PO.TB07.02 · 肿瘤生物学
靶向Bmi-1可抑制黏液表皮样癌的癌症干性和肿瘤生长
Targeting Bmi-1 suppresses cancer stemness and tumor growth in mucoepidermoid carcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
唾液腺癌表现出相当大的组织病理学多样性，其中黏液表皮样癌（MEC）被认为是最常见的恶性亚型。然而，化疗在MEC中的获益有限，凸显了对新型治疗方法的需求。近期研究强调了癌症干性在治疗耐药和肿瘤进展中的影响。Bmi-1是一种多梳家族蛋白，也是头颈部癌症干性的主调控因子，因此是一个潜在的治疗靶点。本研究旨在评估靶向Bmi-1治疗对唾液腺MEC的影响。三种MEC细胞系（UM-HMC-1、UM-HMC-3A、UM-HMC-3B）经Bmi-1抑制剂PTC596（Unesbulin）处理，该药目前正在针对实体瘤进行临床评估。开展了Western blotting、流式细胞术和成球实验。对于Western blotting和流式细胞术，PTC596以0-500 nM给药24-72小时。在超低吸附板中的成球实验以0-100 nM进行10天。异种移植模型通过将接种UM-HMC-3A和UM-HMC-3B细胞的支架植入免疫缺陷小鼠而建立。当肿瘤达到200 mm³时，将小鼠随机分组，每三天给予溶媒、5 mg/kg或10 mg/kg PTC596，持续30天。整个治疗期间记录肿瘤体积和体重。我们观察到，PTC596暴露后所有MEC细胞系中Bmi-1蛋白表达呈剂量和时间依赖性抑制。流式细胞术显示ALDH high CD44 high细胞比例显著降低，表明有效靶向了癌症干细胞。成球实验进一步证实成球能力呈显著的剂量依赖性下降。在体内，PTC596诱导肿瘤快速消退，肿瘤缩小并此后保持稳定抑制。5 mg/kg和10 mg/kg PTC596方案产生的抗肿瘤效果相当。重要的是，小鼠维持或增加了体重，未观察到明显的治疗相关毒性。值得注意的是，PTC596清除了癌症干细胞（ALDH high CD44 high），并在临床前唾液腺MEC模型中产生抗肿瘤反应。总的来说，这些发现提供了令人信服的临床前证据，表明Bmi-1是唾液腺黏液表皮样癌一个有前景且具有临床相关性的治疗靶点，支持进一步的转化和临床研究。
查看英文原文 English abstract
Salivary gland carcinomas display considerable histopathological diversity and mucoepidermoid carcinoma (MEC) is recognized as the most frequent malignant subtype. However, chemotherapy provides limited benefit in MEC, highlighting the need for novel therapeutic approaches. Recent studies have highlighted the impact of cancer stemness in treatment resistance and tumor progression. Bmi-1 is a polycomb group protein and master regulator of stemness in head and neck cancers and therefore is a potential therapeutic target. This study aimed to evaluate the impact of therapeutic Bmi-1 in salivary gland MEC. Three MEC cell lines (UM-HMC-1, UM-HMC-3A, UM-HMC-3B) were treated with the Bmi-1 inhibitor PTC596 (Unesbulin), currently under clinical evaluation for solid tumors. Western blotting, flow cytometry, and sphere formation assays were performed. For Western blotting and flow cytometry, PTC596 was administered at 0-500 nM for 24-72 hours. Sphere assays in ultra-low attachment plates were performed with 0-100 nM for 10 days. Xenograft models were generated by implanting cell-seeded scaffolds of UM-HMC-3A and UM-HMC-3B into immunodeficient mice. When tumors reached 200 mm³, mice were randomized to receive vehicle, 5 mg/kg or 10 mg/kg PTC596 every three days for 30 days. Tumor volume and body weight were recorded throughout treatment. We observed dose- and time-dependent inhibition of Bmi-1 protein expression in all MEC cell lines following PTC596 exposure. Flow cytometry revealed marked reductions in the fraction of ALDH high CD44 high cells, indicating effective targeting of cancer stem cells. Sphere formation assays further confirmed a significant dose-dependent decrease in sphere-forming capacity. In vivo , PTC596 induced rapid tumor regression, with tumors shrinking and remaining stably suppressed thereafter. Both 5 mg/kg and 10 mg/kg PTC596 regimens produced comparable antitumor effects. Importantly, mice maintained or gained body weight, and no overt treatment-associated toxicity was observed. Notably, PTC596 ablated cancer stem cells (ALDH high CD44 high ) and produced antitumor responses in preclinical salivary gland MEC models. Collectively, these findings provide compelling preclinical evidence that Bmi-1 represents a promising and clinically relevant therapeutic target for salivary gland mucoepidermoid carcinoma, supporting further translational and clinical investigation.
利益披露 Disclosure
S. Yamada, None..
K. Warner, None..
J. V. Vanini, None..
Z. Zhang, None..
R. Tsuboi, None..
J. E. Nör, None.