Neuropilins (NRPs) are receptors for class 3 Semaphorins and function as co-receptors for vascular endothelial growth factor isoforms, VEGF165 and VEGF145 and related molecules. NRPs are expressed in a variety of neural and non-neural tissues and are required for normal development. Interestingly, class 3 Semaphorins and VEGF compete for common NRP binding. As a consequence, Semaphorins and VEGF appear to be mutually antagonistic. In the lung, NRP levels increase during development and NRPs and Semaphorins are involved in lung branching, probably by altering cell morphology or by regulating cell motility and migration. During lung tumorigenesis, both NRP and VEGF expression increase on dysplastic lung epithelial cells; SEMA3F expression is reduced and SEMA3F protein is delocalized from the membrane to the cytoplasm. In lung cancers, SEMA3F staining correlates inversely with tumor stage with high SEMA3F associated with less aggressive tumors. Conversely, more aggressive tumors are associated with increased VEGF staining and a corresponding loss in membranous SEMA3F.
Neuropilin (NRP) 1 and 2 are transmembrane glycoproteins involved in neuronal cell guidance, axon growth and fasciculation.1 In addition to its role in the nervous system, NRP1 is expressed in the developing heart, vasculature, skeleton and lung. NRP2 has a similar expression profile. Neuropilins are receptors for two types of very different ligands: semaphorins2,3 and vascular endothelial growth factor, VEGF.4
Semaphorins are a large family of secreted and membrane associated molecules containing a characteristic 500 amino acid Sema domain. They have been classified into eight groups based on their overall similarity and structural features.5 Collapsin, now known as Sema3A, was originally identified on the basis of its chemorepellent activity. Secreted semaphorins from class 3 are the only semaphorins that bind neuropilins and have been implicated in axon steering, fasciculation, branching and synapse formation.6 While Sema3A only binds NRP1, Sema3C binds NRP1 and NRP2 equally whereas Sema3F has greater affinity for NRP2 than NRP1.7 This binding is essential for semaphorin function2,3,8and NRP2 is the functional receptor for Sema3F in the nervous system.9–12 Other molecules are necessary to transduce semaphorin signals which include plexins13 and collapse response mediator protein CRMP.14
VEGF, a 40-45 kDa homodimeric protein, regulates normal embryonic vasculogenesis, physiological angiogenesis and tumor angiogenesis. Originally defined as an endothelial cell (EC) mitogen and chemotactic factor, there is now growing evidence that VEGF stimulates non-EC cells.15–18 Five different isoforms of VEGF monomers consisting of 121, 145, 165, 186 and 206 amino acids produced by alternative splicing have been identified with VEGF121 and VEGF165 being the most abundant.
NRP1 was identified as a receptor for VEGF165 but not for VEGF121.4 NRP2 binds both VEGF165 and VEGF145.19 Importantly, the presence of NRP1 together with the high affinity VEGF receptor 2 (KDR/flk-1) result in greater tyrosine kinase activity. Further support for the role NRPs in cardiovascular development comes from studies utilizing transgenic and knock-out mice. Mice that overexpress NRP1 develop excess capillaries and blood vessels, dilatation of blood vessels and heart defects in addition to neurological abnormalities.20 When deleted for NRP1, mutant mice die during the second half of gestation. In addition to neurological defects, NRP1 −/− mice exhibit severe defects in the cardiovascular system reflecting either a requirement for Semaphorin signaling and/or the presence of NRP1 as a receptor for critical VEGF isoforms.8 Disruption of Sema3A also causes severe abnormalities in neural and non-neural tissues including hypertrophy of the right ventricle and dilatation of the right atrium.21 The discovery that Neuropilins were capable of binding two distinct ligands suggested that class 3 Semaphorins and VEGF might compete. A competitive interaction was documented between Sema3A and VEGF in endothelial cells.22,23
In addition to their role in the nervous system and in angiogenesis, Neuropilins and Semaphorins have been implicated in other developmental processes and in tumorigenesis. For the remainder of this discussion, we will focus on these molecules in the development of normal lung and lung cancer.
