Koukourakis M I, Giatromanolaki A, Kakolyris S, O'Byrne K J, Apostolikas N, Skarlatos J, Gatter K C, Harris A L
Department of Radiotherapy/Oncology and Saint Nikolas Histopathology Unit, University Hospital of Iraklion, Crete, Greece.
Br J Cancer. 1998 May;77(10):1696-703. doi: 10.1038/bjc.1998.280.
Angiogenesis is recognized as an important step in tumour pathogenesis that is related to invasion and metastatic spread and which consequently results in poor clinical outcome. In this study, we have examined the role of tumour stroma-activated fibroblasts and macrophage infiltration in the development of the angiogenic and metastatic phenotype in non-small-cell lung cancer (NSCLC). A total of 141 cases of early stage I-II NSCLC treated with surgery alone were analysed. The JC-70 (anti-CD31) MAb was used for the assessment of vascular grade. The P-GF.44C MAb was used to assess thymidine phosphorylase (TP) reactivity in cancer cells, stromal fibroblasts and macrophages. Cancer cell TP overexpression related to high vascular grade and to advanced T stage (P = 0.0004 and P = 0.02). Expression of TP in stromal fibroblasts also correlated with high angiogenesis (P = 0.01), but was independent of cancer cell expression. Fibroblast TP overexpression was related to abundant stroma (P = 0.003), suggesting that TP may be a marker of active stroma. Moreover, intense macrophage infiltration was associated with fibroblast TP reactivity, regardless of the amount of stroma, suggesting that macrophages may be a major contributor to TP expression in stroma. Survival analysis showed that cancer cell TP overexpression was related to poor prognosis (P = 0.005). Although stroma TP is related to angiogenesis, in the low vascular grade group it defined a group of patients with better prognosis (P = 0.02). It may be that fibroblast TP reactivity is an indirect marker of tumour infiltration by functional macrophages, which have an antitumour effect. We conclude that stromal macrophage and fibroblast TP reactivity may have an important role in non-small-cell lung cancer behaviour. Understanding the role of stromal fibroblasts and inflammatory cells and their interaction with oncoprotein expression is essential for the elucidation of lung cancer pathogenesis.
血管生成被认为是肿瘤发病机制中的一个重要步骤，它与肿瘤侵袭和转移扩散相关，进而导致临床预后不良。在本研究中，我们检测了肿瘤基质激活的成纤维细胞和巨噬细胞浸润在非小细胞肺癌（NSCLC）血管生成和转移表型发展中的作用。共分析了141例仅接受手术治疗的早期I-II期NSCLC病例。使用JC-70（抗CD31）单克隆抗体评估血管分级。使用P-GF.44C单克隆抗体评估癌细胞、基质成纤维细胞和巨噬细胞中的胸苷磷酸化酶（TP）反应性。癌细胞TP过表达与高血管分级和晚期T分期相关（P = 0.0004和P = 0.02）。基质成纤维细胞中TP的表达也与高血管生成相关（P = 0.01），但与癌细胞表达无关。成纤维细胞TP过表达与丰富的基质相关（P = 0.003），提示TP可能是活跃基质的一个标志物。此外，无论基质数量多少，强烈的巨噬细胞浸润与成纤维细胞TP反应性相关，提示巨噬细胞可能是基质中TP表达的主要贡献者。生存分析显示，癌细胞TP过表达与预后不良相关（P = 0.005）。虽然基质TP与血管生成有关，但在低血管分级组中，它定义了一组预后较好的患者（P = 0.02）。可能是成纤维细胞TP反应性是功能性巨噬细胞肿瘤浸润的间接标志物，而功能性巨噬细胞具有抗肿瘤作用。我们得出结论，基质巨噬细胞和成纤维细胞TP反应性可能在非小细胞肺癌行为中起重要作用。了解基质成纤维细胞和炎性细胞的作用及其与癌蛋白表达的相互作用对于阐明肺癌发病机制至关重要。
