Cells Comprising the Prostate Cancer Microenvironment Lack Recurrent Clonal Somatic Genomic Aberrations
Cells Comprising the Prostate Cancer Microenvironment Lack Recurrent Clonal Somatic Genomic Aberrations
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DOI：
10.1158/1541-7786.mcr-15-0330
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发表时间：
2016-04-01
影响因子：
5.2
通讯作者：
Nelson, Peter S.
中科院分区：
文献类型：
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作者：
Bianchi-Frias, Daniella;Basom, Ryan;Nelson, Peter S.
前列腺癌相关间质(CAS)在肿瘤的恶性转化、进展和转移中起着积极的作用。CAS的分子分析表明，基因表达发生了显著变化；然而，对于构成肿瘤微环境(TME)的良性细胞的基因组变化是否导致基因表达变化和致癌表型，存在相互矛盾的证据。本研究通过全基因组拷贝数分析、TP53的靶向测序和FISH来评估前列腺癌细胞CAS、匹配的良性上皮和良性上皮相关间质的核和线粒体DNA的完整性。CAS的阵列比较基因组杂交(ACGH)显示一个拷贝中性的二倍体基因组，只有罕见和少量的体细胞拷贝数异常(SCNA)。相反，在邻近的前列腺癌细胞中，有几个预期的复发SCNAs是明显的，包括3q、7p和8q的增加，8p和10q的丢失。在CAS中未观察到体细胞TP53突变。从癌细胞和间质中提取的线粒体DNA(MtDNA)在肿瘤上皮细胞中发现了23个体细胞mtDNA突变，但在间质中只发现了一个突变。最后，基因组分析发现，在培养的癌症相关成纤维细胞中没有SCNAs、LOH或拷贝中性LOH，它们被认为是促进前列腺癌活体进展的已知因素。意义：在前列腺癌邻近间质中观察到的基因表达变化以及伴随的间质对前列腺癌的发展和进展的贡献，并不是由于TME中频繁或反复的基因组改变。摩尔癌症资源；14(4)；374-84。(C)2016年AACR。
Prostate cancer-associated stroma (CAS) plays an active role in malignant transformation, tumor progression, and metastasis. Molecular analyses of CAS have demonstrated significant changes in gene expression; however, conflicting evidence exists on whether genomic alterations in benign cells comprising the tumor microenvironment (TME) underlie gene expression changes and oncogenic phenotypes. This study evaluates the nuclear and mitochondrial DNA integrity of prostate carcinoma cells, CAS, matched benign epithelium and benign epithelium-associated stroma by whole-genome copy-number analyses, targeted sequencing of TP53, and FISH. Array comparative genomic hybridization (aCGH) of CAS revealed a copy-neutral diploid genome with only rare and small somatic copy-number aberrations (SCNA). In contrast, several expected recurrent SCNAs were evident in the adjacent prostate carcinoma cells, including gains at 3q, 7p, and 8q, and losses at 8p and 10q. No somatic TP53 mutations were observed in CAS. Mitochondrial DNA (mtDNA) extracted from carcinoma cells and stroma identified 23 somatic mtDNA mutations in neoplastic epithelial cells, but only one mutation in stroma. Finally, genomic analyses identified no SCNAs, LOH, or copy-neutral LOH in cultured cancer-associated fibroblasts, which are known to promote prostate cancer progression in vivo.Implications: The gene expression changes observed in prostate cancer-adjacent stroma and the attendant contribution of the stroma to the development and progression of prostate cancer are not due to frequent or recurrent genomic alterations in the TME. Mol Cancer Res; 14(4); 374-84. (C) 2016 AACR.