| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
,¶
From the Biomedical Graduate Program,* the Departments of Medicine and Pathology and Laboratory Medicine, and the Abramson Cancer Center,¶ University of Pennsylvania, Philadelphia, Pennsylvania; and Bayer Pharmaceuticals Corporation, West Haven, Connecticut
Activation of the Raf-MEK-ERK signal transduction pathway in endothelial cells is required for angiogenesis. Raf is the kinase most efficiently inhibited by the multikinase inhibitor sorafenib, which has shown activity against certain human cancers in clinical trials. To understand the mechanisms underlying this activity, we studied how it controlled growth of K1735 murine melanomas. Therapy caused massive regional tumor cell death accompanied by severe tumor hypoxia, decreased microvessel density, increased percentage of pericyte-covered vessels, and increased caliber and decreased arborization of vessels. These signs of K1735 angiogenesis inhibition, along with its ability to inhibit Matrigel neovascularization, showed that sorafenib is an effective anti-angiogenic agent. Extracellular signal-regulated kinase (ERK) activation in tumor endothelial cells, revealed by immunostaining for phospho-ERK and CD34, was inhibited, whereas AKT activation, revealed by phospho-AKT immunostaining, was not inhibited in K1735 and two other tumor types treated with sorafenib. Treatment decreased endothelial but not tumor cell proliferation and increased both endothelial cell and tumor cell apoptosis. These data indicate that sorafenib’s anti-tumor efficacy may be primarily attributable to angiogenesis inhibition resulting from its inhibition of Raf-MEK-ERK signaling in endothelial cells. Assessing endothelial cell ERK activation in tumor bio-psies may provide mechanistic insights into and allow monitoring of sorafenib’s activity in patients in clinical trials.
This article has been cited by other articles:
 |
|
 |
|
  E J Chung, S Yoo, H J Lim, S H Byeon, J H Lee, and H J Koh Inhibition of choroidal neovascularisation in mice by systemic administration of the multikinase inhibitor, sorafenib Br. J. Ophthalmol., July 1, 2009; 93(7): 958 - 963. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J P. Couto, H Prazeres, P Castro, J Lima, V Maximo, P Soares, and M Sobrinho-Simoes How molecular pathology is changing and will change the therapeutics of patients with follicular cell-derived thyroid cancer J. Clin. Pathol., May 1, 2009; 62(5): 414 - 421. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Horn and A. B. Sandler Angiogenesis in the Treatment of Non-Small Cell Lung Cancer Proceedings of the ATS, April 15, 2009; 6(2): 206 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kunimasa, M.-R. Ahn, T. Kobayashi, R. Eguchi, S. Kumazawa, Y. Fujimori, T. Nakano, T. Nakayama, K. Kaji, and T. Ohta Brazilian Propolis Suppresses Angiogenesis by Inducing Apoptosis in Tube-forming Endothelial Cells through Inactivation of Survival Signal ERK1/2 Evid. Based Complement. Altern. Med., April 7, 2009; (2009) nep024v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. W. Alfano, S. H. Leppla, S. Liu, T. H. Bugge, C. J. Meininger, T. C. Lairmore, A. F. Mulne, S. H. Davis, N. S. Duesbery, and A. E. Frankel Matrix Metalloproteinase-Activated Anthrax Lethal Toxin Inhibits Endothelial Invasion and Neovasculature Formation during In vitro Morphogenesis Mol. Cancer Res., April 1, 2009; 7(4): 452 - 461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Tsai and W. M.F. Lee Tie2 in Tumor Endothelial Signaling and Survival: Implications for Antiangiogenic Therapy Mol. Cancer Res., March 1, 2009; 7(3): 300 - 310. