Abstract
Hsueh-Te Lee1,5,*, Jianfei Xue1,*, Ping-Chieh Chou1, Aidong Zhou1, Phillip Yang1, Charles A. Conrad2, Kenneth D. Aldape3, Waldemar Priebe4, Cam Patterson6, Raymond Sawaya1, Keping Xie7,8 and Suyun Huang1,8
1 Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2 Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
3 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
4 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
5 Institute of Anatomy and Cell Biology, National Yang-Ming University, Taipei, Taiwan
6 Division of Cardiology and McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina, USA
7 Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
8 Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA
* These authors contributed equally to this work
Correspondence to:
Suyun Huang, email:
Keywords: Stat3, VEGFR2, Stat3 inhibitor, brain metastasis, brain endothelial cells
Received: December 11, 2014 Accepted: February 17, 2015 Published: March 12, 2015
Abstract
Brain metastasis is a major cause of morbidity and mortality in patients with breast cancer. Our previous studies indicated that Stat3 plays an important role in brain metastasis. Here, we present evidence that Stat3 functions at the level of the microenvironment of brain metastases. Stat3 controlled constitutive and inducible VEGFR2 expression in tumor-associated brain endothelial cells. Furthermore, inhibition of Stat3 by WP1066 decreased the incidence of brain metastases and increased survival in a preclinical model of breast cancer brain metastasis. WP1066 inhibited Stat3 activation in tumor-associated endothelial cells, reducing their infiltration and angiogenesis. WP1066 also inhibited breast cancer cell invasion. Our results indicate that WP1066 can inhibit tumor angiogenesis and brain metastasis mediated by Stat3 in endothelial and tumor cells.
