Semaphorin 3B (SEMA3B) induces apoptosis in lung and breast cancer, whereas VEGF165 antagonizes this effect.

Semaphorin 3B (SEMA3B) is a secreted member of the semaphorin family, important in axonal guidance. We and others have shown that SEMA3B can act as a tumor suppressor by inducing apoptosis either by reexpression in tumor cells or applied as a soluble ligand. The common method of inactivation of SEMA3B is by allele loss and tumor-acquired promoter methylation. We studied the mechanism of SEMA3B-induced tumor cell apoptosis and found that vascular endothelial growth factor (VEGF)165 significantly decreased the proapoptotic and antimitotic effect of transfected or secreted SEMA3B on lung and breast cancer cells. VEGF165 binds to neuropilin, receptors for SEMA3B, and we found that SEMA3B competed for binding of 125I-VEGF165 to lung and breast cancer cells. We also found that small interfering RNA knockdown of tumor-produced VEGF-A or the use of an anti-VEGF neutralizing antibody (Ab) significantly inhibited tumor cell growth in vitro. By contrast, VEGF121, a VEGF variant that lacks binding to neuropilin (NP)-1 or NP-2 receptors, was not expressed in tumor cells and had no effect on SEMA3B growth-suppressing activities. In conclusion, we hypothesize that VEGF165, produced by tumor cells, acts as an autocrine survival factor and that SEMA3B mediates its tumor-suppressing effects, at least in part, by blocking this VEGF autocrine activity.

[1]  B. Eickholt,et al.  Competing autocrine pathways involving alternative neuropilin-1 ligands regulate chemotaxis of carcinoma cells. , 2003, Cancer research.

[2]  C. Croce,et al.  Allelic loss on chromosome 3p21.3 and promoter hypermethylation of semaphorin 3B in non-small cell lung cancer. , 2003, Cancer research.

[3]  P. Scalia,et al.  Malignant mesothelioma growth inhibition by agents that target the VEGF and VEGF‐C autocrine loops , 2003, International journal of cancer.

[4]  S. Rafii,et al.  Inhibition of human leukemia in an animal model with human antibodies directed against vascular endothelial growth factor receptor 2. Correlation between antibody affinity and biological activity , 2003, Leukemia.

[5]  Nijole Gasiunas,et al.  Neuropilin-1 Binds Vascular Endothelial Growth Factor 165, Placenta Growth Factor-2, and Heparin via Its b1b2 Domain* , 2002, The Journal of Biological Chemistry.

[6]  H. Serve,et al.  Overexpression of vascular endothelial growth factor (VEGF) and its cellular receptor KDR (VEGFR-2) in the bone marrow of patients with acute myeloid leukemia , 2002, Leukemia.

[7]  G. Schinzari,et al.  Expression of vascular endothelial growth factor, mitogen-activated protein kinase and p53 in human colorectal cancer. , 2002, Anticancer research.

[8]  H. Ishida,et al.  Vascular endothelial growth factor overexpression is correlated with von Hippel‐Lindau tumor suppressor gene inactivation in patients with sporadic renal cell carcinoma , 2002, Cancer.

[9]  Chenghua Gu,et al.  Characterization of Neuropilin-1 Structural Features That Confer Binding to Semaphorin 3A and Vascular Endothelial Growth Factor 165* , 2002, The Journal of Biological Chemistry.

[10]  K. Miura,et al.  Vascular endothelial growth factor (VEGF) expression correlates with p53 and ki-67 expressions in tongue squamous cell carcinoma. , 2002, Anticancer research.

[11]  L. Devy,et al.  Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling , 2002, Oncogene.

[12]  C. Tse,et al.  Human Semaphorin 3B (SEMA3B) located at chromosome 3p21.3 suppresses tumor formation in an adenocarcinoma cell line. , 2002, Cancer research.

[13]  H. Kikutani,et al.  The CD100-CD72 interaction: a novel mechanism of immune regulation. , 2001, Trends in immunology.

[14]  J. Minna,et al.  Inhibition of lung cancer cell growth and induction of apoptosis after reexpression of 3p21.3 candidate tumor suppressor gene SEMA3B , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[15]  J. Bolz,et al.  Semaphorin 3A–Vascular Endothelial Growth Factor-165 Balance Mediates Migration and Apoptosis of Neural Progenitor Cells by the Recruitment of Shared Receptor , 2001, The Journal of Neuroscience.

[16]  T. Suda,et al.  Exogenous clustered neuropilin 1 enhances vasculogenesis and angiogenesis. , 2001, Blood.

