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Semaphorins in Lung Cancer

      The secreted class 3 semaphorins, which include SEMA3F, a tumor-suppressor gene in lung cancer, were initially identified as molecules involved in the repulsion of developing nerve growth cones. These molecules are part of a larger family that includes transmembrane and membrane-associated proteins, some of which are expressed widely and implicated in other functions such as development and immune response.
      • Semaphorin Nomenclature Committee
      Unified nomenclature for the semaphorins/collapsins.
      SEMA3B and SEMA3F are both encoded in 3p21.3,
      • Roche J
      • Boldog F
      • Robinson M
      • et al.
      Distinct 3p21.3 deletions in lung cancer and identification of a new human semaphorin.
      • Sekido Y
      • Bader S
      • Latif F
      • et al.
      Human semaphorins A(V) and IV reside in the 3p21.3 small cell lung cancer deletion region and demonstrate distinct expression patterns.
      • Xiang RH
      • Hensel CH
      • Garcia DK
      • et al.
      Isolation of the human semaphorin III/F gene (SEMA3F) at chromosome 3p21, a region deleted in lung cancer.
      a region of frequent loss of heterozygosity in lung cancer,
      • Lerman MI
      • Minna JD
      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.
      which initially suggested that one or both of these genes might have tumor-suppressor activity. Since this hypothesis in 1996, several semaphorins have been implicated in cancer.
      • Nasarre P
      • Constantin B
      • Drabkin HA
      • Roche J
      Semaphorins and cancers: an up ‘dating’.
      • Chedotal A
      • Kerjan G
      • Moreau-Fauvarque C
      The brain within the tumor: new roles for axon guidance molecules in cancers.
      • Klagsbrun M
      • Eichmann A
      A role for axon guidance receptors and ligands in blood vessel development and tumor angiogenesis.
      • Neufeld G
      • Shraga-Heled N
      • Lange T
      • Guttmann-Raviv N
      • Herzog Y
      • Kessler O
      Semaphorins in cancer.
      In this review, we focus on the function and signaling of semaphorins involved in lung cancer.

      SEMAPHORIN SIGNALING

      The neuropilins (NRP) NRP1 and NRP2 are high-affinity receptors for the class 3 semaphorins. However, in the absence of plexin co-receptors, they are insufficient to propagate a signal. Intracellular semaphorin signaling (Figure 1) involves small-GTPases, collapsin response-mediated protein, pERK1/2, and integrins, which result in the reorganization of tubulin and actin leading to modification of the cytoskeleton and changes in cell adhesion and migration.
      • Tamagnone L
      • Comoglio PM
      To move or not to move? Semaphorin signalling in cell migration.
      • Kruger RP
      • Aurandt J
      • Guan KL
      Semaphorins command cells to move.
      • He Z
      • Wang KC
      • Koprivica V
      • Ming G
      • Song HJ
      Knowing how to navigate: mechanisms of semaphorin signaling in the nervous system.
      Importantly, both NRP1 and NRP2 were also identified as vascular endothelial growth factor (VEGF)165 co-receptors and are required for vasculature development. Several reports have indicated that class 3 semaphorins and VEGF165 compete for NRP binding.
      • Nasarre P
      • Constantin B
      • Drabkin HA
      • Roche J
      Semaphorins and cancers: an up ‘dating’.
      • Chedotal A
      • Kerjan G
      • Moreau-Fauvarque C
      The brain within the tumor: new roles for axon guidance molecules in cancers.
      • Klagsbrun M
      • Eichmann A
      A role for axon guidance receptors and ligands in blood vessel development and tumor angiogenesis.
      • Neufeld G
      • Shraga-Heled N
      • Lange T
      • Guttmann-Raviv N
      • Herzog Y
      • Kessler O
      Semaphorins in cancer.
      Although semaphorin activity is likely greater than just a VEGF antagonist, at least part of the antitumor activity appears to stem from this function.
      Figure thumbnail gr1
      FIGURE 1Class 3 semaphorin signaling. Binding of class 3 semaphorins to neuropilin and plexin leads to cytoskeleton reorganization, collapse, cell repulsion, and changes in cell adhesion. By competing with VEGF165 for binding to neuropilin, they inhibit angiogenesis.

