Visit our Expo - Redox and Inflammation signaling 2012

Session XVII : Cell signaling in health and disease Poster XVII, 36
Differential activation of Akt and VEGF in tumor-derived microvascular endothelial
cells: a novel mechanism for acquired chemoresistance in liver cancers
Fanyin Meng, Roger Henson, Hania Wehbe, Molly Lang, and Tushar Patel
Scott and White Clinic, Texas A&M University System Health Science Center College of
Medicine, 2401 South 31st Street, Temple, TX 76508, U.S.A. E-mail:
fmeng@swmail.sw.org
Targeting endothelial cells that line tumor blood vessels is a promising new strategy for the
treatment of cancers such as liver cancer. The transcription factor Nuclear Factor Kappa B
(NF-kB) can regulate the expression of key mediators of angiogenesis and cell survival such
as protein kinase B (PKB/Akt) and vascular endothelial growth factor (VEGF). However, the
involvement and role of these mechanisms in tumor derived endothelial cells is unknown.
Methods: Hepatocellular carcinoma was induced in BALB/c mice using Ndiethylnitrosamine.
Microvascular endothelial cells (MVEC) were isolated from liver tumors
(T-MVECs) as well as normal liver tissues (N-MVECs) using a magnetic bead
immunoaffinity technique. In vitro angiogenesis was quantitated using a commercial assay kit
(Chemicon). Results: In both types of MVEC, transfection with NF-kB increased Akt
phosphorylation and VEGF expression. However, the increased VEGF expression was
blocked by dominant negative Akt in T-MVECs, but not N-MVECs. Moreover, overexpression
of Akt directly increased VEGF expression and NF-kB dependent angiogenesis in
T-MVECs. Incubation with gemcitabine to induce chemotherapeutic stress dramatically
increased NF-kB activation in both T-MVECs and N-MVECs, but increased Akt and VEGF
expression only in T-MVECs. In addition, Akt activation and VEGF expression was
dependent on NF-kB in T-MVECs. Over-expression of Akt decreased gemcitabine-induced
apoptosis in T-MVECs, but not in N-MVECs. In vitro angiogenesis was increased by
chemotherapeutic stress in T-MVECs, not in N-MVECs, and was abolished by inhibition of
either NF-kB or Akt. Conclusions: Akt is selectively activated in tumor derived endothelial
cells and may contribute to NF-kB dependent VEGF expression and angiogenesis and
survival during chemotherapeutic stress. Targeting NF-kB dependent up-regulation of Akt
and VEGF may be useful to decrease chemoresistance and tumor progression in liver cancers.
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