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Journal of Thoracic Oncology:
Pathway of the Month

Semaphorins in Lung Cancer

Clarhaut, Jonathan*; Roche, Joëlle PhD*; Drabkin, Harry A. MD†

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*IPBC, CNRS UMR, Université de Poitiers, Poitiers Cédex, France; and †University of Colorado Health Sciences and Cancer Centers, Aurora, Colorado.

Address for correspondence: Harry Drabkin, MD, University of Colorado Health Sciences Center, P.O. Box 6511, Aurora, CO 80045; email: harry.drabkin@uchsc.edu.

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.1 SEMA3B and SEMA3F are both encoded in 3p21.3,2–4 a region of frequent loss of heterozygosity in lung cancer,5 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.6–9 In this review, we focus on the function and signaling of semaphorins involved in lung cancer.

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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.10–12 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.6–9 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 1
Figure 1
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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.13 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.14 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.15–18 In these model systems, SEMA3F effects were both antiangiogenic16,17 and antimetastatic.16 In the report of Kusy et al.18 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.19 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.20 Furthermore, in this cell line, SEMA3B overexpression induced apoptosis, whereas VEGF165 led to cell proliferation.21

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.22 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.6

The semaphorin molecule itself may prove useful as a therapeutic agent.23 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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REFERENCES

1. Semaphorin Nomenclature Committee. Unified nomenclature for the semaphorins/collapsins. Cell 1999; 97:551–552.

2. Roche J, Boldog F, Robinson M, et al. Distinct 3p21.3 deletions in lung cancer and identification of a new human semaphorin. Oncogene 1996;12:1289–1297.

3. 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. Proc Natl Acad Sci USA 1996;93:4120–4125.

4. 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. Genomics 1996;32:39–48.

5. 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;60:6116–6133.

6. Nasarre P, Constantin B, Drabkin HA, Roche J. Semaphorins and cancers: an up 'dating'. Med Sci (Paris) 2006;21:641–647.

7. Chedotal A, Kerjan G, Moreau-Fauvarque C. The brain within the tumor: new roles for axon guidance molecules in cancers. Cell Death Differ 2006;12:1044–1056.

8. Klagsbrun M, Eichmann A. A role for axon guidance receptors and ligands in blood vessel development and tumor angiogenesis. Cytokine Growth Factor Rev 2006;16:535–548.

9. Neufeld G, Shraga-Heled N, Lange T, Guttmann-Raviv N, Herzog Y, Kessler O. Semaphorins in cancer. Front Biosci 2006;10:751–760.

10. Tamagnone L, Comoglio PM. To move or not to move? Semaphorin signalling in cell migration. EMBO Rep 2004;5:356–361.

11. Kruger RP, Aurandt J, Guan KL. Semaphorins command cells to move. Nat Rev Mol Cell Biol 2006;6:789–800.

12. He Z, Wang KC, Koprivica V, Ming G, Song HJ. Knowing how to navigate: mechanisms of semaphorin signaling in the nervous system. Sci STKE 2002; 119: RE1.

13. 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. Am J Pathol 2000;156:939–950.

14. 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. J Pathol 2003;200:336–347.

15. 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. Cancer Res 2002;62:2637–2643.

16. Bielenberg DR, Hida Y, Shimizu A, et al. Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. J Clin Invest 2004;114:1260–1271.

17. Kessler O, Shraga-Heled N, Lange T, et al. Semaphorin-3F is an inhibitor of tumor angiogenesis. Cancer Res 2004;64:1008–1015.

18. Kusy S, Nasarre P, Chan D, et al. Selective suppression of in vivo tumorigenicity by semaphorin SEMA3F in lung cancer cells. Neoplasia 2006;7:457–465.

19. 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. Cancer Res 2002;62:542–546.

20. 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. Proc Natl Acad Sci USA 2001;98:13954–13959.

21. Castro-Rivera E, Ran S, Thorpe P, Minna JD. Semaphorin 3B (SEMA3B) induces apoptosis in lung and breast cancer, whereas VEGF165 antagonizes this effect. Proc Natl Acad Sci USA 2004;101:11432–11437.

22. 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.

23. Dhanabal M, Wu F, Alvarez E, et al. Recombinant semaphorin 6A-1 ectodomain inhibits in vivo growth factor and tumor cell line-induced angiogenesis. Cancer Biol Ther 2006;4:659–668.

© 2006International Association for the Study of Lung Cancer

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