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Updated: May 4, 2026

A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
Tumor resistance to anti-VEGF therapy through up-regulation of VEGF-C expression
Dong Li1, Kun Xie1, Guitao Ding1
1School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
Abstract:
Increasing evidence has indicated that prolonged use of anti-VEGF (vascular endothelial growth factor) agents for cancer therapy promotes tumor resistance. To gain insight into the molecular mechanism underlying resistance to anti-VEGF therapy, we developed a mouse Lewis lung carcinoma (LLC) cell line that is resistant to treatment with a potent VEGF inhibitor, VEGF-Trap, through repeated in vivo selection. We compared the transcriptome profiles of resistant and non-resistant tumor cells using RNA-seq analysis. VEGF-C was significantly up-regulated in resistant tumor cells, as determined by quantitative real-time PCR and immunohistochemical analyses. Inhibition of VEGF-C in resistant cells suppressed endothelial cell migration in vitro and partially restored sensitivity to VEGF-Trap treatment in vivo. Our findings indicate that tumors may develop resistance to anti-VEGF therapy by activating the VEGF-C pathway.
Insights
Tumors can become resistant to anti-VEGF cancer therapy by activating the VEGF-C pathway. Inhibiting VEGF-C can partially restore sensitivity to VEGF inhibitors, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Prolonged use of anti-vascular endothelial growth factor (VEGF) agents in cancer therapy can lead to tumor resistance.
- Understanding the molecular mechanisms of this resistance is crucial for developing more effective treatments.
Purpose of the Study:
- To investigate the molecular mechanisms underlying resistance to anti-VEGF therapy.
- To identify potential pathways involved in the development of resistance to VEGF inhibitors.
Main Methods:
- Development of a VEGF inhibitor-resistant Lewis lung carcinoma (LLC) cell line through in vivo selection.
- RNA-sequencing (RNA-seq) analysis to compare transcriptome profiles of resistant and non-resistant tumor cells.
- Quantitative real-time PCR and immunohistochemical analyses to validate gene expression changes.
Main Results:
- Vascular endothelial growth factor C (VEGF-C) was significantly up-regulated in resistant tumor cells compared to non-resistant cells.
- Inhibition of VEGF-C in resistant cells suppressed endothelial cell migration in vitro.
- Inhibition of VEGF-C partially restored the sensitivity of resistant cells to VEGF-Trap treatment in vivo.
Conclusions:
- Tumors may develop resistance to anti-VEGF therapy by activating the VEGF-C pathway.
- Targeting the VEGF-C pathway could be a strategy to overcome or prevent resistance to anti-VEGF cancer therapies.
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