Inhibition of Tumor Lymphangiogenesis is an Important Part that EGFR-TKIs Play in the Treatment of NSCLC
Source : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930403/
J Cancer. 2020; 11(1): 241-250. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been widely used to treat non-small cell lung cancer (NSCLC) because they inhibit tumour growth and metastasis. However, the underlying mechanisms are not fully understood. Here, we investigate whether anti-lymphangiogenesis mechanisms contribute to the anti-tumour effects of EGFR-TKIs.
Conclusion: Inhibition of lymphangiogenesis is another important role that the three EGFR-TKIs play in the treatment of lung cancer and the Janus kinase/signal transducers and activators of transcription 3 (JAK/STAT3) maybe an important signalling pathway regulating lymphangiogenesis, which provides a new idea for clinical therapy of lung cancer.
• Conclusion: “Taken together, these results demonstrated that EGFR-TKIs inhibited lung cancer progression and metastasis by suppressing lymphangiogenesis in vitro and in vivo. Understanding the interaction between lymphangiogenesis and tumour metastases may provide new clinical therapy strategies for cancer patients.”
• In the current preclinical study, investigators examined whether anti-lymphangiogenesis mechanisms played a role in the antineoplastic impact of EGFR-TKIs both in vitro and in vivo. The EGFR-TKIs included gefitinib, afatinib, and AZD9291.
• “EGFR-TKIs inhibited human lymphatic endothelial cells (HLEC) proliferation, migration and tube formation at the indicated concentrations,” the authors wrote. “Conditioned medium from human lung adenocarcinoma HCC827 cells treated with EGFR-TKIs also inhibited HLEC migration and tube formation. EGFR-TKIs inhibited VEGFC secretion, which further influenced HLEC behaviour in vitro.”
• Lymphatic -vessel densities and tube diameters decreased in a dose-dependent manner on exposure to EGFR-TKIs. This exposure also inhibited the expression of lymphangiogenesis regulatory factors vascular endothelial growth factor 2/3 (VEGF2/3), VEGFC, and chemokine receptor 7 (CCR7). On further analysis, JAK/STAT3 signalling pathways are key to the anti-lymphangiogenesis process initiated by EGFR-TKI
• The researchers also discovered decreased lymphatic vessel. Which was evidenced by detection of the biomarker LYVE-1, which was the first lymphatic endothelial marker.
• “Inhibition of lymphangiogenesis is another important role that the three EGFR-TKIs play in the treatment of lung cancer and the Janus kinase/signal transducers and activators of transcription 3 (JAK/STAT3) maybe an important signalling pathway regulating lymphangiogenesis, which provides a new idea for clinical therapy of lung cancer,” the authors wrote.
• One of the main signals regulating tumor-induced lymphangiogenesis is VEGFR-3 activation. VEGFR-3 is stimulated by VEGFC and VEGF-D, which belong to the VEGF family of growth factors.
• In various cancers, the JAK/STAT3 signalling pathway moderates proliferation, cell survival, migration, invasion, lymphangiogenesis, angiogenesis, and immune evasion. These neoplasms include prostate cancer, hepatocellular carcinoma, and gastric cancer.