Genetic and phenotypic determinants of morphologies in 3D cultures and xenografts of lung tumor cell lines.
Genetic and phenotypic determinants of morphologies in 3D cultures and xenografts of lung tumor cell lines.
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我们之前提出将肺腺癌分为两组：支气管上皮表型（BE表型），具有支气管上皮标志物的高水平表达和酪氨酸激酶受体的可操作遗传异常，以及非BE表型，具有支气管支气管上皮（BE）上皮标志物的低水平表达和酪氨酸激酶受体的无可操作遗传异常。在这里，我们对一组肺癌细胞系的3D培养物和异种移植物中的肿瘤形态进行了全面分析。首先，我们证明了40种肺癌细胞系（23种BE和17种非BE）可以根据Matrigel上3D培养物的形态分为三组：圆形（n = 31），星状（n = 5）和葡萄状（n = 4）。后两种形态在非BE表型中显著频繁（1/23 BE，8/17非BE，p = 0.0014），星状形态仅见于非BE表型。SMARCA 4突变在星状细胞中显著频繁（4/4星状细胞，4/34非星状细胞，p = 0.0001）。接下来，从40个细胞系中，我们在NOD/SCID小鼠中成功建立了28个异种移植肿瘤（18个BE和10个非BE），并将异种移植肿瘤的组织学模式分为三组：实体（n = 20），结缔组织增生中的小巢（n = 4）和腺泡/乳头状（n = 4）。后两种模式的特征性发现在BE表型。非BE表型表现出实心模式，α-SMA阳性成纤维细胞（p = 0.0004）和胶原蛋白（p = 0.0006）的含量显著低于BE表型。因此，3D培养物和异种移植物中肿瘤的形态，包括基质发生，反映了癌细胞系的内在特性。此外，这项研究作为一个很好的资源，肺腺癌细胞系，与临床相关的信息，分子和形态学特征和药物敏感性。在这里，我们专注于3D培养和异种移植肿瘤中的细胞系形态。在支气管上皮表型中，大多数细胞系在3D培养中显示圆形形态，其中一些细胞系在异种移植瘤中显示腺泡或乳头状图案和促纤维增生反应。相比之下，非支气管上皮表型细胞系在3D培养中经常显示星状或葡萄样形态，并在异种移植肿瘤中显示实心模式，无促纤维增生反应。这项研究为肺腺癌细胞系提供了一个很好的资源，具有分子和形态学特征的临床相关信息。
We previously proposed the classification of lung adenocarcinoma into two groups: the bronchial epithelial phenotype (BE phenotype) with high‐level expressions of bronchial epithelial markers and actionable genetic abnormalities of tyrosine kinase receptors and the non‐BE phenotype with low‐level expressions of bronchial Bronchial epithelial (BE) epithelial markers and no actionable genetic abnormalities of tyrosine kinase receptors. Here, we performed a comprehensive analysis of tumor morphologies in 3D cultures and xenografts across a panel of lung cancer cell lines. First, we demonstrated that 40 lung cancer cell lines (23 BE and 17 non‐BE) can be classified into three groups based on morphologies in 3D cultures on Matrigel: round (n = 31), stellate (n = 5), and grape‐like (n = 4). The latter two morphologies were significantly frequent in the non‐BE phenotype (1/23 BE, 8/17 non‐BE, p = 0.0014), and the stellate morphology was only found in the non‐BE phenotype. SMARCA4 mutations were significantly frequent in stellate‐shaped cells (4/4 stellate, 4/34 non‐stellate, p = 0.0001). Next, from the 40 cell lines, we successfully established 28 xenograft tumors (18 BE and 10 non‐BE) in NOD/SCID mice and classified histological patterns of the xenograft tumors into three groups: solid (n = 20), small nests in desmoplasia (n = 4), and acinar/papillary (n = 4). The latter two patterns were characteristically found in the BE phenotype. The non‐BE phenotype exhibited a solid pattern with significantly less content of alpha‐SMA‐positive fibroblasts (p = 0.0004) and collagen (p = 0.0006) than the BE phenotype. Thus, the morphology of the tumors in 3D cultures and xenografts, including stroma genesis, reflects the intrinsic properties of the cancer cell lines. Furthermore, this study serves as an excellent resource for lung adenocarcinoma cell lines, with clinically relevant information on molecular and morphological characteristics and drug sensitivity. Here, we focused on cell line morphology in 3D cultures and xenograft tumors. In the bronchial epithelial phenotype, most of the cell lines displayed a round morphology in 3D culture, and some of them showed acinar or papillary patterns and desmoplastic reactions in xenograft tumors. In contrast, the non‐bronchial epithelial phenotype cell lines frequently displayed stellate or grape‐like morphologies in 3D culture and showed solid patterns with no desmoplastic reactions in xenograft tumors. This study serves as an excellent resource for lung adenocarcinoma cell lines with clinically relevant information on molecular and morphological characteristics.
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影响因子：
5.7
作者：
Murakami F;Tsuboi Y;Takahashi Y;Horimoto Y;Mogushi K;Ito T;Emi M;Matsubara D;Shibata T;Saito M;Murakami Y
通讯作者：
Murakami Y
影响因子：
0.7
作者：
Desmoulière, A;Guyot, C;Gabbiani, C
通讯作者：
Gabbiani, C
影响因子：
2
作者：
Kong, Dexin;Yamazaki, Kanami;Yamori, Takao
通讯作者：
Yamori, Takao
影响因子：
6
作者：
Matsubara, Daisuke;Ishikawa, Shumpei;Niki, Toshiro
通讯作者：
Niki, Toshiro
影响因子：
64.5
作者：
HIRANO, S;KIMOTO, N;TAKEICHI, M
通讯作者：
TAKEICHI, M