Xie Wen, Bharathy Savita, Kim David, Haffty Bruce G, Rimm David L, Reiss Michael
Division of Medical Oncology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA.
Oncol Res. 2003;14(2):61-73. doi: 10.3727/000000003108748612.
Head and neck squamous cell carcinoma (HNSCC) ranks as the sixth most frequent cancer worldwide. HNSCC cell lines are typically refractory to transforming growth factor-beta (TGF-beta)-mediated cell cycle arrest. A number of these cell lines carry inactivating mutations of the TGF-beta type II (TbetaR-II) receptor, and fail to phosphorylate receptor-associated Smads, Smad2 and Smad3. In addition, we identified several intragenic mutations of the TbetaR-I gene in a small series of metastatic HNSCC specimens, suggesting that disruptions of TGF-beta signaling might contribute to the development and progression of HNSCC. To test this idea, we have now embarked on a larger scale analysis of the patterns of expression and activation of Smads in 170 HNSCC specimens assembled in tissue microarrays. Smad2 protein was expressed by 99% (95% CI: 96-100%) of tumors. The activated form of Smad2, pSmad2, was expressed in 86% (95% CI: 80-91%) of HNSCC, indicating their ability to survive and proliferate in spite of the presence of bioactive TGF-beta within the tissue microenvironment. In the 24 remaining cases (14%; 95% CI: 9-20%), pSmad2 was not detected in the tumor cells, although it was expressed by surrounding stromal cells and capillaries. In addition, 38 tumors (22%; 95% CI: 16-29%) failed to express Smad4 protein. Thus, we found evidence of loss of TGF-beta/Smad signaling in approximately 15-20% of HNSCC specimens, which is consistent with the phenotype of established human SCC lines. Moreover, we found that these Smad signaling defects were associated with a greater tendency for metastatic spread and regional or distant recurrence of HNSCC. These results indicate that inactivation of TGF-beta/Smad signaling occurs frequently in HNSCC and might have an adverse effect on patient outcome.
头颈部鳞状细胞癌（HNSCC）是全球第六大常见癌症。HNSCC细胞系通常对转化生长因子-β（TGF-β）介导的细胞周期停滞具有抗性。许多这些细胞系携带TGF-β II型（TβR-II）受体的失活突变，并且无法使受体相关的Smad蛋白（Smad2和Smad3）磷酸化。此外，我们在一小系列转移性HNSCC标本中鉴定出TβR-I基因的几个基因内突变，这表明TGF-β信号传导的破坏可能有助于HNSCC的发生和发展。为了验证这一想法，我们现在对组织微阵列中收集的170个HNSCC标本中Smad蛋白的表达和激活模式进行了更大规模的分析。99%（95%置信区间：96-100%）的肿瘤表达Smad2蛋白。活化形式的Smad2，即pSmad2，在86%（95%置信区间：80-91%）的HNSCC中表达，这表明尽管组织微环境中存在生物活性TGF-β，它们仍具有存活和增殖的能力。在其余24例病例（14%；95%置信区间：9-20%）中，虽然肿瘤周围的基质细胞和毛细血管表达pSmad2，但在肿瘤细胞中未检测到pSmad2。此外，38个肿瘤（22%；95%置信区间：16-29%）未表达Smad4蛋白。因此，我们发现约15-20%的HNSCC标本中有TGF-β/Smad信号传导缺失的证据，这与已建立的人SCC细胞系的表型一致。此外，我们发现这些Smad信号传导缺陷与HNSCC转移扩散以及局部或远处复发的更大倾向相关。这些结果表明，TGF-β/Smad信号传导失活在HNSCC中频繁发生，可能对患者预后产生不利影响。