Neuropilin and Semaphorin in Normal Mice Lung Development
Fetal lung development involves coordinated cell proliferation, migration, branching morphogenesis and differentiation and normal development depends on reciprocal induction between epithelial and mesenchymal cells. Several growth factors are known to affect lung epithelial cell proliferation. For example, epidermal growth factor and fibroblast growth factors positively influence proliferation, whereas bone morphogenetic protein BMP-4 and TGFβ have negative effects.24–28 Many factors which affect branching morphogenesis are also becoming elucidated. Guidance molecules such as Semaphorins are likely candidates to affect these processes as both neuropilins and semaphorins are expressed in the lung.2,3,11,21,29,30 Moreover, rCRMP-2 which is an intra-cellular protein required for Sema3A signaling14 is expressed in the lung31 as it is also the case for CRMP-1.32
Only a few lung effects have been reported in mice overexpressing NRP1 or in mice with a NRP1 knock-out. When the lung was examined in NRP1 homozygous null (nrp1−/−) animals, it was found to be smaller and the number of branches in the left lung significantly lower than in wild-type (nrp1+/+) or heterozygous (nrp1+/-) animals.33 In contrast to nrp1−/− mice, manynrp2−/− mice survive into adulthood despite the existence of numerous neurological deficits, some of which are complementary to those observed previously in NRP1 mutants.34,35 However, no effects involving the lungs were reported for either the nrp2−/− mice or for Sema3A knock-outs.21,36,37
The absence of severe developmental effects in the lung may be the result of redundancy. Other data indicate that semaphorins and neuropilins are likely to be critically involved in lung development.33,38 Expression studies indicate that Sema3A is expressed at high levels mainly in the distal mesenchyme around the airway epithelium and this expression decreases with time. In epithelial cells, Sema3A is strongly expressed in intermediate bronchioles at E15.5. Expression of Sema3C was restricted predominantly to the lobar bronchus. These expression patterns overlapped or were adjacent to regions expressing NRP1 and NRP2. In contrast, SEMA3F expression was weak and diffuse in the distal epithelium and in the surrounding mesenchyme in early stages, but became confined to the terminal epithelium by E15.5. NRP1 levels rise dramatically during development along with CRMP-2 immunoreactivity in developing and adult alveolar epithelium.
Ito et al.33 treated lung explant culture with different semaphorins. A striking feature of early lung development is the budding and branching which is retained even in culture. Treatment of explant cultures with Sema3A resulted in fewer terminal buds. Co-treatment with a soluble form of NRP139 lacking the transmembrane and intracellular regions attenuated the Sema3A effects whereas sNRP1 alone had no activity. The reduction in terminal buds was not attributable to growth as no effects were detected with BrdU incorporation. In contrast, Sema3C and Sema3F stimulated branching morphogenesis in lung explants from fetal mice and these effects were blocked with sNRP1 or sNRP2, respectively.38 Cell proliferation was stimulated as shown by BrdU labeling. These data indicate that multiple semaphorins exert counterbalancing effects on branching morphogenesis, constituting a novel regulatory system in lung development. Dual effects of Semaphorins were first reported in the nervous system10,12,40 which, in at least some cases, are the result of different cGMP concentrations.41
How do Semaphorins/Neuropilins affect lung branching? One hypothesis from Kagoshima et al.38 is that Semaphorins could promote or inhibit airway branching by the alteration of cell morphology or by the regulation of cell motility and migration. Alterations of cell morphology were seen in COS cells transfected with Sema3A42 and in mammary adenocarcinoma cells transfected with SEMA3F (Nasarre et al., submitted). In the later case, transfected cells rounded up and detached. Cell motility and migration might also be involved as Sema3A inhibits endothelial cell motility22 and has been shown to regulate neural crest migration.43 Likewise, in C. elegans, Semaphorin-2a prevents ectopic cell contacts during epidermal morphogenesis.44 We also demonstrated that SEMA3F is localized in motile regions such as in leading edges or ruffling membranes of lamellipodia in HeLa cells.45
Neuropilins and Its Ligands in Human Lung Tumor
Following the cloning of SEMA3F, by our group and others, from a recurrent homozygous deletion region in small-cell lung cancer (SCLC)46–48 and SEMA3B48, we were intrigued by the possibility that neural guidance molecules such as semaphorins could be involved in lung tumorigenesis. This chromosomal region is well known for loss of heterozygosity (LOH) as an early event in lung tumors and was postulated to contain a tumor suppressor gene.49,50 More direct evidence for such an activity came from the transfection of P1 clones containing SEMA3F into a mouse tumor cell line51 and it was also shown that SEMA3F by itself suppresses tumor formation in nude mice.52 It is also notable that another 3p homozygous deletion region, identified in the SCLC cell line U2020 encodes a repulsive neural guidance molecule DUTT1 (Deleted in U Twenty-Twenty).53 DUTT1 is the probable human homologue of the Drosophila gene Roundabout (Robo)54 which is the receptor for the midline ligand, Slit.
