participates in a series of other physiological processes including regulating cell adhesion, proliferation and migration of vascular endothelial cells, and mediating angiogenesis [5][6][7] . EGFL6 expression can also regulate cell movement, reduce contact inhibition and make cell anchoring independent; these processes can enhance the invasion and metastasis of tumor cells [8] .…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: EGFL6 Modulates WNT Signaling to Drive Esophageal Cancer Metastasis and Proliferation

Wang

Kang

Tian

et al. 2020

Preprint

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Background Esophageal cancer (EC) is the sixth deadliest cancer in the world. There has been no breakthrough in the research on EC in the past few decades. Epidermal growth factor-like protein 6 (EGFL6), as a member of the epidermal growth factor superfamily, plays an important role in the occurrence and development of some tumors. However, the role of EGFL6 in the EC has never explored. Methods Immunohistochemical staining was used to evaluate the expression level of EGEC6 protein in human EC and its adjacent non-tumor tissues, and analyzed the correlation between the expression level of EGFL6 protein and clinical pathological indexes and survival rate. In vitro, by constructing EGFL6 silence and overexpressed EC cells,used CCK-8, clone formation, wound healing assays, transwell experiment and flow cytometry to explore the effects of EGFL6 on the proliferation, invasion, migration and apoptosis of EC. By using real-time PCR or western blot to detect the related marker genes of epithelial-mesenchymal transformation (EMT), tumor stem cells (TSCs) and Wnt/β-catenin. In vivo, established a nude mouse EC transplantation tumor model. Results The results showed that the expression level of EGFL6 in EC is significantly higher than that in adjacent non-tumor tissues, and is related to poor prognosis of patients. In vitro, CCK-8, clone formation, wound healing assays, transwell experiment and flow cytometry results show that EGFL6 overexpression can promotes proliferation, invasion and migration of EC cells and inhibits apoptosis. EGFL6 silencing inhibits proliferation, invasion and migration of EC cells and promotes apoptosis. Real-time PCR and Western-blot detection of EMT-related markers found that EGFL6 can induce EC cells EMT. Real-time PCR detection of esophageal cancer stem cell-related genes showed that EGFL6 may maintain the expression of esophageal cancer stem cell-like cell population. Western-blot detection of Wnt/β-catenin signaling marker genes showed that EGFL6 participated in the expression of Wnt/β-catenin signaling pathway. In vivo experiments found that knockout of EGFL6 could inhibit the formation of subcutaneous tumors in nude mice. Conclusion Taken together, our study identified a novel role and mechanism of EGFL6 in EC and provided epigenetic therapeutic strategies for the treatment of EC.

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“…Angiogenic activators include angiopoietins, CCL2, EGFL6, endothelins, FGF, HIF1, IGF1, MMPs, PDGF, TGF, VEGF, and et al (48)(49)(50)(51)(52)(53)(54)(55)(56). On the other hand, angiostatin, endostatin, TSP1, and PAI2 are among the endogenous inhibitors of angiogenesis (57)(58)(59)(60).…”

Section: Angiogenesis In Prostate Cancermentioning

confidence: 99%

Molecular Links Between Angiogenesis and Neuroendocrine Phenotypes in Prostate Cancer Progression

Wang

Zhao

et al. 2020

Front. Oncol.

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As a common therapy for prostate cancer, androgen deprivation therapy (ADT) is effective for the majority of patients. However, prolonged ADT promotes drug resistance and progression to an aggressive variant with reduced androgen receptor signaling, so called neuroendocrine prostate cancer (NEPC). Until present, NEPC is still poorly understood, and lethal with no effective treatments. Elevated expression of neuroendocrine related markers and increased angiogenesis are two prominent phenotypes of NEPC, and both of them are positively associated with cancers progression. However, direct molecular links between the two phenotypes in NEPC and their mechanisms remain largely unclear. Their elucidation should substantially expand our knowledge in NEPC. This knowledge, in turn, would facilitate the development of effective NEPC treatments. We recently showed that a single critical pathway regulates both ADT-enhanced angiogenesis and elevated expression of neuroendocrine markers. This pathway consists of CREB1, EZH2, and TSP1. Here, we seek new insights to identify molecules common to pathways promoting angiogenesis and neuroendocrine phenotypes in prostate cancer. To this end, our focus is to summarize the literature on proteins reported to regulate both neuroendocrine marker expression and angiogenesis as potential molecular links. These proteins, often described in separate biological contexts or diseases, include AURKA and AURKB,

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Differential Effects of EGFL6 on Tumor versus Wound Angiogenesis

Cited by 37 publications

References 33 publications

Thalidomide targets EGFL6 to inhibit EGFL6/PAX6 axis-driven angiogenesis in small bowel vascular malformation

Thalidomide targets EGFL6 to inhibit EGFL6/PAX6 axis-driven angiogenesis in small bowel vascular malformation

WITHDRAWN: EGFL6 Modulates WNT Signaling to Drive Esophageal Cancer Metastasis and Proliferation

Molecular Links Between Angiogenesis and Neuroendocrine Phenotypes in Prostate Cancer Progression

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