Dose dependent effects of cadmium on tumor angiogenesis

Tianshu Wei, Jin Jia, Youichiro Wada, Carolyn M. Kapron and Ju Liu _

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Oncotarget. 2017; 8:44944-44959. https://doi.org/10.18632/oncotarget.16572

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Tianshu Wei1,*, Jin Jia1,*, Youichiro Wada2, Carolyn M. Kapron3 and Ju Liu1

1 Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China

2 The Research Center for Advanced Science and Technology, Isotope Science Center, The University of Tokyo, Komaba, Meguro-Ku, Tokyo, Japan

3 Department of Biology, Trent University, Peterborough, Ontario, Canada

* These authors have contributed equally to the work

Correspondence to:

Ju Liu, email:

Keywords: tumor angiogenesis, cadmium, dose dependent effect, endothelial cells, oxidative stress

Received: February 09, 2017 Accepted: March 16, 2017 Published: March 25, 2017


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.

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