A double hit to kill tumor and endothelial cells by TRAIL and antiangiogenic 3TSR.
As tumor development relies on a coordination of angiogenesis and tumor growth, an efficient antitumor strategy should target both the tumor and its associated vessels. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner. Additionally, thrombospondin-1, a naturally occurring inhibitor of angiogenesis, and a recombinant protein containing functional domains of thrombospondin-1, 3TSR, have been shown to be necessary and sufficient to inhibit tumor angiogenesis. Here, we show that a combination of a TRAIL receptor 2 agonist antibody, Lexatumumab, and 3TSR results in a significantly enhanced and durable tumor inhibition. We further observed that 3TSR induces apoptosis in primary endothelial cells by up-regulating the expression of TRAIL receptors 1 and 2 in a CD36 and Jun NH(2)-terminal kinase-dependent manner leading to the activation of both intrinsic and extrinsic apoptotic machineries. The modulation of these pathways is critical for 3TSR-induced apoptosis as disrupting either via specific inhibitors reduced apoptosis. Moreover, 3TSR attenuates the Akt survival pathway. These studies indicate that 3TSR plays a critical role in regulating the proapoptotic signaling pathways that control growth and death in endothelial cells and that a combination of TRAIL and 3TSR acts as a double hit against tumor and tumor-associated vessels.
Department of Pathology, Division of Cancer Biology and Angiogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Bin
B
Ren
Keli
K
Song
Sareh
S
Parangi
Taiguang
T
Jin
Min
M
Ye
Robin
R
Humphreys
Mark
M
Duquette
Xuefeng
X
Zhang
Nordine
N
Benhaga
Jack
J
Lawler
Roya
R
Khosravi-Far
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D004789:Enzyme Activation; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D010446:Peptide Fragments / Q000008:administration & dosage; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000008:administration & dosage; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology; D019699:Thrombospondins / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D010446:Peptide Fragments; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D019699:Thrombospondins; C101863:thrombospondin 3; C510234:lexatumumab; D048670:MAP Kinase Kinase 4; D053148:Caspase 3; D053181:Caspase 8