title: Metronomic gemcitabine targeted tumor vascular microenvironment decreases the population of CD133(+) cells in hepatocarcinoma xenografts.
abstract: Recently, compelling evidence shows that cancer stem-like cells (CSLC) are thought to be critical for initiation and propagation of many types of cancers. Most of CSLC are dependent upon the vascular microenvironments that promote their long-term growth and self-renewal. However, it is not known if when we disrupted their vascular microenvironments, CSLC would be eliminated. Considering these possibilities, we have investigated the influence of different chemotherapy regimens on the CSLC population of hepatocarcinoma xenografts model. The mouse models of hepatocarcinoma were treated with different therapeutic regimens: low-dose metronomic (LDM) regimens, combination therapies of Bolus dose and low-dose metronomic regimens, for the purpose of comparison, a conventional cytotoxic schedule of maximum tolerated dose (MTD) chemotherapy using gemcitabine (GEM). All therapies produced a significant tumor growth delay. LDM GEM and Bolus+LDM GEM significantly reduced the tumor spheres, whereas MTD GEM had no effect on the tumor spheres. Furthermore, Bolus+LDM GEM could more significantly decrease both the population of CSLC and the levels of viable endothelial progenitor cells (EPC). Overall, our data indicate that Bolus+LDM GEM is a potent treatment regimen for inhibiting angiogenesis, attacking the tumor vascular microenvironments, and decreasing the population of CSLC. Targeting the unique microenvironment of CSLC may be the key to effective cancer therapy, and shows great promise for the clinical practice.
authors.affiliation: Department of Oncology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Shan-Yong
authors.initials: SY
authors.lastname: Yi
authors.affiliation: Department of Optometry, College of Optometry of Tianjin Medical University, Tianjin, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ruan
authors.affiliation: Department of Oncology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Oncology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ke
authors.affiliation: Department of Chest Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Xiang-Nan
authors.initials: XN
authors.lastname: Li
mesh_terms: D000071916:AC133 Antigen; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D010455:Peptides / Q000235:genetics; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000071916:AC133 Antigen; D020533:Angiogenesis Inhibitors; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: Metronomic chemotherapy; cancer stem-like cells; gemcitabine; hepatocarcinoma; tumor vascular microenvironment