Kim Jiyoung, Nam Gilyeong, Shin You Keun, Vilaplana-Lopera Nuria, Jeung Hei-Cheul, Moon Eui Jung, Lee Ik Jae
Department of Radiation Oncology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea.
MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Headington OX3 7DQ, UK.
Cancers (Basel). 2023 Mar 21;15(6):1882. doi: 10.3390/cancers15061882.
Bile duct cancer, or cholangiocarcinoma, is a rare disease with limited treatment options that include surgery and cytotoxic chemotherapy. The high recurrence rate and poor prognosis of this type of cancer highlights the need to identify new and more effective therapeutic targets. In this study, we found that AXL, a receptor tyrosine kinase, is highly expressed in biliary cancer patients and significantly correlated with poor patient outcomes, including metastasis and low survival rates. We also demonstrated that targeting AXL inhibits tumor progression. In vitro studies with bile duct cancer cells (SNU1196 and HUCCT1) showed that genetic knockdown of AXL significantly reduced both tumor cell growth and invasion. In addition, in vivo studies using subcutaneous and orthotopic intrahepatic models demonstrated that genetic inhibition of AXL resulted in tumor-growth delay. To further examine the possible clinical translation of AXL inhibition in the clinic, we tested the efficacy of AVB-500, a soluble AXL receptor, in reducing AXL activation and tumor growth. AVB-500 was effective at inhibiting AXL activation and decreasing the growth and invasion of SNU1196 and HUCCT1 tumors which possess high AXL expression. Most importantly, AVB-500 was highly effective at decreasing tumor dissemination of bile duct tumor cells in the peritoneal cavity. This study strongly supports the idea of using the AXL receptor as a new therapeutic target to treat the growth and progression of biliary cancer.
胆管癌，即胆管细胞癌，是一种罕见疾病，治疗选择有限，包括手术和细胞毒性化疗。这类癌症的高复发率和不良预后凸显了识别新的、更有效的治疗靶点的必要性。在本研究中，我们发现受体酪氨酸激酶AXL在胆管癌患者中高表达，且与患者的不良预后显著相关，包括转移和低生存率。我们还证明，靶向AXL可抑制肿瘤进展。对胆管癌细胞（SNU1196和HUCCT1）的体外研究表明，AXL基因敲低显著降低了肿瘤细胞的生长和侵袭。此外，使用皮下和原位肝内模型的体内研究表明，AXL基因抑制导致肿瘤生长延迟。为了进一步研究AXL抑制在临床上的可能转化应用，我们测试了可溶性AXL受体AVB - 500在降低AXL激活和肿瘤生长方面的疗效。AVB - 500能有效抑制AXL激活，并减少高表达AXL的SNU1196和HUCCT1肿瘤的生长和侵袭。最重要的是，AVB - 500在减少胆管肿瘤细胞在腹腔内的播散方面非常有效。本研究有力地支持了将AXL受体作为治疗胆管癌生长和进展的新治疗靶点的观点。
