Human melanoma cytolysis by combined inhibition of mammalian target of rapamycin and vascular endothelial growth factor/vascular endothelial growth factor receptor-2.
Vascular endothelial growth factor (VEGF) plays a vital role in tumor angiogenesis. VEGF is produced by human melanomas, and the VEGF receptor 2 (VEGFR-2) is expressed by most advanced stage melanomas, suggesting the possibility of an autocrine loop. Here, we show that bevacizumab, an anti-VEGF antibody, inhibits proliferation of VEGFR-2(+) melanoma cell lines by an average of 41%; however, it failed to inhibit proliferation of VEGFR-2(neg) melanoma cell lines. The growth inhibitory effect of bevacizumab was eliminated by VEGFR-2 knockdown with small interfering RNA, showing that VEGF autocrine growth in melanoma is mediated through VEGFR-2. However, bevacizumab inhibition of autocrine signals did not completely inhibit cell proliferation nor cause cell death. Cell survival is mediated partially through mammalian target of rapamycin (mTOR), which is inhibited by rapamycin. Combination of bevacizumab with rapamycin caused loss of half of the VEGFR-2(+) melanoma cells, but no reduction in the number of VEGFR-2(neg) melanoma cells. The results show (a) an autocrine growth loop active in VEGFR-2(+) melanoma, (b) a nonangiogenic mechanism for inhibition of melanoma by blocking autocrine VEGFR-2 activation, and (c) a possible therapeutic role for combination of inhibitors of mTOR plus VEGF in selected melanomas.
Department of Surgery, Division of Surgical Oncology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Kerrington R
KR
Molhoek
Heinrich
H
Griesemann
Jianfen
J
Shu
Jeffrey E
JE
Gershenwald
David L
DL
Brautigan
Craig L
CL
Slingluff
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D000068258:Bevacizumab; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011494:Protein Kinases / Q000187:drug effects*; D034741:RNA, Small Interfering; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D011494:Protein Kinases; C546842:MTOR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus