Cancer Genetics Lab, Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi 221005, India.
Department of Obstetrics and Gynecology, Institute of Medical sciences, Banaras Hindu University, Varanasi 221005, India.
Int J Biochem Cell Biol. 2022 Jan;142:106122. doi: 10.1016/j.biocel.2021.106122. Epub 2021 Nov 24.
VEGF secretion into the tumor microenvironment by cancer cells regulates several oncogenic signaling pathways and cancer-regulated angiogenesis. VEGFR receptors are exclusively present on endothelial cells to maintain their biological homeostasis. The acquisition of unique VEGFR2 receptor and VEGFa in cervical cancer (CC) cells reflects VEGFa/VEGFR2 autocrine machinery. Given the critical role of VEGFR2 in endothelial cell proliferation, migration, and angiogenesis, we explored its function in CC epithelial-mesenchymal transition (EMT) and stemness. Here we report that VEGFR2 regulates cancer-induced angiogenesis and EMT-linked stemness in CC cells via AKT/GSK3β/β-catenin and Snail pathway. Receptor tyrosine kinase inhibitor (RTKi) of VEGFR, Pazopanib (PAZ), shows potential anti-VEGFR2 activity and inhibits VEGFa induced metastatic events such as migration, invasion, and anoikis resistance in CC cells. Similarly, PAZ also attenuates cancer-regulated angiogenesis by inhibiting VE-cadherin internalization in endothelial cells followed by inhibition of endothelial cell migration. Selective depletion of VEGFR2 ligand VEGFa in CC cells also attenuates EMT, metastatic events, and inhibition of cancer-induced angiogenesis. In addition, blocking of VEGFR2 signaling in CC cells via PAZ or shRNA alters the formation of cervical tumorspheres (TS) and their successive generation. Collectively, inhibition of functional VEGFa/VEGFR2 autocrine and paracrine axis ceases the cancer-promoting events in cervical cancer cells. Based on the finding in this study, this oncogenic pathways could be used as a potential therapeutic target in a clinical setting with conventional radio-chemotherapy to achieve synergistic killing of CC cells.
癌细胞向肿瘤微环境中分泌 VEGF 调节多种致癌信号通路和肿瘤调控的血管生成。VEGFR 受体仅存在于血管内皮细胞上，以维持其生物学的内稳态。宫颈癌（CC）细胞中独特的 VEGFR2 受体和 VEGFa 的获得反映了 VEGFa/VEGFR2 自分泌机制。鉴于 VEGFR2 在血管内皮细胞增殖、迁移和血管生成中的关键作用，我们研究了其在 CC 上皮间质转化（EMT）和干性中的功能。在这里，我们报告 VEGFR2 通过 AKT/GSK3β/β-catenin 和 Snail 通路调节 CC 细胞中癌症诱导的血管生成和 EMT 相关干性。VEGFR 的受体酪氨酸激酶抑制剂（RTKi）帕唑帕尼（PAZ）显示出潜在的抗 VEGFR2 活性，并抑制 CC 细胞中 VEGFa 诱导的迁移、侵袭和无附著生存抵抗等转移事件。类似地，PAZ 还通过抑制内皮细胞 VE-钙粘蛋白内化，随后抑制内皮细胞迁移，抑制癌症调控的血管生成。CC 细胞中 VEGFR2 配体 VEGFa 的选择性耗竭也可减弱 EMT、转移事件，并抑制癌症诱导的血管生成。此外，通过 PAZ 或 shRNA 阻断 CC 细胞中的 VEGFR2 信号会改变宫颈肿瘤球（TS）的形成及其连续产生。总之，抑制功能性 VEGFa/VEGFR2 自分泌和旁分泌轴可停止宫颈癌细胞中的促癌事件。基于本研究中的发现，该致癌通路可与常规放化疗一起用于临床，作为一种潜在的治疗靶点，以协同杀伤 CC 细胞。
