Cancer-Stromal Interaction in Lung Adenocarcinoma

VEGF家族是一组调节内皮细胞生长的生长因子。研究表明VEGF-A参与肿瘤的侵袭和转移。采用定量RT-PCR方法检测60例肺腺癌组织中VEGF-A、-B、-C和-D的表达水平，探讨其表达水平与肺腺癌淋巴结转移的关系。我们发现有淋巴结转移的肿瘤与低VEGF-D和高VEGF-A、VEGF-B和VEGF-C的模式相关。此外，大淋巴结转移的肿瘤中VEGF-A的水平高于小淋巴结转移的肿瘤，而VEGF-B或VEGF-C的水平则无差异。这些结果与两个VEGF家族成员参与两个不同步骤的假设一致; VEGF-C促进癌细胞进入淋巴管，而VEGF-A通过血管生成促进转移性肿瘤的生长。层粘连蛋白-5蛋白是已知促进癌细胞运动的细胞外基质蛋白。总的来说，层粘连蛋白-5的表达在82例观察：7/18支气管肺泡癌和75/84浸润性腺癌。层粘连蛋白-5优先定位于肿瘤-基质界面处的肿瘤细胞的细胞质中，其中经常观察到癌细胞的出芽或解离。生存分析显示，层粘连蛋白-5的过度表达（24例，23.5%）是一个独立的预后因素，在单因素和多因素分析。进一步的体外实验表明，肺腺癌细胞系中层粘连蛋白-5 γ2链mRNA水平与erbB-2表达和MAPK磷酸化相关。TGF-α、HGF、TNF-α和IL-1 β以时间依赖性方式增加层粘连蛋白5 γ 2链mRNA水平。

The VEGF family is a group of growth factors that regulate the growth of endothelial cells. Studies suggest that VEGF-A is involved in tumor invasion and metastasis. We investigated the expression levels of VEGF-A, -B, -C, and -D in 60 cases of lung adenocarcinomas by quantitative RT-PCR analyses, and explored whether their expression levels were correlated with lymph node metastasis. We found that tumors with lymph node metastasis were associated with a pattern of low VEGF-D and high VEGF-A, VEGF-B, and VEGF-C.Also, levels of VEGF-A, but not of VEGF-B or VEGF-C, were higher in tumors with large nodal metastasis than in those with small nodal metastasis. These results are consistent with the hypothesis that two VEGF family members are involved at two distinct steps ; VEGF-C facilitates entry of cancer cells into lymph vasculature, whereas VEGF-A promotes the growth of metastatic tumor through angiogenesis.Next, we immunohistochemically investigated the expression of laminin-5 in 102 cases of small lung adenocarcinomas. The laminin-5 protein is an extracellular matrix protein that is known to facilitate motility of cancer cells. Overall, laminin-5 expression was observed in 82 cases : 7 of 18 bronchiolo-alveolar carcinomas and 75 of 84 invasive adenocarcinomas. Laminin-5 was preferentially localized in the cytoplasm of tumor cells at the tumor-stromal interface, where budding or dissociation of cancer cells was frequently observed. Survival analysis revealed that over-expression of laminin-5 (24 cases, 23.5%) was an independent prognostic factor in both univariate and multivariate analyses. Further in vitro experiments showed that laminin-5 γ2 chain mRNA levels were correlated with erbB-2 expression and MAPK phosphorylation in lung adenocarcinoma cell lines. Treatment with TGF-α, HGF, TNF-α, and IL-1 β increased the laminin-5 γ 2 chain mRNA levels in a time-dependent manner.