Targeting filamin A reduces K-RAS–induced lung adenocarcinomas and endothelial response to tumor growth in mice
1 Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Sahlgrenska Academy, SE-405 30, Göteborg, Sweden
2 Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Göteborg, Sweden
3 Sahlgrenska Cancer Center, University of Gothenburg, Göteborg, Sweden
4 Current address: Department of Medicine, Columbia University, New York, USA
5 Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, Göteborg, Sweden
6 Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden
7 Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden
Molecular Cancer 2012, 11:50 doi:10.1186/1476-4598-11-50Published: 2 August 2012
Many human cancer cells express filamin A (FLNA), an actin-binding structural protein that interacts with a diverse set of cell signaling proteins, but little is known about the biological importance of FLNA in tumor development. FLNA is also expressed in endothelial cells, which may be important for tumor angiogenesis. In this study, we defined the impact of targeting Flna in cancer and endothelial cells on the development of tumors in vivo and on the proliferation of fibroblasts in vitro.
First, we used a Cre-adenovirus to simultaneously activate the expression of oncogenic K-RAS and inactivate the expression of Flna in the lung and in fibroblasts. Second, we subcutaneously injected mouse fibrosarcoma cells into mice lacking Flna in endothelial cells.
Knockout of Flna significantly reduced K-RAS–induced lung tumor formation and the proliferation of oncogenic K-RAS–expressing fibroblasts, and attenuated the activation of the downstream signaling molecules ERK and AKT. Genetic deletion of endothelial FLNA in mice did not impact cardiovascular development; however, knockout of Flna in endothelial cells reduced subcutaneous fibrosarcoma growth and vascularity within tumors.
We conclude that FLNA is important for lung tumor growth and that endothelial Flna impacts local tumor growth. The data shed new light on the biological importance of FLNA and suggest that targeting this protein might be useful in cancer therapeutics.