Department of Oral and Dental Science, University of Bristol, Bristol BS1 2LY, UK; Department of Clinical Sciences, South Bristol, University of Bristol, Bristol, UK.
Cancer Lett. 2010 Dec 1;298(1):107-18. doi: 10.1016/j.canlet.2010.06.008.
It is now generally accepted that TGF-β acts as a pro-metastatic factor in advanced human breast cancer. However, it is well documented, that TGF-β is context dependent, and whether the TGF-β pathway switches to promote metastasis during the progression of squamous cell carcinoma (SCC) is unknown. This study examined the role of TGF-β signalling in SCC using a series of genetically related keratinocyte cell lines representing later stages of the disease, stably transduced with a dominant negative TβRII cDNA (dnTβRII). We demonstrated that clones expressing dnTβRII lost their growth inhibitory response to TGF-βin vitro, while ligand expression remained unchanged. Following transplantation of transduced cells to athymic mice in vivo, we showed that attenuation of the TGF-β signal resulted in a loss of differentiation and increased metastasis. In human tissue samples loss of TGF-β signal transduction as measured by pSmad2 activity also correlated with a loss of differentiation. Id1, previously shown to be down regulated by TGF-β, an inhibitor of differentiation and associated with metastasis, was weakly expressed in focal areas of a small number of human tumours but expression did not correlate with low levels of pSmad2. Our data demonstrate that TGF-β does not switch to promote metastasis in late stage human SCC of the skin and that inhibition of TGF-β signalling results in a loss of differentiation and increased metastasis in the later stages of this disease.
现在普遍认为 TGF-β 在晚期人乳腺癌中充当促转移因子。然而，有充分的文献记载表明 TGF-β 具有上下文依赖性，并且 TGF-β 途径是否在鳞状细胞癌（SCC）进展过程中切换为促进转移尚不清楚。本研究使用一系列遗传相关的角蛋白细胞系（代表疾病的后期阶段），通过稳定转染显性失活 TβRII cDNA（dnTβRII），检查了 TGF-β 信号在 SCC 中的作用。我们证明表达 dnTβRII 的克隆在体外失去了对 TGF-β 的生长抑制反应，而配体表达保持不变。在体内将转导的细胞移植到无胸腺小鼠后，我们表明 TGF-β 信号的衰减导致分化丧失和转移增加。在人组织样本中，通过 pSmad2 活性测量的 TGF-β 信号转导的丧失也与分化丧失相关。Id1 先前被证明被 TGF-β 下调，是分化的抑制剂，与转移相关，在少数人类肿瘤的小灶中弱表达，但表达与低水平的 pSmad2 无关。我们的数据表明，TGF-β 在皮肤晚期人 SCC 中不会切换为促进转移，并且 TGF-β 信号抑制会导致该疾病后期分化丧失和转移增加。