Several reports in the literature have implicated semaphorins in cancers as survival factors with increased metastatic ability. SEMA3E was identified in human cancer to confer non-MDR (Multi Drug Resistance) resistance55 and was also overexpressed in metastatic human lung adenocarcinomas.56 Similarly, Sema3E expression has been correlated with the metastatic ability of certains tumors.57 SEMA4D (CD100) downregulation occurs in non-Hodgkin's B-cell lymphomas and has been postulated to regulate adhesiveness and metastatic potential.58 Therefore some semaphorins show overexpression in tumors whereas others are downregulated. This may reflect the bifunctional effects of semaphorins previously observed in the nervous system.
In normal lung, we studied SEMA3F expression using a specific affinity purified antibody.59 SEMA3F expression was found in epithelial cells. In large bronchi, there was strong membrane staining in addition to mild diffuse cytoplasmic staining.45 In bronchioles, SEMA3F was restricted to basal epithelial cells. Endothelial cells of the alveolar capillary bed did not express SEMA3F, whereas about 20% of vessels more than 100 mm diameter were positive for expression. In lung tumors, SEMA3F localization was predominantly cytoplasmic and the overall levels were reduced (Fig. 1). In resected NSCLC cancers (Non Small Cell Lung Cancer), low levels of SEMA3F correlated with higher stage (more aggressive) disease. In all lung cancer subtypes, an exclusive cytoplasmic localization of SEMA3F was associated with VEGF overexpression which suggested that SEMA3F could compete with VEGF for binding to cell surface NRP receptors.45 These studies have now been expanded to include 112 lung cancers and 50 preneoplasic lesions (Lantuejoul et al., submitted). In preneoplasic lesions, SEMA3F was low indicating that loss of SEMA3F protein, like the previous LOH studies would predict, is an early event in lung tumorigenicity. Recently, expression of CRMP-1, a mediator in the Semaphorin pathway, was found to be inversely correlated with the invasive capability of lung cancer cell lines.32 In normal lung, we found NRP1 and NRP2 expressed in bronchial basal cells (Lantuejoul et al., submitted). In preinvasive bronchial lesions NRP1 and NRP2 expression was significantly increased from hyperplastic mucosa to moderate dysplasia with a plateau reached in severe dysplasia (Fig. 1). Increased neuropilin staining was also observed in conjunction with increased VEGF.
