Disruption of tumor cell adhesion promotes angiogenic switch and progression to micrometastasis in RAF-driven murine lung cancer (Cancer Cell, 2007, 12:145-159)

報告日期: 2007/11/02
報告時間: 15:10/16:00
報告學生: 翁子玉
講評老師: 王憶卿
附件下載:

Disruption of tumor cell adhesion promotes angiogenic switch and progression to micrometastasis in RAF-driven murine lung cancer

Cancer Cell, 2007, 12:145-159

Student:翁子玉

Commentator:王憶卿老師

Time:11/02, 2007

Place: Room 602

Abstract:

Lung cancer accounts for most people death worldwide. Among all the types of lung cancer, non-small-cell lung cancer (NSCLC) is the most frequent type and has high metastatic rate. The authors has a NSCLC mouse model, which harbors an constitutively active form C-RAF (SP-C C-RAF BXB)1 , and mice form benign adenoma but will not progress to malignant adenocarcinoma or cause metastasis. Therefore, it is a good model to test what molecules cause lung cancer progression. E-cadherin is an important adhesion molecule that controls cell-cell adhesion and plays an important role in NSCLC metastasis2. They wanted to investigate whether disruption of E-cadherin might lead to the C-RAF driven lung cancer progression. Under the genetic base of C-RAF mice (SPC C-RAF BXB), the authors generated two transgenic mice, one is doxycycline-inducible Cre/loxP cadherin 1 gene ablation and the other is doxycycline-reversible dominant negative E-cadherin. Once the mutant cadherin expressed, the cell would form separation morphology, increased angiogenesis, lymphogenesis and β-catenin partially accumulated in the nucleus. Micrometastasis was also observed in lymph node and bone marrow, and transgenic mice finally formed adenocarcinoma under constitutive mutant E-cadherin expression. In search of the pathway involved, they found that β-catenin would upregulate VEGF-A and VEGF-C expression, and many β-catenin downstream genes were also activated. Above all, blocking cell-cell adhesion and subsequent agniogenisis could be another strategy for malignant therapy in the future.

References:

1. Kerkhoff, E., et al. (2000). Lung-targeted expression of the c-Raf-1 kinase in transgenic mice exposes a novel oncogenic character of the wild-type protein. Cell Growth Differ. 11, 185–190.

2. Huang, C., et al. (2005). Clinical application of biological markers for treatments of resectable non-small-cell lung cancers. Br. J. Cancer 92, 1231–1239.