背景:泌乳素瘤是最常见的垂体瘤亚型。尽管他们中的大多数人对医疗有反应,一个比例具有耐药性,并成为临床管理中的一个挑战。Wnt/β-Catenin途径与几种癌症有关,包括垂体瘤和其他鞍区恶性肿瘤。有趣的是,Wnt/β-Catenin抑制增强了化学治疗剂替莫唑胺(TMZ)在不同癌症中的细胞毒性。TMZ现在被实施为积极的垂体腺瘤治疗的抢救疗法。然而,在垂体瘤中与TMZ作用相关的分子机制仍不清楚.
目的:我们在本研究中的目的是评估β-Catenin在人耐药催乳素瘤中的差异表达和Wnt/β-Catenin信号激活以及在泌乳素(PRL)分泌实验模型中的参与用TMZ治疗。
结果:我们首先通过免疫组织化学评估了β-Catenin在人耐药泌乳素瘤中的定位,其中我们证明了与正常垂体相比,泌乳素瘤细胞中膜β-Catenin减少,独立于Ki-67增殖指数。反过来,在体内15mg/kg口服给药的TMZ显着降低了患有异种移植的泌乳素瘤的小鼠的PRL产生并增加了泌乳素瘤细胞凋亡。肿瘤内β-连环蛋白与Prl和CyclinD1密切相关,重要的是,TMZ下调β-Catenin和CyclinD1,支持它们在催乳素瘤生长中的意义,并作为治疗靶标的候选。在体外测试时,TMZ直接降低MMQ细胞活力,细胞凋亡增加并产生G2/M细胞周期阻滞。值得注意的是,TMZ在体外抑制β-Catenin激活和VEGF分泌。
结论:我们得出结论,多巴胺耐药的催乳素瘤与正常垂体发生β-Catenin再定位,TMZ通过减少PRL产生和β-Catenin激活来抑制实验性催乳素瘤的致瘤性。一起,我们的发现有助于了解Wnt/β-Catenin在泌乳素瘤维持和TMZ治疗中的意义,为侵袭性和耐药性垂体瘤开辟了新的治疗策略的机会。
BACKGROUND: Prolactinomas are the most frequent pituitary tumor subtype. Despite most of them respond to medical treatment, a proportion are resistant and become a challenge in clinical management. Wnt/β-Catenin pathway has been implicated in several cancers including pituitary tumors and other sellar region malignancies. Interestingly, Wnt/β-Catenin inhibition augments the cytotoxicity of the chemotherapeutic agent Temozolomide (TMZ) in different cancers. TMZ is now being implemented as rescue therapy for aggressive pituitary adenoma treatment. However, the molecular mechanisms associated with TMZ action in pituitary tumors remain unclear.
OBJECTIVE: Our aims in the present study were to evaluate differential β-Catenin expression in human resistant
prolactinomas and Wnt/β-Catenin signaling activation and involvement in Prolactin (PRL) secreting experimental models treated with TMZ.
RESULTS: We first evaluated by immunohistochemistry β-Catenin localization in human resistant
prolactinomas in which we demonstrated reduced membrane β-Catenin in prolactinoma cells compared to normal pituitaries, independently of the Ki-67 proliferation indexes. In turn, in vivo 15 mg/kg of orally administered TMZ markedly reduced PRL production and increased prolactinoma cell apoptosis in mice bearing xenografted
prolactinomas. Intratumoral β-Catenin strongly correlated with Prl and Cyclin D1, and importantly, TMZ downregulated both β-Catenin and Cyclin D1, supporting their significance in prolactinoma growth and as candidates of therapeutic targets. When tested in vitro, TMZ directly reduced MMQ cell viability, increased apoptosis and produced G2/M cell cycle arrest. Remarkably, β-Catenin activation and VEGF secretion were inhibited by TMZ in vitro.
CONCLUSIONS: We concluded that dopamine resistant
prolactinomas undergo a β-Catenin relocalization in relation to normal pituitaries and that TMZ restrains experimental prolactinoma tumorigenicity by reducing PRL production and β-Catenin activation. Together, our findings contribute to the understanding of Wnt/β-Catenin implication in prolactinoma maintenance and TMZ therapy, opening the opportunity of new treatment strategies for aggressive and resistant pituitary tumors.