Interestingly, we observed using a wound assay of HeLa cells that cells at the border of the wound had increased staining for NRP1 but NRP1 was translocated to the cytoplasm (Fig. 2). Since cells at the wound border are apparently stimulated to migrate, up-regulation of NRP1 and translocation to the cytoplasm would be expected to facilitate this process (Lantuejoul et al., submitted). NRP1 has been previously implicated in tumor progression through its effects on angiogenesis and NRP1 overexpression likely represents a biomarker for tumor aggressiveness. In prostate carcinoma AT2.1 cells, overexpression of NRP1 resulted in increased basal cell motility and VEGF165 binding.60 Furthermore, the tumors were enlarged in vivo and showed increased microvessel density, proliferation of endothelial cells, dilated blood vessels and, notably, less tumor cell apoptosis.60 The expression of NRP1 in Neuropilin-deficient breast carcinoma cells protects them from apoptosis.61 NRP1 expression has also been correlated with an advanced stage of prostatic cancer and malignant behavior in astrocytomas.62,63 Likewise, NRP1 was higher in rat estrogen-induced pituitary tumors and promoted angiogenesis.64 In addition, experimentally overexpressed soluble NRP1 (sNRP1), a naturally occurring antagonist, leads to tumors which are apoptotic, hemorrhagic and full of disrupted blood vessels.65
VEGF is expressed in normal lung by bronchial basal cells as well as hyperplastic type II pneumocytes in addition to endothelial cells. Expression includes a frequent reinforcement at the membrane. We found that VEGF increased significantly with the histological grades of preneoplasic lesions and culminated in corresponding invasive carcinoma in parallel to neuropilins (Fig. 1). Lung tumors stained positively for VEGF with more intense staining at the periphery of tumor lobules than inside. VEGF may stimulate an autocrine signaling pathway, independent of angiogenesis, to maintain cell survival as it was proposed for NRP1 expressing breast carcinoma cell lines.61 Surprisingly, we also found isolated clusters of tumors cells in lung tumors which stained strongly for SEMA3F, Neuropilins and VEGF (Fig. 3). While as yet unproven, this raises the possibility that Semaphorin expression may be dynamic as has been reported for β-catenin and E-cadherin in colon tumors66 and in breast cancers undergoing migration in vitro.67 However, overexpression of SEMA3B in lung carcinoma cell lines induces apoptosis68 and Semaphorins were also described as death inducers in sensory neurons69 and neural progenitors.23 Therefore, extra SEMA3F would rather lead to elimination of transformed cells but there is a balance between SEMA3F and VEGF and it is hard to predict on which side, proliferation or apoptosis, cells will go.
A model for these various interactions is shown in Figure 4. Normal stationary cells in the lung express Neuropilins and a substantial amount of SEMA3F. During the process of tumor development, VEGF and Neuropilin expression increase while SEMA3F binding to the surface of epithelial cells declines. Further downregulation of SEMA3F occurs at the transcriptional level. It is possible that hypoxia may regulate components of the system other than VEGF but this has not been reported. Not only does the reduction in SEMA3F levels facilitate growth or survival activities of VEGF on primary tumors, which appears to occur even in the absence of VEGFR2 (Vascular endothelial growth factor Receptor 2/ KDR/ Flk-1), but increased VEGF levels compete for Semaphorin binding and overcome its inhibitory actions. With this scenario, we would anticipate that semaphorin replacement combined with anti-VEGF therapies should be additive or even synergistic in the treatment of established tumors or preneoplastic lesions.
This work was supported by CNRS, ARC and Ligue Nationale Contre le Cancer for JR, by the University of Colorado Lung Cancer SPORE CA5187-07 for HD and by INSERM, Ligure Nationale Contre le Cancer and PHRC 1999 for EB.
