1. Lymphangiogenesis in Gastric Cancer regulated through Akt/mTOR-VEGF-C/VEGF-D axis
- Author
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Xiaolong Qi, Hongxia Chen, Ruoxu Dou, Runnian Guan, Jianyong Chen, Changyan Chen, Hao Liu, Yupeng Lei, Hongyuan Chen, Xiaodong Zhou, Xiaoshen Zhang, and Qi Ge
- Subjects
Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Morpholines ,Vascular Endothelial Growth Factor C ,Vascular Endothelial Growth Factor D ,Metastasis ,chemistry.chemical_compound ,Stomach Neoplasms ,Biomarkers, Tumor ,Genetics ,Humans ,Medicine ,LY294002 ,Enzyme Inhibitors ,Lymphangiogenesis ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Neovascularization, Pathologic ,business.industry ,Cell growth ,TOR Serine-Threonine Kinases ,Cancer ,Akt/mTOR ,medicine.disease ,Immunohistochemistry ,VEGF ,Oncology ,chemistry ,Chromones ,Cancer research ,Female ,Gastric cancer ,business ,Proto-Oncogene Proteins c-akt ,Signal Transduction ,Research Article - Abstract
Background: Lymphangiogenesis plays a significant role in metastasis and recurrence of gastric cancer. There is no report yet focusing on the modulation of VEGF pathway and lymphangiogenesis of gastric cancer by targeting Akt/mTOR pathway. This study aims to demonstrate the relationship between Akt/mTOR pathway and VEGF-C/-D in gastric cancer. Methods: We collected surgically resected gastric adenocarcinoma specimens from 55 consented patients. Immunohistochemistry staining of p-Akt, p-mTOR, VEGF-C, VEGF-D were performed and scored by two independent pathologists. The results were presented as staining intensity and positive staining cell rate. We also measured lymphatic vessel density (LVD) by D2-40 staining. Different dosages of p-Akt inhibitor LY294002 (12.5 μM, 25 μM, 50 μM) and p-mTOR inhibitor Rapamycin (25 nM, 50 nM, 100 nM) were given to gastric cancer cell line SGC-7901 in vitro. The inhibition rate of cell growth was tested by MTT at 24 h, 48 h and 72 h, respectively and protein expressions of Akt, p-Akt, mTOR, p-mTOR, VEGF-C and VEGF-D were examined by Western blot. Results: The positive staining rates of p-Akt, p-mTOR, VEGF-C and VEGF-D in 55 gastric cancer clinical specimens were 74.54%, 85.45%, 72.73% and 58.18%. p-Akt and p-mTOR were positively correlated with VEGF-C and VEGF-D (p < 0.01). The LVD increased with incremental tendency of staining intensity of p-Akt, p-mTOR, VEGF-C and VEGF-D. LY294002 or Rapamycin significantly suppressed SGC-7901 cell growth and the inhibition rate was dose and time dependent (p < 0.001). In addition, the protein expression of p-Akt and p-mTOR were positively correlated with that of VEGF-C and VEGF-D (p < 0.05). Conclusions: The level of LVD in gastric cancer specimens was significant higher than that of normal gastric tissue and was positively correlated with p-Akt, p-mTOR, VEGF-C and VEGF-D. Inhibition of p-Akt and p-mTOR, in vitro, decreased tumor cell VEGF-C and VEGF-D significantly. Therefore, we concluded that lymphangiogenesis of gastric cancer might be related to Akt/mTOR-VEGF-C/VEGF-D axis.
- Published
- 2015