Selective suppression of in vivo tumorigenicity by semaphorin SEMA3F in lung cancer cells.
Loss of the 3p21.3-encoded semaphorins, SEMA3B and SEMA3F, is implicated in lung cancer development. Although both antagonize VEGF binding/response to neuropilin (NRP) receptors, in lung cancer lines, SEMA3F is predominantly expressed and preferentially utilizes NRP2. In lung cancer patients, SEMA3F loss correlates with advanced disease and increased VEGF binding to tumor cells. In cell lines, VEGF enhances adhesion and migration in an integrin-dependent manner, and exogenous SEMA3F causes cells to round and lose extracellular contacts. Using retroviral infections, we established stable SEMA3F transfectants in two NSCLC cell lines, NCI-H157 and NCI-H460. When orthotopically injected into nude rats, both control lines caused lethal tumors in all recipients. In contrast, all animals receiving H157-SEMA3F cells, survived to 100 days, whereas all H157 controls succumbed. In H460 cells, which express NRP1 but not NRP2, SEMA3F did not prolong survival. This antitumor effect in H157 cells was associated with loss of activated alpha(v)beta(3) integrin and adhesion to extracellular matrix components. In addition, H157-SEMA3F cells, and parental H157 cells exposed to SEMA3F-conditioned medium, showed loss of p42/p44 MAPK phosphorylation. Thus, in this in vivo lung cancer model, SEMA3F has potent antitumor effects, which may impinge on activated integrin and MAPK signaling.
Kusy
Sophie
S
IPBC, CNRS UMR 6187, Faculté des Sciences de Poitiers, 40 avenue du Recteur Pineau, Poitiers 86022, France.
Nasarre
Patrick
P
Chan
Daniel
D
Potiron
Vincent
V
Meyronet
David
D
Gemmill
Robert M
RM
Constantin
Bruno
B
Drabkin
Harry A
HA
Roche
Joëlle
J
D000818:Animals; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D017077:Culture Media, Conditioned / Q000494:pharmacology; D017931:DNA Primers / Q000737:chemistry; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D008168:Lung / Q000473:pathology*; D008175:Lung Neoplasms / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011923:Rats, Nude; D015398:Signal Transduction; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D017077:Culture Media, Conditioned; D017931:DNA Primers; D039302:Integrin alphaVbeta3; D016023:Integrins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C491230:SEMA3F protein, human; D042461:Vascular Endothelial Growth Factor A; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3