- Fujisawa H, Kitsukawa T. Receptors for collapsin/Semaphorins. Curr Opin Neurobiol. 1998;8:587–592. [PubMed: 9811625]
- He Z, Tessier-Lavigne M. Neuropilin is a receptor for the axonal chemorepellent Semaphorin III. Cell. 1997;90:739–751. [PubMed: 9288753]
- Kolodkin A, Levengood D, Rowe E. et al. Neuropilin is a Semaphorin III receptor. Cell. 1997;90:753–762. [PubMed: 9288754]
- Soker S, Takashima S, Miao H. et al. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell. 1998;92:735–745. [PubMed: 9529250]
- Unified nomenclature for the Semaphorins/collapsinsSemaphorin Nomenclature Committee.Cell 199997551–2. [PubMed: 10367884]
- Raper J. Semaphorins and their receptors in vertebrates and invertebrates. Curr Opin Neurobiol. 2000;10:88–94. [PubMed: 10679438]
- Chen H, Chédotal A, He Z. et al. Neuropilin-2, a novel member of the Neuropilin family, is a high affinity receptor for the Semaphorins Sema E and Sema IV but not Sema III. Neuron. 1997;19:547–559. [PubMed: 9331348]
- Kitsukawa T, Shimizu M, Sanbo M. et al. Neuropilin-Semaphorin III/D-mediated chemorepulsive signals play a crucial role in peripheral nerve projection in mice. Neuron. 1997;19:995–1005. [PubMed: 9390514]
- Chedotal A, Del Rio JA, Ruiz M. et al. Semaphorins III and IV repel hippocampal axons via two distinct receptors. Development. 1998;125:4313–4323. [PubMed: 9753685]
- Chen H, He Z, Tessier-Lavigne M. Axon guidance mechanisms: Semaphorins as simultaneous repellents and anti-repellents. Nat Neurosci. 1998;1:436–439. [PubMed: 10196539]
- Giger RJ, Urquhart ER, Gillespie SK. et al. Neuropilin-2 is a receptor for Semaphorin IV: insight into the structural basis of receptor function and specificity. Neuron. 1998;21:1079–1092. [PubMed: 9856463]
- Takahashi T, Nakamura F, Jin Z. et al. Semaphorins A and E act as antagonists of Neuropilin-1 and agonists of Neuropilin-2 receptors. Nat Neurosci. 1998;1:487–493. [PubMed: 10196546]
- Tamagnone L, Artigiani S, Chen H. et al. Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored Semaphorins in vertebrates. Cell. 1999;99:71–80. [PubMed: 10520995]
- Goshima Y, Nakamura F, Strittmatter P. et al. Collapsin-induced growth cone collapse mediated by an intracellular protein related to UNC-33. Nature. 1995;376:509–514. [PubMed: 7637782]
- Deckers MM, Karperien M, van der Bent C. et al. Expression of vascular endothelial growth factors and their receptors during osteoblast differentiation. Endocrinology. 2000;141:1667–74. [PubMed: 10803575]
- Midy V, Plouet J. Vasculotropin/vascular endothelial growth factor induces differentiation in cultured osteoblasts. Biochem Biophys Res Commun. 1994;199:380–6. [PubMed: 8123039]
- Sondell M, Lundborg G, Kanje M. Vascular endothelial growth factor stimulates Schwann cell invasion and neovascularization of acellular nerve grafts. Brain Res. 1999;846:219–28. [PubMed: 10556639]
- Byzova TV, Goldman CK, Pampori N. et al. A mechanism for modulation of cellular responses to VEGF: activation of the integrins. Mol Cell. 2000;6:851–60. [PubMed: 11090623]
- Gluzman-Poltorak Z, Cohen T, Herzog Y. et al. Neuropilin-2 and Neuropilin-1 are receptors for VEGF165 and PLGF- 2, but only Neuropilin-2 functions as a receptor for VEGF145. J Biol Chem. 2000;275:18040–18045. [PubMed: 10748121]
- Kitsukawa T, Shimono A, Kawakami A. et al. Overexpression of a membrane protein, Neuropilin, in chimeric mice causes anomalies in the cardiovascular system, nervous system and limbs. Development. 1995;121:4309–18. [PubMed: 8575331]
- Behar O, Golden JA, Mashimo H. et al. Semaphorin III is needed for normal patterning and growth of nerves, bones and heart. Nature. 1996;383:525–528. [PubMed: 8849723]
- Bagnard D, Vaillant C, Khuth ST. et al. Semaphorin 3A-vascular endothelial growth factor-165 balance mediates migration and apoptosis of neural progenitor cells by the recruitment of shared receptor. J Neurosci. 2001;21:3332–41. [PubMed: 11331362]
- Hogan BL, Yingling JM. Epithelial/mesenchymal interactions and branching morphogenesis of the lung. Curr Opin Genet Dev. 1998;8:481–6. [PubMed: 9729726]
- Metzger RJ, Krasnow MA. Genetic control of branching morphogenesis. Science. 1999;284:1635–9. [PubMed: 10383344]
- Cardoso WV. Lung morphogenesis revisited: old facts, current ideas. Dev Dyn. 2000;219:121–30. [PubMed: 11002333]
- Warburton D, Schwarz M, Tefft D. et al. The molecular basis of lung morphogenesis. Mech Dev. 2000;92:55–81. [PubMed: 10704888]
- Bellusci S, de Maximy A, Thiéry JP. Contrôle moléculaire de la morphogénèse pulmonaire chez la souris. Med Sci. 1999;15:815–822.
