Department of Oncologic Pathology, School of Medicine, Kanazawa Medical University, Kanazawa, Japan.
Department of Anatomy and Cell Biology, Kyushu University Graduate School of Medical Sciences, Fukuoka City, Japan.
Cancer Sci. 2024 Nov;115(11):3817-3828. doi: 10.1111/cas.16331. Epub 2024 Sep 22.
Metastasis to the liver is a leading cause of death in patients with colorectal cancer. To investigate the characteristics of cancer cells prone to metastasis, we utilized an isogenic model of BALB/c and colon tumor 26 (C26) cells carrying an active KRAS mutation. Liver metastatic (LM) 1 cells were isolated from mice following intrasplenic transplantation of C26 cells. Subsequent injections of LM1 cells generated LM2 cells, and after four cycles, LM4 cells were obtained. In vitro, using a perfusable capillary network system, we found comparable extravasation frequencies between C26 and LM4 cells. Both cell lines showed similar growth rates in vitro. However, C26 cells showed higher glucose consumption, whereas LM4 cells incorporated more fluorescent fatty acids (FAs). Biochemical analysis revealed that LM4 cells had higher cholesterol levels than C26 cells. A correlation was observed between fluorescent FAs and cholesterol levels detected using filipin III. LM4 cells utilized FAs as a source for cholesterol synthesis through acetyl-CoA metabolism. In cellular analysis, cholesterol accumulated in punctate regions, and upregulation of NLRP3 and STING proteins, but not mTOR, was observed in LM4 cells. Treatment with a cholesterol synthesis inhibitor (statin) induced LM4 cell death in vitro and suppressed LM4 cell growth in the livers of nude mice. These findings indicate that colorectal cancer cells prone to liver metastasis show cholesterol-dependent growth and that statin therapy could help treat liver metastasis in immunocompromised patients.
肝转移是结直肠癌患者死亡的主要原因。为了研究易发生转移的癌细胞的特征，我们利用 BALB/c 和带有活性 KRAS 突变的结肠肿瘤 26（C26）细胞的同基因模型。在 C26 细胞脾内移植后，从小鼠中分离出肝转移（LM）1 细胞。随后注射 LM1 细胞产生 LM2 细胞，经过四个周期后，获得 LM4 细胞。在体外，使用可灌注的毛细血管网络系统，我们发现 C26 和 LM4 细胞之间的渗出频率相当。两种细胞系在体外的生长速度相似。然而，C26 细胞表现出更高的葡萄糖消耗，而 LM4 细胞则掺入更多的荧光脂肪酸（FAs）。生化分析显示，LM4 细胞的胆固醇水平高于 C26 细胞。荧光 FAs 与 Filipin III 检测到的胆固醇水平之间存在相关性。LM4 细胞通过乙酰辅酶 A 代谢将 FAs 用作胆固醇合成的来源。在细胞分析中，胆固醇在点状区域积累，并且在 LM4 细胞中观察到 NLRP3 和 STING 蛋白的上调，但不是 mTOR。胆固醇合成抑制剂（他汀类药物）的处理在体外诱导 LM4 细胞死亡，并抑制裸鼠肝脏中 LM4 细胞的生长。这些发现表明，易发生肝转移的结直肠癌细胞表现出胆固醇依赖性生长，他汀类药物治疗可能有助于治疗免疫功能低下患者的肝转移。
