title: Ovarian cancer stem-like cells differentiate into endothelial cells and participate in tumor angiogenesis through autocrine CCL5 signaling.
abstract: Cancer stem cells (CSCs) are well known for their self-regeneration and tumorigenesis potential. In addition, the multi-differentiation potential of CSCs has become a popular issue and continues to attract increased research attention. Recent studies demonstrated that CSCs are able to differentiate into functional endothelial cells and participate in tumor angiogenesis. In this study, we found that ovarian cancer stem-like cells (CSLCs) activate the NF-κB and STAT3 signal pathways through autocrine CCL5 signaling and mediate their own differentiation into endothelial cells (ECs). Our data demonstrate that CSLCs differentiate into ECs morphologically and functionally. Anti-CCL5 antibodies and CCL5-shRNA lead to markedly inhibit EC differentiation and the tube formation of CSLCs, both in vitro and in vivo. Recombinant human-CCL5 significantly promotes ovarian CSLCs that differentiate into ECs and form microtube network. The CCL5-mediated EC differentiation of CSLCs depends on binding to receptors, such as CCR1, CCR3, and CCR5. The results demonstrated that CCL5-CCR1/CCR3/CCR5 activates the NF-κB and STAT3 signal pathways, subsequently mediating the differentiation of CSLCs into ECs. Therefore, this study was conducted based on the theory that CSCs improve tumor angiogenesis and provides a novel strategy for anti-angiogenesis in ovarian cancer.
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Tang
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Department of Oncology, No. 421 Hospital of PLA, Guangzhou 510318, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Xiang
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Huang
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Xinqiao Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Rongkai
authors.initials: R
authors.lastname: Xie
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China. Electronic address: longhaixialhx@163.com.
authors.forename: Haixia
authors.initials: H
authors.lastname: Long
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China. Electronic address: b.davis.zhu@gmail.com.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhu
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D054338:Cell Transdifferentiation; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D034622:RNA Interference; D054389:Receptors, CCR1 / Q000378:metabolism; D054397:Receptors, CCR3 / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: C483024:CCL5 protein, human; C515300:CCR1 protein, human; C515350:CCR3 protein, human; C584933:CCR5 protein, human; D018946:Chemokine CCL5; D016328:NF-kappa B; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D019713:Receptors, CCR5; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: Angiogenesis; CCL5; Cancer stem cell; Endothelial cell differentiation; Ovarian cancer