title: Dose dependent effects of cadmium on tumor angiogenesis.
abstract: Angiogenesis is crucial for tumor growth and metastasis. Cadmium (Cd) exposure is associated with elevated cancer risk and mortality. Such association is, at least in part, attributable to Cd-induced tumor angiogenesis. Nevertheless, the reported effects of Cd on tumor angiogenesis appear to be either stimulatory or inhibitory, depending on the concentrations. Ultra-low concentrations of Cd (<0.5 μM) inhibit endothelial nitric oxide synthase activation, leading to reduced endothelial nitric oxide production and attenuated tumor angiogenesis. In contrast, low-lose Cd (1-10 μM) up-regulates vascular endothelial growth factor (VEGF)-mediated tumor angiogenesis by exerting sub-apoptotic levels of oxidative stress on both tumor cells and endothelial cells (ECs). The consequent activation of protein kinase B/Akt, nuclear factor-κB, and mitogen-activated protein kinase signaling cascades mediate the increased secretion of VEGF by tumor cells and the up-regulated VEGF receptor-2 expression in ECs. Furthermore, Cd in high concentrations (>10 μM) induces EC apoptosis via the activation of caspase-3, resulting in destruction of tumor vasculature. In this review, we summarize the current knowledge concerning the roles of Cd in tumor angiogenesis, with a focus on molecular mechanisms underlying the dose dependent effects of Cd on various EC phenotypes.
authors.affiliation: Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China.
authors.forename: Tianshu
authors.initials: T
authors.lastname: Wei
authors.affiliation: Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Jia
authors.affiliation: The Research Center for Advanced Science and Technology, Isotope Science Center, The University of Tokyo, Komaba, Meguro-Ku, Tokyo, Japan.
authors.forename: Youichiro
authors.initials: Y
authors.lastname: Wada
authors.affiliation: Department of Biology, Trent University, Peterborough, Ontario, Canada.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Kapron
authors.affiliation: Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China.
authors.forename: Ju
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D002104:Cadmium / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000009:adverse effects*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D004785:Environmental Pollutants; D042461:Vascular Endothelial Growth Factor A; D002104:Cadmium; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt
keywords: cadmium; dose dependent effect; endothelial cells; oxidative stress; tumor angiogenesis