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Jilaveanu, C. Zito, S. J. Lee, K. L. Nathanson, R. L. Camp, D. L. Rimm, K. T. Flaherty, and H. M. Kluger Expression of Sorafenib Targets in Melanoma Patients Treated with Carboplatin, Paclitaxel and Sorafenib Clin. Cancer Res., February 1, 2009; 15(3): 1076 - 1085. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Pang, T. Yi, Z. Yi, S. G. Cho, W. Qu, D. Pinkaew, K. Fujise, and M. Liu Morelloflavone, a Biflavonoid, Inhibits Tumor Angiogenesis by Targeting Rho GTPases and Extracellular Signal-Regulated Kinase Signaling Pathways Cancer Res., January 15, 2009; 69(2): 518 - 525. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Gupta-Abramson, A. B. Troxel, A. Nellore, K. Puttaswamy, M. Redlinger, K. Ransone, S. J. Mandel, K. T. Flaherty, L. A. Loevner, P. J. O'Dwyer, et al. Phase II Trial of Sorafenib in Advanced Thyroid Cancer J. Clin. Oncol., October 10, 2008; 26(29): 4714 - 4719. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. T. Flaherty, J. Schiller, L. M. Schuchter, G. Liu, D. A. Tuveson, M. Redlinger, C. Lathia, C. Xia, O. Petrenciuc, S. R. Hingorani, et al. A Phase I Trial of the Oral, Multikinase Inhibitor Sorafenib in Combination with Carboplatin and Paclitaxel Clin. Cancer Res., August 1, 2008; 14(15): 4836 - 4842. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Yi, S.-G. Cho, Z. Yi, X. Pang, M. Rodriguez, Y. Wang, G. Sethi, B. B. Aggarwal, and M. Liu Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and extracellular signal-regulated kinase signaling pathways Mol. Cancer Ther., July 1, 2008; 7(7): 1789 - 1796. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Moreno-Vinasco, M. Gomberg-Maitland, M. L. Maitland, A. A. Desai, P. A. Singleton, S. Sammani, L. Sam, Y. Liu, A. N. Husain, R. M. Lang, et al. Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension Physiol Genomics, April 1, 2008; 33(2): 278 - 291. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ding, E. A. Boguslawski, B. D. Berghuis, J. J. Young, Z. Zhang, K. Hardy, K. Furge, E. Kort, A. E. Frankel, R. V. Hay, et al. Mitogen-activated protein kinase kinase signaling promotes growth and vascularization of fibrosarcoma Mol. Cancer Ther., March 1, 2008; 7(3): 648 - 658. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Feng, R. E. Brown, C. D. Trung, W. Li, L. Wang, T. Khoury, S. Alrawi, J. Yao, K. Xia, and D. Tan Morphoproteomic Profile of mTOR, Ras/Raf Kinase/ERK, and NF-{kappa}B Pathways in Human Gastric Adenocarcinoma Ann. Clin. Lab. Sci., January 1, 2008; 38(3): 195 - 209. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Huang, Y. Ding, W.-M. Luo, S. Bender, C.-N. Qian, E. Kort, Z.-F. Zhang, K. VandenBeldt, N. S. Duesbery, J. H. Resau, et al. Inhibition of MAPK Kinase Signaling Pathways Suppressed Renal Cell Carcinoma Growth and Angiogenesis In vivo Cancer Res., January 1, 2008; 68(1): 81 - 88. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. N. Stein and K. T. Flaherty CCR Drug Updates: Sorafenib and Sunitinib in Renal Cell Carcinoma Clin. Cancer Res., July 1, 2007; 13(13): 3765 - 3770. [Full Text] [PDF]
|
|
|
|
|
|
R. E. Brown, D. Tan, J. S. Taylor, M. Miller, J. W. Prichard, and M. M. Kott Morphoproteomic Confirmation of Constitutively Activated mTOR, ERK, and NF-kappaB Pathways in High Risk Neuro-blastoma, with Cell Cycle and Protein Analyte Correlates Ann. Clin. Lab. Sci., January 1, 2007; 37(2): 141 - 147. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
