Hypoxia-induced epithelial VEGF-C/VEGFR-3 upregulation in carcinoma cell lines

  • Authors:
    • Nektaria Simiantonaki
    • Caren Jayasinghe
    • Romi Michel-Schmidt
    • Kirsten Peters
    • Maria Iris Hermanns
    • Charles James Kirkpatrick
  • View Affiliations

  • Published online on: March 1, 2008     https://doi.org/10.3892/ijo.32.3.585
  • Pages: 585-592
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Abstract

Adaptation to hypoxia, a universal hallmark of carcinomas, is a critical step for tumor cell survival and growth. One of the principal regulators of hypoxia-responsive pathways is the transcription factor hypoxia-inducible factor-1 α (HIF-1α). Currently, it is known that tumoral production of members of the vascular endothelial growth factor (VEGF)-family (VEGFs) may promote tumor growth and progression by acting on carcinoma cells that express the cognate receptors (VEGFRs). However, the influence of hypoxia in the formation of such a tumoral VEGF/VEGFR loop is not completely understood. In the present study we examined the potential existence of a HIF-1α/VEGF/VEGFR autocrine loop on commonly occuring carcinomas. The experiments were performed on five colorectal carcinoma cell lines, one breast (MCF7) and one lung (A549) adenocarcinoma cell line under normoxic and oxygen stress conditions using HIF-1α-EIA, VEGFs-ELISA as well as RT-PCR and immunofluorescence for VEGFRs. HIF-1α overexpression was found already after 2 h of exposure to hypoxia in all above mentioned cell lines, thus documenting that activation of the transcription factor HIF-1α is an early cellular event. Under hypoxic conditions a significant upregulation and activation of HIF-1α accompanied by an increased production of VEGF in MCF7 and A549 was observed. The well-differentiated colorectal carcinoma cell lines were ‘hypoxia-resistant’ showing unchanged levels of HIF-1α and VEGF under hypoxia. None of the cell lines used in this study expressed the VEGF receptors VEGFR-1 and VEGFR-2 under normoxia and hypoxia. Additionally, all colorectal carcinoma cell lines were negative for VEGFR-3 transcripts in both conditions. However, VEGFR-3 mRNA and protein were expressed and under hypoxia overexpressed in MCF7 and A549. Hypoxic cultures of both cell lines secreted in elevated levels the VEGFR-3 ligand VEGF-C but not VEGF-D. Our findings suggest that under hypoxic conditions an autocrine loop between VEGF-C/VEGFR-3 and HIF-1α is possible in breast carcinoma and lung carcinoma but not in colorectal carcinoma cell lines.

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March 2008
Volume 32 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Simiantonaki N, Jayasinghe C, Michel-Schmidt R, Peters K, Hermanns MI and Kirkpatrick CJ: Hypoxia-induced epithelial VEGF-C/VEGFR-3 upregulation in carcinoma cell lines. Int J Oncol 32: 585-592, 2008
APA
Simiantonaki, N., Jayasinghe, C., Michel-Schmidt, R., Peters, K., Hermanns, M.I., & Kirkpatrick, C.J. (2008). Hypoxia-induced epithelial VEGF-C/VEGFR-3 upregulation in carcinoma cell lines. International Journal of Oncology, 32, 585-592. https://doi.org/10.3892/ijo.32.3.585
MLA
Simiantonaki, N., Jayasinghe, C., Michel-Schmidt, R., Peters, K., Hermanns, M. I., Kirkpatrick, C. J."Hypoxia-induced epithelial VEGF-C/VEGFR-3 upregulation in carcinoma cell lines". International Journal of Oncology 32.3 (2008): 585-592.
Chicago
Simiantonaki, N., Jayasinghe, C., Michel-Schmidt, R., Peters, K., Hermanns, M. I., Kirkpatrick, C. J."Hypoxia-induced epithelial VEGF-C/VEGFR-3 upregulation in carcinoma cell lines". International Journal of Oncology 32, no. 3 (2008): 585-592. https://doi.org/10.3892/ijo.32.3.585