- Luo Y, Raible D, Raper A. Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell. 1993;75:217–227. [PubMed: 8402908]
- Takahashi T, Nakamura F, Stittmatter S. Neuronal and non-neuronal collapsin-1 binding sites in developing chick are distinct from other Semaphorin binding sites. J Neurosci. 1997;17:9183–9193. [PubMed: 9364065]
- Wang L, Strittmatter S. A family of rat CRMP genes is differentially expressed in the nervous system. J Neurosci. 1996;16:6197–6207. [PubMed: 8815901]
- Shih JY, Yang SC, Hong TM. et al. Collapsin response mediator protein-1 and the invasion and metastasis of cancer cells. J Natl Cancer Inst. 2001;93:1392–1400. [PubMed: 11562390]
- Ito T, Kagoshima M, Sasaki Y. et al. Repulsive axon guidance molecule Sema3A inhibits branching morphogenesis of fetal mouse lung. Mech Dev. 2000;97:35–45. [PubMed: 11025205]
- Giger RJ, Cloutier JF, Sahay A. et al. Neuropilin-2 is required in vivo for selective axon guidance responses to secreted Semaphorins. Neuron. 2000;25:29–41. [PubMed: 10707970]
- Chen H, Bagri A, Zupicich JA. et al. Neuropilin-2 regulates the development of selective cranial and sensory nerves and hippocampal mossy fiber projections. Neuron. 2000;25:43–56. [PubMed: 10707971]
- Taniguchi M, Yuasa S, Fujisawa H. et al. Disruption of Semaphorin III/D gene causes severe abnormality in peripheral nerve projection. Neuron. 1997;19:519–530. [PubMed: 9331345]
- White FA, Behar O. The development and subsequent elimination of aberrant peripheral axon projections in Semaphorin3A null mutant mice. Dev Biol. 2000;225:79–86. [PubMed: 10964465]
- Kagoshima M, Ito T. Diverse gene expression and function of Semaphorins in developing lung: positive and negative regulatory roles of Semaphorins in lung branching morphogenesis. Genes Cells. 2001;6:559–71. [PubMed: 11442635]
- Goshima Y, Hori H, Sasaki Y. et al. Growth cone Neuropilin-1 mediates collapsin-1/Sema III facilitation of antero- and retrograde axoplasmic transport. J Neurobiol. 1999;39:579–89. [PubMed: 10380079]
- Bagnard D, Lohrum M, Uziel D. et al. Semaphorins act as attractive and repulsive guidance signals during the development of cortical projections. Development. 1998;125:5043–5053. [PubMed: 9811588]
- Song H, Ming G, He Z. et al. Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science. 1998;281:1515–1518. [PubMed: 9727979]
- Takahashi T, Fournier A, Nakamura F. et al. Plexin-Neuropilin-1 complexes form functional Semaphorin-3A receptors. Cell. 1999;99:59–69. [PubMed: 10520994]
- Eickholt B, Mackenzie S, Graham A. et al. Evidence for collapsin-1 functioning in the control of neural crest migration in both trunk and hindbrain regions. Development. 1999;126:2181–2189. [PubMed: 10207143]
- Roy PJ, Zheng H, Warren CE. et al. mab-20 encodes Semaphorin-2a and is required to prevent ectopic cell contacts during epidermal morphogenesis in Caenorhabditis elegans. Development. 2000;127:755–767. [PubMed: 10648234]
- Roche J, Boldog F, Robinson M. et al. Distinct 3p21.3 deletions in lung cancer, analysis of deleted genes and identification of a new human Semaphorin. Oncogene. 1996;12:1289–1297. [PubMed: 8649831]
- Xiang R, Hensel C, Garcia D. et al. Isolation of the human Semaphorin III/F gene (SEMA3F) at chromosome 3p21, a region deleted in lung cancer. Genomics. 1996;32:39–48. [PubMed: 8786119]
- Kok K, Naylor S, Buys C. Deletions of the short arm of chromosome 3 in solid tumors and the search for suppressor genes. Adv Cancer Res. 1997;71:27–92. [PubMed: 9111863]
- 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. Cancer Res. 2000;60:6116–33. [PubMed: 11085536]
- Todd M, Xiang R, Garcia D. et al. An 80 Kb P1 clone from chromosome 3p21.3 suppresses tumor growth in vivo. Oncogene. 1996;13:2387–2396. [PubMed: 8957080]
- Xiang R, Xhou X, Tse C. Expression of human Semaphorin 3F in a human ovarian cancer cell line (Hey) suppresses tumor formation in nude mice and blocks program cell death caused by adriamycin or taxol. 1st Proceedings of the America Association for Cancer Research; San Francisco. 2000. Abstract 5216.
