PDGFRβ Is a Novel Marker of Stromal Activation in Oral Squamous Cell Carcinomas.
PDGFRβ Is a Novel Marker of Stromal Activation in Oral Squamous Cell Carcinomas.
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DOI：
10.1371/journal.pone.0154645
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Trojanowska M
中科院分区：
文献类型：
--
作者：
Kartha VK;Stawski L;Han R;Haines P;Gallagher G;Noonan V;Kukuruzinska M;Monti S;Trojanowska M
癌相关成纤维细胞（CAFs）是肿瘤间质的主要成分，在肿瘤的生长和侵袭中起重要作用。CAF的存在是头颈部鳞状细胞癌预后不良的有力预测因素。尽管在确定CAF在肿瘤进展中的作用方面取得了重大进展，但导致其活化的机制仍然缺乏表征，部分原因是成纤维细胞异质性和缺乏可靠的成纤维细胞表面标志物。为了在口腔鳞状细胞癌（OSCC）中寻找这些标记物，我们采用了一种新的方法，该方法使用来自癌症基因组图谱（TCGA）的RNA测序数据。具体来说，我们的策略允许无偏见的基因，其表达与一组真正的基质特异性转录物，即间质胶原COL 1A 1，COL 1A 2和COL 3A 1密切相关的鉴定。其中最热门的是参与细胞基质重塑和肿瘤侵袭和迁移的基因，包括血小板衍生生长因子受体β（PDGFRβ），它被发现是全基因组中排名最高的受体蛋白。对另外10个TCGA癌症数据集进行的类似分析显示，其他肿瘤类型与OSCC共享CAF标志物，包括PDGFRβ，发现其与测试的11种癌症类型中的10种中的参考胶原蛋白表达显著相关。免疫组化结果显示，PDGFRβ在所有受试病例的间质成纤维细胞中表达丰富（12/12），而在肿瘤细胞中不表达，其特异性高于其他已知的标志物，如α平滑肌肌动蛋白或podoplanin（3/11）。总体而言，本研究确定PDGFRβ为OSCC中基质活化的新标志物，并进一步表征了可能与其他癌症相关的有希望的候选CAF标志物列表。我们的新方法提供了一种快速准确的方法来识别CAF标记，而不需要大规模的免疫染色实验。
Carcinoma associated fibroblasts (CAFs) form the main constituents of tumor stroma and play an important role in tumor growth and invasion. The presence of CAFs is a strong predictor of poor prognosis of head and neck squamous cell carcinoma. Despite significant progress in determining the role of CAFs in tumor progression, the mechanisms contributing to their activation remain poorly characterized, in part due to fibroblast heterogeneity and the scarcity of reliable fibroblast surface markers. To search for such markers in oral squamous cell carcinoma (OSCC), we applied a novel approach that uses RNA-sequencing data derived from the cancer genome atlas (TCGA). Specifically, our strategy allowed for an unbiased identification of genes whose expression was closely associated with a set of bona fide stroma-specific transcripts, namely the interstitial collagens COL1A1, COL1A2, and COL3A1. Among the top hits were genes involved in cellular matrix remodeling and tumor invasion and migration, including platelet-derived growth factor receptor beta (PDGFRβ), which was found to be the highest-ranking receptor protein genome-wide. Similar analyses performed on ten additional TCGA cancer datasets revealed that other tumor types shared CAF markers with OSCC, including PDGFRβ, which was found to significantly correlate with the reference collagen expression in ten of the 11 cancer types tested. Subsequent immunostaining of OSCC specimens demonstrated that PDGFRβ was abundantly expressed in stromal fibroblasts of all tested cases (12/12), while it was absent in tumor cells, with greater specificity than other known markers such as alpha smooth muscle actin or podoplanin (3/11). Overall, this study identified PDGFRβ as a novel marker of stromal activation in OSCC, and further characterized a list of promising candidate CAF markers that may be relevant to other carcinomas. Our novel approach provides for a fast and accurate method to identify CAF markers without the need for large-scale immunostaining experiments.