Targeting Slit-Roundabout signaling inhibits tumor angiogenesis in chemical-induced squamous cell carcinogenesis.
Slit is a secreted protein known to function through the Roundabout (Robo) receptor as a repellent for axon guidance and neuronal migration, and as an inhibitor in leukocyte chemotaxis. We have previously shown that Slit2 is also secreted by a variety of human cancer cells whereby it acts as a chemoattractant to vascular endothelial cells for tumor angiogenesis. We used a blocking antibody to investigate the role of Slit-Robo signaling in tumor angiogenesis during oral carcinogenesis. In this report we undertook a multistage model of 7,12-dimethyl-1,2-benzanthracene-induced squamous cell carcinoma in the hamster buccal pouch. R5, a monoclonal antibody against the first immunoglobulin domain of Robo1, was used to study whether R5 blocks the Slit-Robo interaction and furthermore inhibits tumor angiogenesis and growth in our model. In addition, the expression of Slit2, von Willebrand factor, and vascular endothelial growth factor were examined using human tissue of oral cheek mucosa with oral squamous cell carcinoma. Our data showed that Slit2 was expressed minimally in normal and hyperplastic mucosa, moderately in dysplastic mucosa, and highly in neoplastic mucosa obtained from hamster buccal pouch. We also found that increased Slit2 expression was associated with higher tumor angiogenesis, as reflected by increased vascular endothelial growth factor expression and microvessel density. A similar Slit2 expression profile was found in human tissue. Importantly, interruption of the Slit2-Robo interaction using R5 inhibited tumor angiogenesis and growth in our in vivo model, which indicates that Slit2-mediated tumor angiogenesis is a critical process underlying the carcinogenesis of chemical-induced squamous cell carcinoma. Therefore, targeting Slit-Robo signaling may offer a novel antiangiogenesis approach for oral cancer therapy.
Wang
Li-Jing
LJ
Department of Biochemistry and Molecular Biology, Schools of Life Sciences, Lanzhou University, Lanzhou, China.
Zhao
Yuan
Y
Han
Bing
B
Ma
Yu-Guang
YG
Zhang
Jie
J
Yang
Ding-Ming
DM
Mao
Jian-Wen
JW
Tang
Fu-Tian
FT
Li
Wei-Dong
WD
Yang
Yang
Y
Wang
Rui
R
Geng
Jian-Guo
JG
D015127:9,10-Dimethyl-1,2-benzanthracene; D000482:Allantois / Q000378:metabolism; D000818:Animals; D002273:Carcinogens; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000139:chemically induced / Q000378:metabolism; D002642:Chick Embryo / Q000378:metabolism; D006224:Cricetinae; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
D015127:9,10-Dimethyl-1,2-benzanthracene; D002273:Carcinogens; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D042461:Vascular Endothelial Growth Factor A; D014841:von Willebrand Factor; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein