Combined therapy using metastatic suppressor gene therapy and angiogenesis inhibitors for non-small cell lung cancers

采用裸鼠体内接种肿瘤细胞系或肿瘤组织的方法建立自发性转移模型。肿瘤转移抑制基因和血管生成因子表达的综合分析显示，MRP-1/CD9表达降低，KAI1/CD82表达降低，E-钙粘素表达降低与肺转移相关。至于血管生成因子，VEGF-A的表达和IL-8的表达与肿瘤内的血管生成有关。在肺癌中，HGF-cMET途径与肿瘤的增殖有关，但与血管生成无关(BR J癌症2004)。利用基因芯片对基因表达的综合分析表明，MRP-1/CD9基因转导抑制了Wnt信号通路(Oncogene 2004)和WAVE2表达(Oncogene 2006)。此外，我们发现Wnt1的表达与瘤内VEGF-A的表达有关，Wnt5a的表达与间质的VEGF-A的表达有关(J Clin Oncol2005)。MRP-1/CD9转导诱导WNT靶点之一的血管内皮生长因子A表达下调，提示转移抑制基因治疗和血管生成抑制剂联合治疗可能具有协同作用。因此，我们利用裸鼠自发转移模型，对肿瘤转移抑制基因治疗和血管生成抑制剂联合治疗进行了实验研究。腺病毒转染腺病毒MRP-1/CD9和KAI1/CD82分别抑制肿瘤肺转移。血管生成抑制剂TNP-470和CGS27023A也抑制肺转移。虽然TNP-470抑制了肿瘤的生长，但它引起了体重减轻的副作用。然而，在各种类型的转移抑制基因治疗和血管生成抑制剂的联合治疗中，我们没有发现任何协同作用。

We constructed the spontaneous metastasis model using the inoculation of tumor cell lines or tumor tissues into nude mice. The comprehensive analysis of expressions of tumor metastatic suppressor genes and angiogenesis factors revealed a reduced MRP-1/CD9 expression, a reduced KAI1/CD82 expression, and a reduced E-cadherin expression to be associated with pulmonary metastases. Regarding angiogenesis factors, a VEGF-A expression and a interleukin-8 expression were associated with intratumoral angiogenesis. In lung cancers, the HGF-cMet pathway was associated with the tumor proliferation, but not with angiogenesis (Br J Cancer 2004). The comprehensive analyses of gene expressions using cDNA microarray assays have demonstrated that the MRP-1/CD9 gene transduction suppresses the Wnt signal pathways (Oncogene 2004) and a WAVE2 expression (Oncogene 2006). Furthermore, we found the Wnt1 expression to be associated with the intratumoral VEGF-A expression, and the Wnt5a expression to be associated with the stromal VEGF-A expression (J Clin Oncol 2005). The finding that the MRP-1/CD9 transduction induces the down-regulation of VEGF-A, one of a Wnt target, suggested the possibility of the synergic effect of the combined therapy using metastatic suppressor gene therapy and angiogenesis inhibitors. Therefore, we performed experimental studies on combined therapy of metastatic suppressor gene therapy and angiogenesis inhibitors using the spontaneous metastasis model of nude mice. The adenoviral transfection of MRP-1/CD9 and KAI1/CD82 suppressed pulmonary metastases of tumors, respectively. TNP-470 and CGS27023A, angiogenesis inhibitors, also suppressed pulmonary metastases. Although TNP-470 inhibited tumor growth, but it caused weight loss as a side effect. However, we could not find any synergic effects in various types of the combined therapy of metastatic suppressor gene therapy and angiogenesis inhibitors.