[17]  A. Barzilai,et al.  Induction of neuronal apoptosis by Semaphorin3A-derived peptide. , 2000, Brain research. Molecular brain research.

[18]  J. Minna,et al.  The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium. , 2000, Cancer research.

[19]  J. Minna,et al.  Selective inhibition of vascular endothelial growth factor (VEGF) receptor 2 (KDR/Flk-1) activity by a monoclonal anti-VEGF antibody blocks tumor growth in mice. , 2000, Cancer research.

[20]  M. Lohrum,et al.  Plexin/neuropilin complexes mediate repulsion by the axonal guidance signal semaphorin 3A , 2000, Mechanisms of Development.

[21]  M. Poo,et al.  Plexins Are a Large Family of Receptors for Transmembrane, Secreted, and GPI-Anchored Semaphorins in Vertebrates , 1999, Cell.

[22]  V. Gagliardini,et al.  Semaphorin III Can Induce Death in Sensory Neurons , 1999, Molecular and Cellular Neuroscience.

[23]  A. Barzilai,et al.  Semaphorins as Mediators of Neuronal Apoptosis , 1999, Journal of neurochemistry.

[24]  U. Hellman,et al.  Differential Binding of Vascular Endothelial Growth Factor B Splice and Proteolytic Isoforms to Neuropilin-1* , 1999, The Journal of Biological Chemistry.

[25]  S. Soker,et al.  Neuropilin-1 Mediates Collapsin-1/Semaphorin III Inhibition of Endothelial Cell Motility , 1999, The Journal of cell biology.

[26]  C. Goodman,et al.  Plexin A Is a Neuronal Semaphorin Receptor that Controls Axon Guidance , 1998, Cell.

[27]  R. Kalb,et al.  Neuropilin-1 Extracellular Domains Mediate Semaphorin D/III-Induced Growth Cone Collapse , 1998, Neuron.

[28]  M. Shibuya,et al.  Neuropilin-1 Is a Placenta Growth Factor-2 Receptor* , 1998, The Journal of Biological Chemistry.

[29]  Shay Soker,et al.  Neuropilin-1 Is Expressed by Endothelial and Tumor Cells as an Isoform-Specific Receptor for Vascular Endothelial Growth Factor , 1998, Cell.

[30]  S. Hirohashi,et al.  Identification of semaphorin E as a non-MDR drug resistance gene of human cancers. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[31]  G. Freeman,et al.  Human CD100, a novel leukocyte semaphorin that promotes B-cell aggregation and differentiation. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Jeffrey A. Golden,et al.  Semaphorin III is needed for normal patterning and growth of nerves, bones and heart , 1996, Nature.

[33]  A. Püschel.  The Semaphorins: A Family of Axonal Guidance Molecules? , 1996, The European journal of neuroscience.

[34]  J. Minna,et al.  Human semaphorins A(V) and IV reside in the 3p21.3 small cell lung cancer deletion region and demonstrate distinct expression patterns. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Shay Soker,et al.  Characterization of Novel Vascular Endothelial Growth Factor (VEGF) Receptors on Tumor Cells That Bind VEGF via Its Exon 7-encoded Domain (*) , 1996, The Journal of Biological Chemistry.

[36]  E. Maestrini,et al.  A family of transmembrane proteins with homology to the MET-hepatocyte growth factor receptor. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[37]  T. Kitsukawa,et al.  Overexpression of a membrane protein, neuropilin, in chimeric mice causes anomalies in the cardiovascular system, nervous system and limbs. , 1995, Development.

[38]  S. Takagi,et al.  Plexin: A novel neuronal cell surface molecule that mediates cell adhesion via a homophilic binding mechanism in the presence of calcium ions , 1995, Neuron.

[39]  M. Shibuya,et al.  Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. , 1994, The Journal of biological chemistry.

[40]  C. Goodman,et al.  The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules , 1993, Cell.

[41]  J. Winer,et al.  The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. , 1991, Molecular endocrinology.

[42]  H. Drabkin,et al.  Semaphorin SEMA3F and VEGF have opposing effects on cell attachment and spreading. , 2003, Neoplasia.

[43]  Yusuke Nakamura,et al.  Identification of semaphorin3B as a direct target of p53. , 2002, Neoplasia.

[44]  Kharitonov Sv,et al.  The psychophysiology of neuroses , 1999 .

[45]  L. Shaw,et al.  Advances in Brief Vascular Endothelial Growth Factor Is an Autocrine Survival Factor for Neuropilin-expressing Breast Carcinoma Cells 1 , 2022 .