Regorafenib induces adaptive resistance of colorectal cancer cells via inhibition of vascular endothelial growth factor receptor
Regorafenib induces adaptive resistance of colorectal cancer cells via inhibition of vascular endothelial growth factor receptor
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DOI：
10.2152/jmi.64.262
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发表时间：
2017-08-01
影响因子：
0.7
通讯作者：
Teshima-Kondo, Shigetada
中科院分区：
文献类型：
--
作者：
Tomida, Chisato;Nagano, Hikaru;Teshima-Kondo, Shigetada
近年来，抑制肿瘤血管生成已成为一种重要的抗癌治疗方法。肿瘤血管生成受多种信号通路调控，包括VEGF及VEGF受体（VEGF- r）、FGF及FGF受体（FGF- r）、PDGF及PDGF受体（PDGF- r）通路。因此，抗血管生成药物，如瑞非尼，同时靶向血管内皮细胞上的受体。除了内皮细胞外，癌细胞也表达这三种受体，这表明抗血管生成抑制剂对肿瘤细胞有影响。事实上，我们之前已经证明regorafenib直接作用于人类结直肠癌细胞，并加速其凋亡抵抗和迁移能力。因此，我们在这里阐明了瑞非尼如何诱导结直肠癌细胞的恶性表型。为了在regorafenib靶向的促血管生成受体中确定负责受体，我们研究了VEGF-R、FGF-R或PDGF-R的有效选择性抑制剂对细胞凋亡抵抗和迁移能力的影响。我们澄清了VEGF-R的阻断，而不是FGF-R和PDGF-R，诱导了恶性表型。我们证实，阻断来自结直肠癌细胞的VEGF配体也会诱导表型。这些结果表明，瑞非尼通过阻止结直肠癌细胞中的自分泌和旁分泌VEGF信号传导而进展恶性肿瘤。
Recently, inhibition of tumor angiogenesis has become an important anti-cancer therapy. Tumor angiogenesis is regulated by multiple signaling pathways, including VEGF and VEGF receptor (VEGF-R), FGF and FGF receptor (FGF-R), and PDGF and PDGF receptor (PDGF-R) pathways. Thus, the antiangiogenic agents, such as regorafenib, simultaneously target those receptors on vascular endothelial cells. In addition to endothelial cells, cancer cells express the three receptors, suggesting that the antiangiogenic inhibitors affect tumor cells. In fact, we previously demonstrated that regorafenib directly acted on human colorectal cancer cells and accelerated their apoptosis resistance and migration capability. Thus, we here elucidated how regorafenib induced the malignant phenotypes in colorectal cancer cells. To identify the responsible receptor among the regorafenib-targeting proangiogenic receptors, we examined the effects of a potent selective inhibitor for VEGF-R, FGF-R or PDGF-R on apoptosis resistance and migration capability. We clarified that blockade of VEGF-R, but not FGF-R and PDGF-R, induced the malignant phenotypes. We confirmed that blocking of VEGF ligands derived from colorectal cancer cells also induced the phenotypes. These results suggest that regorafenib progressed the malignancy via prevention of autocrine and paracrine VEGF signaling in colorectal cancer cells.