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Hypoxic Macrophage-Derived VEGF Promotes Proliferation and Invasion of Gastric Cancer Cells

  • Fei Ma
  • Bin Zhang
  • Sheqing Ji
  • Hongtao Hu
  • Ye Kong
  • Yawei Hua
  • Suxia LuoEmail author
Original Article
  • 26 Downloads

Abstract

Background

Gastric cancer (GC) is one of the most common causes of cancer death. Hypoxia is an important property of the tumor microenvironment of GC. Increasing evidence demonstrates that tumor-associated macrophages are related to the metastasis of GC, while the precise mechanism of how hypoxic macrophages affect tumor progression is still not fully understood.

Aims

To examine whether the mediators released from hypoxic macrophages contribute to the invasion and proliferation of GC cells.

Methods

Cell Counting Kit-8 was utilized to determine the proliferation of SGC7901 and MKN45 cells. The invasion of SGC7901 and MKN45 cells was measured by transwell invasion assay. Expression of VEGF mRNA in THP-1-derived macrophages was determined by RT-PCR, and protein level of VEGF in the culture medium was detected by ELISA.

Results

The proliferation and invasion of SGC7901 and MKN45 cells were dramatically increased after treatment with conditioned medium (CM) collected from THP-1-derived macrophages under hypoxia (H-CM), and the phosphorylation of Akt and p38 in SGC7901 and MKN45 cells was also up-regulated by H-CM stimulation. Notably, blockage of PI3K-Akt or p38 MAP kinase abolished the effects of H-CM on the proliferation and invasion of SGC7901 and MKN45 cells. Furthermore, VEGF was increased in macrophages after hypoxia and administration with nintedanib, an inhibitor of VEGFR, significantly decreases the phosphorylation of Akt and p38, as well as the proliferation and invasion of SGC7901 and MKN45 cells in response to H-CM.

Conclusions

Our findings suggest that hypoxia-injured macrophages contribute to the proliferation and invasion of GC cells through the release of mediators such as VEGF.

Keywords

Gastric cancer Hypoxia Macrophage VEGF 

Notes

Acknowledgments

This study was funded by the National Natural Science Foundation of China under Grant No. U1504816.

Author's contribution

FM, BZ, and SJ performed the experiments of this study. SL, HH, and YK participated in its design and coordination and interpretation of results and helped to draft the manuscript. YH and SL wrote the manuscript. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interests.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of General SurgeryAffiliated Cancer Hospital of Zhengzhou UniversityZhengzhouChina
  2. 2.Department of Intervention RadiologyAffiliated Cancer Hospital of Zhengzhou UniversityZhengzhouChina
  3. 3.Department of Medical OncologyAffiliated Cancer Hospital of Zhengzhou UniversityZhengzhouChina

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