- Sundaresan V, Roberts I, Bateman A. et al. The DUTT1 Gene, a Novel NCAM Family Member Is Expressed in Developing Murine Neural Tissues and Has an Unusually Broad Pattern of Expression. Mol Cell Neurosci. 1998;11:29–35. [PubMed: 9608531]
- Kidd T, Brose K, Mitchell KJ. et al. Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors. Cell. 1998;92:205–15. [PubMed: 9458045]
- Martin-Satue M, Blanco J. Identification of Semaphorin E gene expression in metastatic human lung adenocarcinoma cells by mRNA differential display. J Surg Oncol. 1999;72:18–23. [PubMed: 10477871]
- Christensen CR, Klingelhofer J, Tarabykina S. et al. Transcription of a novel mouse Semaphorin gene, M-semaH, correlates with the metastatic ability of mouse tumor cell lines. Cancer Res. 1998;58:1238–1244. [PubMed: 9515811]
- Hirsch E, Hu L -J, Prigent A. et al. Distribution of Semaphorin IV in adult human brain. Brain Res. 1999;823:67–79. [PubMed: 10095013]
- Miao HQ, Lee P, Lin H. et al. Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression. FASEB J. 2000;14:2532–9. [PubMed: 11099472]
- Bachelder RE, Crago A, Chung J. et al. Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells. Cancer Res. 2001;61:5736–40. [PubMed: 11479209]
- Latil A, Bieche I, Pesche S. et al. VEGF overexpression in clinically localized prostate tumors and Neuropilin-1 overexpression in metastatic forms. Int J Cancer. 2000;89:167–71. [PubMed: 10754495]
- Ding H, Wu X, Roncari L. et al. Expression and regulation of Neuropilin-1 in human astrocytomas. Int J Cancer. 2000;88:584–92. [PubMed: 11058875]
- Banerjee SK, Zoubine MN, Tran TM. et al. Overexpression of vascular endothelial growth factor164 and its co- receptor Neuropilin-1 in estrogen-induced rat pituitary tumors and GH3 rat pituitary tumor cells. Int J Oncol. 2000;16:253–60. [PubMed: 10639567]
- Brabletz T, Jung A, Hermann K. et al. Nuclear overexpression of the oncoprotein beta-catenin in colorectal cancer is localized predominantly at the invasion front. Pathol Res Pract. 1998;194:701–4. [PubMed: 9820866]
- Graff JR, Gabrielson E, Fujii H. et al. Methylation patterns of the E-cadherin 5' CpG island are unstable and reflect the dynamic, heterogeneous loss of E-cadherin expression during metastatic progression. J Biol Chem. 2000;275:2727–32. [PubMed: 10644736]
- Gagliardini V, Fankhauser C. Semaphorin III Can Induce Death in Sensory Neurons. Mol Cell Neurosci. 1999;14:301–316. [PubMed: 10588386]
Joëlle Roche, Harry Drabkin, and Elisabeth Brambilla.
Landes Bioscience, Austin (TX)
Roche J, Drabkin H, Brambilla E. Neuropilin and Its Ligands in Normal Lung and Cancer. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.