      SEMAPHORIN ANTITUMOR ACTIVITY IN LUNG CANCER

      Initial expression studies demonstrated that levels of SEMA3F mRNA were reduced in a majority of lung cancer cell lines. In patient samples, protein levels of SEMA3F were often reduced and its subcellular localization was shifted from the plasma membrane to the cytoplasm.
      • Brambilla E
      • Constantin B
      • Drabkin H
      • Roche J
      Semaphorin SEMA3F localization in malignant human lung and cell lines: a suggested role in cell adhesion and cell migration.
      In non–small-cell lung cancer, low SEMA3F levels were significantly correlated with advanced stage disease. In addition, the presence of an exclusive cytoplasmic localization was significantly correlated with high levels of VEGF165, increased tumor grade, and aggressive disease.
      In preneoplastic lesions, loss of SEMA3F protein staining was frequently observed.
      • Lantuejoul S
      • Constantin B
      • Drabkin H
      • Brambilla C
      • Roche J
      • Brambilla E
      Expression of VEGF, semaphorin SEMA3F, and their common receptors neuropilins NP1 and NP2 in preinvasive bronchial lesions, lung tumours, and cell lines.
      Similarly, VEGF165 immunostaining increased from low- to high-grade dysplasia and NRP levels increased between dysplastic and microinvasive lesions. Thus, deregulation of the VEGF165/SEMA3F/NRP pathway is a frequent and early event in lung cancer pathogenesis. Subsequent in vivo studies using immunodeficient mice or rats have confirmed the capacity of SEMA3F to reduce or inhibit tumor development.
      • Xiang R
      • Davalos AR
      • Hensel CH
      • Zhou XJ
      • Tse C
      • Naylor SL
      Semaphorin 3F gene from human 3p21.3 suppresses tumor formation in nude mice.
      • Bielenberg DR
      • Hida Y
      • Shimizu A
      • et al.
      Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype.
      • Kessler O
      • Shraga-Heled N
      • Lange T
      • et al.
      Semaphorin-3F is an inhibitor of tumor angiogenesis.
      • Kusy S
      • Nasarre P
      • Chan D
      • et al.
      Selective suppression of in vivo tumorigenicity by semaphorin SEMA3F in lung cancer cells.
      In these model systems, SEMA3F effects were both antiangiogenic
      • Bielenberg DR
      • Hida Y
      • Shimizu A
      • et al.
      Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype.
      • Kessler O
      • Shraga-Heled N
      • Lange T
      • et al.
      Semaphorin-3F is an inhibitor of tumor angiogenesis.
      and antimetastatic.
      • Bielenberg DR
      • Hida Y
      • Shimizu A
      • et al.
      Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype.
      In the report of Kusy et al.
      • Kusy S
      • Nasarre P
      • Chan D
      • et al.
      Selective suppression of in vivo tumorigenicity by semaphorin SEMA3F in lung cancer cells.
      using a lung cancer orthotopic model, the antitumor effects of SEMA3F were dramatic, with additional potential mechanisms involving reduced adhesion to extracellular matrix substrates and impaired signaling through the ERK pathway.
      SEMA3B also has potent antitumor activity, as demonstrated in nude mice where an ovarian adenocarcinoma cell line transfected with SEMA3B showed reduced tumorigenicity and cell proliferation.
      • Tse C
      • Xiang RH
      • Bracht T
      • Naylor SL
      Human semaphorin 3B (SEMA3B) located at chromosome 3p21.3 suppresses tumor formation in an adenocarcinoma cell line.
      These in vivo results were confirmed in cell culture by SEMA3B transfection into the non–small-cell lung cancer cell line, H1299, which resulted in a greater than 90% reduction of colony formation.
      • Tomizawa Y
      • Sekido Y
      • Kondo M
      • et al.
      Inhibition of lung cancer cell growth and induction of apoptosis after reexpression of 3p21.3 candidate tumor suppressor gene SEMA3B.
      Furthermore, in this cell line, SEMA3B overexpression induced apoptosis, whereas VEGF165 led to cell proliferation.
      • Castro-Rivera E
      • Ran S
      • Thorpe P
      • Minna JD
      Semaphorin 3B (SEMA3B) induces apoptosis in lung and breast cancer, whereas VEGF165 antagonizes this effect.
      In summary, both SEMA3F and SEMA3B exhibit tumor-suppressor activity in lung cancer and other tumor types. Also of interest is the reported correlation between low levels of collapsin response mediator protein 1 and increasing tumor grade, invasion, and metastasis.
      • Shih JY
      • Yang SC
      • Hong TM
      • et al.
      Collapsin response mediator protein-1 and the invasion and metastasis of cancer cells.
      Together with deregulation of VEGF165 and NRP receptors, it is apparent that the overall pathway(s) is affected in many, if not most, lung cancers. Potential therapeutic approaches include up-regulation of SEMA3F and SEMA3B expression by agents that target chromatin reorganization and DNA methylation.
      • Nasarre P
      • Constantin B
      • Drabkin HA
      • Roche J
      Semaphorins and cancers: an up ‘dating’.
      The semaphorin molecule itself may prove useful as a therapeutic agent.
      • Dhanabal M
      • Wu F
      • Alvarez E
      • et al.
      Recombinant semaphorin 6A-1 ectodomain inhibits in vivo growth factor and tumor cell line-induced angiogenesis.
      In addition, we suggest that a combined approach involving VEGF inhibition and up-regulation of SEMA3F/SEMA3B might be even more effective.

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