title: Combretastatin A4 phosphate treatment induces vasculogenic mimicry formation of W256 breast carcinoma tumor in vitro and in vivo.
abstract: The purpose of this study was to investigate the effect of combretastatin A4 phosphate (CA4P) on vasculogenic mimicry (VM) channel formation in vitro and in vivo after a single-dose treatment and the underlying mechanism involved in supporting VM. In vitro model of three-dimensional cultures was used to test the effect of CA4P on the tube formation of Walker 256 cells. Western blot analysis was conducted to assess the expression of hypoxia-inducible factor (HIF)-1α and VM-associated markers. W256 tumor-bearing rat model was established to demonstrate the effect of CA4P on VM formation and tumor hypoxia by double staining and a hypoxic marker pimonidazole. Anti-tumor efficacy of CA4P treatment was evaluated by tumor growth curve. Under hypoxic conditions for 48 h in vitro, W256 cells formed VM network associated with increased expression of VM markers. Pretreatment with CA4P did not influence the amount of VM in 3-D culture as well as the expression of these key molecules. In vivo, W256 tumors showed marked intratumoral hypoxia after CA4P treatment, accompanied by increased VM formation. CA4P exhibited only a delay in tumor growth within 2 days but rapid tumor regrowth afterward. VM density was positively related to tumor volume and tumor weight at day 8. CA4P causes hypoxia which induces VM formation in W256 tumors through HIF-1α/EphA2/PI3K/matrix metalloproteinase (MMP) signaling pathway, resulting in the consequent regrowth of the damaged tumor.
authors.affiliation: Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, Jiangsu Province, People's Republic of China.
authors.forename: Nan
authors.initials: N
authors.lastname: Yao
authors.affiliation: Department of Orthopaedics, Zhongda Hospital, Southeast University, 87 Ding Jia Qiao, Nanjing, 210009, Jiangsu Province, People's Republic of China.|Department of Orthopedics, The Third Affiliated Hospital of Soochow University (The First People's Hospital of Changzhou), Changzhou City, 213003, Jiangsu Province, People's Republic of China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ren
authors.affiliation: Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, Jiangsu Province, People's Republic of China.
authors.forename: Cuihua
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, Jiangsu Province, People's Republic of China.
authors.forename: Meng
authors.initials: M
authors.lastname: Gao
authors.affiliation: Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, Jiangsu Province, People's Republic of China.
authors.forename: Dejian
authors.initials: D
authors.lastname: Huang
authors.affiliation: Center Laboratory of Cancer Center, The Jingdu Hospital of Nanjing, No. 34 Yanggongjin, Nanjing, 210002, Jiangsu Province, People's Republic of China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Lu
authors.affiliation: Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, Jiangsu Province, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Lou
authors.affiliation: Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, Jiangsu Province, People's Republic of China.
authors.forename: Fei
authors.initials: F
authors.lastname: Peng
authors.affiliation: Center Laboratory of Cancer Center, The Jingdu Hospital of Nanjing, No. 34 Yanggongjin, Nanjing, 210002, Jiangsu Province, People's Republic of China.
authors.forename: Aizhen
authors.initials: A
authors.lastname: Yang
authors.affiliation: Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, Jiangsu Province, People's Republic of China.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Wang
authors.affiliation: Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, Jiangsu Province, People's Republic of China.|Faculty of Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: Yicheng
authors.initials: Y
authors.lastname: Ni
authors.affiliation: Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, No. 100, Shizi Street, Hongshan Road, Nanjing, 210028, Jiangsu Province, People's Republic of China. zjwonderful@hotmail.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009593:Nitroimidazoles / Q000008:administration & dosage; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000008:administration & dosage*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009593:Nitroimidazoles; D013267:Stilbenes; C033815:pimonidazole; D019869:Phosphatidylinositol 3-Kinases; C058728:fosbretabulin
keywords: Combretastatin A4 phosphate (CA4P); Hypoxia; Tumor regrowth; Vasculogenic mimicry