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Lymphangiogenesis in gastric cancer regulated through Akt/mTOR-VEGF-C/VEGF-D axis.

Chen H, Guan R, Lei Y, Chen J, Ge Q, Zhang X, Dou R, Chen H, Liu H, Qi X, Zhou X, Chen C - BMC Cancer (2015)

Bottom Line: The results were presented as staining intensity and positive staining cell rate.LY294002 or Rapamycin significantly suppressed SGC-7901 cell growth and the inhibition rate was dose and time dependent (p < 0.001).Inhibition of p-Akt and p-mTOR, in vitro, decreased tumor cell VEGF-C and VEGF-D significantly.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Nanchang, 330006, China. yfychx@163.com.

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.

No MeSH data available.


Related in: MedlinePlus

Immunohistochemistry staining of D2-40 for LVD (×400). A: Gastric cancer tissue, B: Matched normal tissue, C: The correlation between LVD and p-Akt/p-mTOR/VEGF-C/VEGF-D. LVD = lymphatic vessel density.
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Fig2: Immunohistochemistry staining of D2-40 for LVD (×400). A: Gastric cancer tissue, B: Matched normal tissue, C: The correlation between LVD and p-Akt/p-mTOR/VEGF-C/VEGF-D. LVD = lymphatic vessel density.

Mentions: D2-40 staining was used to calculate the LVD for gastric cancer (Figure 2A) and matched normal gastric tissue (Figure 2B). According to the results, D2-40 stained mainly in lymphatic endothelium in scattered or clustered distribution. Thin lymphatic vessel wall was lacking basal layer. The highest LVD was observed at the edge of tumor with a dense cluster-like morphology. In addition, D2-40 was expressed in the submucosa of normal tissue, with a weaker expression in the mucosa or muscle layer as well. The average LVD of gastric carcinoma and normal tissue were 94.18 ± 72.965 vs 23.31 ± 21.569 number/5 high power fields, p < 0.001.Figure 2


Lymphangiogenesis in gastric cancer regulated through Akt/mTOR-VEGF-C/VEGF-D axis.

Chen H, Guan R, Lei Y, Chen J, Ge Q, Zhang X, Dou R, Chen H, Liu H, Qi X, Zhou X, Chen C - BMC Cancer (2015)

Immunohistochemistry staining of D2-40 for LVD (×400). A: Gastric cancer tissue, B: Matched normal tissue, C: The correlation between LVD and p-Akt/p-mTOR/VEGF-C/VEGF-D. LVD = lymphatic vessel density.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4358729&req=5

Fig2: Immunohistochemistry staining of D2-40 for LVD (×400). A: Gastric cancer tissue, B: Matched normal tissue, C: The correlation between LVD and p-Akt/p-mTOR/VEGF-C/VEGF-D. LVD = lymphatic vessel density.
Mentions: D2-40 staining was used to calculate the LVD for gastric cancer (Figure 2A) and matched normal gastric tissue (Figure 2B). According to the results, D2-40 stained mainly in lymphatic endothelium in scattered or clustered distribution. Thin lymphatic vessel wall was lacking basal layer. The highest LVD was observed at the edge of tumor with a dense cluster-like morphology. In addition, D2-40 was expressed in the submucosa of normal tissue, with a weaker expression in the mucosa or muscle layer as well. The average LVD of gastric carcinoma and normal tissue were 94.18 ± 72.965 vs 23.31 ± 21.569 number/5 high power fields, p < 0.001.Figure 2

Bottom Line: The results were presented as staining intensity and positive staining cell rate.LY294002 or Rapamycin significantly suppressed SGC-7901 cell growth and the inhibition rate was dose and time dependent (p < 0.001).Inhibition of p-Akt and p-mTOR, in vitro, decreased tumor cell VEGF-C and VEGF-D significantly.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Nanchang, 330006, China. yfychx@163.com.

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.

No MeSH data available.


Related in: MedlinePlus