Tomida Chisato, Nagano Hikaru, Yamagishi Naoko, Uchida Takayuki, Ohno Ayako, Hirasaka Katsuya, Nikawa Takeshi, Teshima-Kondo Shigetada
Department of Physiological Nutrition, Institute of Medical Nutrition, University of Tokushima Graduate School.
Department of Anatomy and Cell Biology, School of Medicine, Wakayama Medical University.
J Med Invest. 2017;64(3.4):262-265. doi: 10.2152/jmi.64.262.
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. J. Med. Invest. 64: 262-265, August, 2017.
最近，抑制肿瘤血管生成已成为一种重要的抗癌疗法。肿瘤血管生成受多种信号通路调控，包括血管内皮生长因子（VEGF）及其受体（VEGF-R）、成纤维细胞生长因子（FGF）及其受体（FGF-R）以及血小板衍生生长因子（PDGF）及其受体（PDGF-R）通路。因此，抗血管生成药物，如瑞戈非尼，可同时作用于血管内皮细胞上的这些受体。除了内皮细胞，癌细胞也表达这三种受体，这表明抗血管生成抑制剂也会影响肿瘤细胞。事实上，我们之前证明瑞戈非尼可直接作用于人类结肠癌细胞，并增强其抗凋亡能力和迁移能力。因此，我们在此阐明了瑞戈非尼如何在结肠癌细胞中诱导恶性表型。为了确定瑞戈非尼靶向的促血管生成受体中起作用的受体，我们研究了一种针对VEGF-R、FGF-R或PDGF-R的强效选择性抑制剂对细胞抗凋亡能力和迁移能力的影响。我们明确了阻断VEGF-R而非FGF-R和PDGF-R会诱导恶性表型。我们还证实，阻断源自结肠癌细胞的VEGF配体也会诱导这些表型。这些结果表明，瑞戈非尼通过抑制结肠癌细胞中自分泌和旁分泌的VEGF信号通路促进了肿瘤的恶性发展。《医学研究杂志》64: 262 - 265，2017年8月。
