Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25124 Brescia, Italy.
Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), 8091 Zürich, Switzerland.
Cells. 2022 Apr 24;11(9):1439. doi: 10.3390/cells11091439.
Adrenocortical carcinoma is a heterogeneous and aggressive cancer that originates from steroidogenic cells within the adrenal cortex. In this study, we have assessed for the preclinical gold standard NCI-H295 in direct comparison with the more recently established MUC-1 and a here newly reported ACC cell line (TVBF-7) the mutational status of important driver genes (TP53, MEN1, PRKAR1A, CTNNB1, APC, ZNRF-3, IGF-2, EGFR, RB1, BRCA1, BRCA2, RET, GNAS and PTEN), Wnt-signaling specificities (CTNNB1 mutation vs. APC mutation vs. wildtype), steroidogenic-(CYP11A1, CYP17A1, HSD3B2, HSD17B4, CYP21A2, CYP11B1, CYP11B2, MC2R, AT1R) and nuclear-receptor-signaling (AR, ER, GCR), varying electrophysiological potentials as well as highly individual hormone secretion profiles (Cortisol, Aldosterone, DHEA, DHEAS, Testosterone, 17-OH Progesterone, among others) which were investigated under basal and stimulated conditions (ACTH, AngII, FSK). Our findings reveal important genetic and pathophysiological characteristics for these three cell lines and reveal the importance of such cell-line panels reflecting differential endocrine functionalities to thereby better reflect clinically well-known ACC patient heterogeneities in preclinical studies.
肾上腺皮质癌是一种异质性和侵袭性的癌症，起源于肾上腺皮质中的类固醇生成细胞。在这项研究中，我们评估了 NCI-H295 这一临床前金标准，并与最近建立的 MUC-1 以及我们新报道的 ACC 细胞系（TVBF-7）进行了直接比较，评估了重要驱动基因（TP53、MEN1、PRKAR1A、CTNNB1、APC、ZNRF-3、IGF-2、EGFR、RB1、BRCA1、BRCA2、RET、GNAS 和 PTEN）、Wnt 信号特异性（CTNNB1 突变与 APC 突变与野生型）、类固醇生成（CYP11A1、CYP17A1、HSD3B2、HSD17B4、CYP21A2、CYP11B1、CYP11B2、MC2R、AT1R）和核受体信号（AR、ER、GCR）、不同的电生理潜能以及高度个体化的激素分泌谱（皮质醇、醛固酮、DHEA、DHEAS、睾酮、17-OH 孕酮等）的突变状态，这些都是在基础状态和刺激状态（ACTH、AngII、FSK）下进行的。我们的发现揭示了这三个细胞系的重要遗传和病理生理学特征，并揭示了此类细胞系面板的重要性，这些面板反映了不同的内分泌功能，从而在临床前研究中更好地反映了众所周知的 ACC 患者异质性。
