Differential Effects of EGFL6 on Tumor versus Wound Angiogenesis

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

doi:10.1016/j.celrep.2017.11.020

Differential Effects of EGFL6 on Tumor versus Wound Angiogenesis

Cell Rep. 2017 Dec 5;21(10):2785-2795. doi: 10.1016/j.celrep.2017.11.020.

Authors

Kyunghee Noh¹, Lingegowda S Mangala², Hee-Dong Han³, Ningyan Zhang⁴, Sunila Pradeep⁵, Sherry Y Wu⁶, Shaolin Ma⁶, Edna Mora⁷, Rajesha Rupaimoole⁶, Dahai Jiang², Yunfei Wen⁶, Mian M K Shahzad⁶, Yasmin Lyons⁶, MinSoon Cho⁸, Wei Hu⁶, Archana S Nagaraja⁶, Monika Haemmerle⁶, Celia S L Mak⁶, Xiuhui Chen⁶, Kshipra M Gharpure⁶, Hui Deng⁴, Wei Xiong⁴, Charles V Kingsley⁹, Jinsong Liu¹⁰, Nicholas Jennings⁶, Michael J Birrer¹¹, Richard R Bouchard⁹, Gabriel Lopez-Berestein¹², Robert L Coleman⁶, Zhiqiang An⁴, Anil K Sood¹³

Affiliations

¹ Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Gene Therapy Research Unit, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
² Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³ Department of Immunology, School of Medicine, Konkuk University, Chungju 380-701, South Korea.
⁴ Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
⁵ Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
⁶ Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Department of Surgery, University of Puerto Rico, San Juan 00936, Puerto Rico; University of Puerto Rico Comprehensive Cancer Center, San Juan 00936, Puerto Rico; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77584, USA.
⁸ Department of Benign Hematology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁹ Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹¹ University of Alabama Comprehensive Cancer Center, Birmingham, AL 35294, USA.
¹² Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹³ Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: [email protected].

Abstract

Angiogenesis inhibitors are important for cancer therapy, but clinically approved anti-angiogenic agents have shown only modest efficacy and can compromise wound healing. This necessitates the development of novel anti-angiogenesis therapies. Here, we show significantly increased EGFL6 expression in tumor versus wound or normal endothelial cells. Using a series of in vitro and in vivo studies with orthotopic and genetically engineered mouse models, we demonstrate the mechanisms by which EGFL6 stimulates tumor angiogenesis. In contrast to its antagonistic effects on tumor angiogenesis, EGFL6 blockage did not affect normal wound healing. These findings have significant implications for development of anti-angiogenesis therapies.

Keywords: chitosan nanoparticles; ovarian cancer; tumor endothelial cells; tumor vasculature; wound healing.

MeSH terms

Animals
Blotting, Western
Calcium-Binding Proteins
Cell Adhesion Molecules
Cell Line, Tumor
Cell Movement / genetics
Cell Movement / physiology
Chitosan / metabolism
Female
Glycoproteins / genetics
Glycoproteins / metabolism*
Humans
In Vitro Techniques
Integrins / genetics
Integrins / metabolism
Mice
Mice, Knockout
Nanoparticles / chemistry
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Neovascularization, Pathologic / genetics
Neovascularization, Pathologic / metabolism
Peptides / genetics
Peptides / metabolism*
Phosphatidylinositol 3-Kinases / metabolism
Phosphorylation / genetics
Phosphorylation / physiology
Proto-Oncogene Proteins c-akt / metabolism
Receptor, TIE-2 / genetics
Receptor, TIE-2 / metabolism
Twist-Related Protein 1 / genetics
Twist-Related Protein 1 / metabolism
Wound Healing / genetics
Wound Healing / physiology

Substances

Calcium-Binding Proteins
Cell Adhesion Molecules
Egfl6 protein, mouse
Glycoproteins
Integrins
Neoplasm Proteins
Peptides
Twist-Related Protein 1
Chitosan
Receptor, TIE-2
Tek protein, mouse
Proto-Oncogene Proteins c-akt

Abstract

MeSH terms

Substances

Grants and funding