Inhibition of tumor endothelial ERK activation, angiogenesis, and tumor growth by sorafenib (BAY43-9006).
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.
Murphy
Danielle A
DA
Biomedical Graduate Program, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Makonnen
Sosina
S
Lassoued
Wiem
W
Feldman
Michael D
MD
Carter
Christopher
C
Lee
William M F
WM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000494:pharmacology* / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000187:drug effects; D004338:Drug Combinations; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology / Q000473:pathology; D007797:Laminin / Q000187:drug effects; D008545:Melanoma / Q000098:blood supply / Q000473:pathology*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010766:Phosphorylation / Q000187:drug effects; D011509:Proteoglycans / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D000077157:Sorafenib
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D004338:Drug Combinations; D007797:Laminin; D010671:Phenylurea Compounds; D011509:Proteoglycans; D011725:Pyridines; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D009536:Niacinamide; D003094:Collagen; D000077157:Sorafenib; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases