Cirillo N, Hassona Y, Celentano A, Lim K P, Manchella S, Parkinson E K, Prime S S
Melbourne Dental School and Oral Health CRC, University of Melbourne, 3053 Carlton, Victoria, Australia,
Department of Dentistry, University of Jordan, Amman, Jordan.
Carcinogenesis. 2017 Jan;38(1):76-85. doi: 10.1093/carcin/bgw113. Epub 2016 Nov 1.
The interrelationship between malignant epithelium and the underlying stroma is of fundamental importance in tumour development and progression. In the present study, we used cancer-associated fibroblasts (CAFs) derived from genetically unstable oral squamous cell carcinomas (GU-OSCC), tumours that are characterized by the loss of genes such as TP53 and p16 and with extensive loss of heterozygosity, together with CAFs from their more genetically stable (GS) counterparts that have wild-type TP53 and p16 and minimal loss of heterozygosity (GS-OSCC). Using a systems biology approach to interpret the genome-wide transcriptional profile of the CAFs, we show that transforming growth factor-β (TGF-β) family members not only had biological relevance in silico but also distinguished GU-OSCC-derived CAFs from GS-OSCC CAFs and fibroblasts from normal oral mucosa. In view of the close association between TGF-β family members, we examined the expression of TGF-β1 and TGF-β2 in the different fibroblast subtypes and showed increased levels of active TGF-β1 and TGF-β2 in CAFs from GU-OSCC. CAFs from GU-OSCC, but not GS-OSCC or normal fibroblasts, induced epithelial-mesenchymal transition and down-regulated a broad spectrum of cell adhesion molecules resulting in epithelial dis-cohesion and invasion of target keratinocytes in vitro in a TGF-β-dependent manner. The results demonstrate that the TGF-β family of cytokines secreted by CAFs derived from genotype-specific oral cancer (GU-OSCC) promote, at least in part, the malignant phenotype by weakening intercellular epithelial adhesion.
恶性上皮细胞与下层基质之间的相互关系在肿瘤的发生和发展中至关重要。在本研究中，我们使用了源自基因不稳定的口腔鳞状细胞癌（GU-OSCC）的癌症相关成纤维细胞（CAF），这类肿瘤的特征是TP53和p16等基因缺失以及广泛的杂合性缺失，同时还使用了来自基因更稳定（GS）的口腔鳞状细胞癌（GS-OSCC）的CAF，后者具有野生型TP53和p16且杂合性缺失极少。通过系统生物学方法解读CAF的全基因组转录谱，我们发现转化生长因子-β（TGF-β）家族成员不仅在计算机模拟中有生物学相关性，还能区分GU-OSCC来源的CAF与GS-OSCC来源的CAF以及正常口腔黏膜来源的成纤维细胞。鉴于TGF-β家族成员之间的密切关联，我们检测了不同成纤维细胞亚型中TGF-β1和TGF-β2的表达，结果显示GU-OSCC来源的CAF中活性TGF-β1和TGF-β2水平升高。GU-OSCC来源的CAF，而非GS-OSCC来源的CAF或正常成纤维细胞，可诱导上皮-间质转化并下调多种细胞黏附分子，导致上皮细胞解离，并以TGF-β依赖的方式在体外侵袭靶角质形成细胞。结果表明，源自基因型特异性口腔癌（GU-OSCC）的CAF分泌的TGF-β细胞因子家族至少部分通过削弱细胞间上皮黏附来促进恶性表型。
