Cholesterol synthesis is essential for the growth of liver metastasis-prone colorectal cancer cells

IF 4.5 2区 医学 Q1 ONCOLOGY
Cancer Science Pub Date : 2024-09-22 DOI:10.1111/cas.16331
Kumiko Taniguchi, Kei Sugihara, Takashi Miura, Daisuke Hoshi, Susumu Kohno, Chiaki Takahashi, Eishu Hirata, Etsuko Kiyokawa
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Abstract

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.

Abstract Image

胆固醇合成对于易发生肝转移的结直肠癌细胞的生长至关重要。
肝脏转移是结直肠癌患者死亡的主要原因。为了研究容易发生转移的癌细胞的特征,我们利用了携带活性 KRAS 突变的 BALB/c 和结肠肿瘤 26(C26)细胞的同源模型。在小鼠脾内移植 C26 细胞后,从小鼠体内分离出肝转移(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,使用可灌注毛细管网络系统,我们发现 C26 和 LM4 细胞的外渗频率相当。两种细胞系在体外的生长速度相似。但是,C26 细胞的葡萄糖消耗量更高,而 LM4 细胞则掺入了更多的荧光脂肪酸(FAs)。生化分析表明,LM4 细胞的胆固醇含量高于 C26 细胞。荧光脂肪酸与使用丝裂蛋白 III 检测到的胆固醇水平之间存在相关性。LM4 细胞通过乙酰-CoA 代谢利用 FAs 作为胆固醇合成的来源。在细胞分析中,胆固醇在点状区域聚集,在LM4细胞中观察到NLRP3和STING蛋白的上调,但没有观察到mTOR的上调。胆固醇合成抑制剂(他汀类药物)可诱导体外 LM4 细胞死亡,并抑制 LM4 细胞在裸鼠肝脏中的生长。这些研究结果表明,易发生肝转移的结直肠癌细胞表现出胆固醇依赖性生长,他汀类药物疗法有助于治疗免疫力低下患者的肝转移。
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来源期刊
Cancer Science
Cancer Science 医学-肿瘤学
自引率
3.50%
发文量
406
审稿时长
2 months
期刊介绍: Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
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