Gliomas are the most common tumor in the central nervous system. High-grade glioblastomas are characterized by their high invasiveness and resistance to radiotherapy, leading to high recurrence rate and short median survival despite radical surgical resection. Characterizations of gliomas at molecular level have revealed aberrations of various growth factor receptors, receptor tyrosine kinases, and tumor suppressor genes that lead to deregulation of multiple signaling pathways, thereby contributing to abnormal proliferation, invasion, and resistance to apoptosis in cancer cells. Recently, accumulating evidence points to the emerging role of axon guidance molecules in glioma progression. Notably, many signaling events harnessed by guidance molecules to regulate cell migration and axon navigation during development are also found to be involved in the modulation of deregulated pathways in gliomas. This paper focused on the signalings triggered by the guidance molecule semaphorins and their receptors plexins and neuropilins, and how their crosstalk with oncogenic pathways in gliomas might modulate cancer progression. The emerging role of semaphorins and plexins as tumor suppressors or oncogenes is also discussed. 1. Introduction Gliomas are the most common tumor in the central nervous system, with an incidence rate of 5 to 10 per 100,000 for the malignant form [1]. Based on their histological characteristics and expression of lineage markers, gliomas can be classified into astrocytoma, oligodendroglioma, and ependymoma [2]. Astrocytomas account for 60% of all primary brain tumors and the World Health Organization (WHO) classification system grades them on a scale of I to IV according to their increasing degree of malignancy [3]. Among them, Grade IV is one of the most highly invasive types of tumor [4], characterized by microvascular proliferation. Its aggressive infiltrative growth leads to an extremely high recurrence rate within a short period of time even after radical surgical resection. Worse still, many glioblastomas are found to be resistant to chemo- or radiotherapy due to DNA repair by the protein O6-methylguanine-methyltransferase (MGMT) and impaired apoptotic pathways. Median survival after initial diagnosis is therefore currently only around 12 to 18 months [5]. This apparently calls for a more thorough understanding of the pathoetiology at both cellular and molecular level to provide insight into the devise of novel and effective therapeutic treatments. This paper revisits the biological features of various genetic pathways deregulated in
References
[1]
J. M. Legler, L. A. Gloeckler Ries, M. A. Smith et al., “Brain and other central nervous system cancers: recent trends in incidence and mortality,” Journal of the National Cancer Institute, vol. 91, no. 16, pp. 1382–1390, 1999.
[2]
P. Kleihues and W. K. Cavenee, Pathology and Genetics of Tumors of the Nervous System, International Agency for Research on Cancer, Lyon, France, 2000.
[3]
D. N. Louis, H. Ohgaki, O. D. Wiestler et al., “The 2007 WHO classification of tumours of the central nervous system,” Acta Neuropathologica, vol. 114, no. 2, pp. 97–109, 2007.
[4]
E. A. Maher, F. B. Furnari, R. M. Bachoo et al., “Malignant glioma: Genetics and biology of a grave matter,” Genes and Development, vol. 15, no. 11, pp. 1311–1333, 2001.
[5]
H. Ohgaki and P. Kleihues, “Epidemiology and etiology of gliomas,” Acta Neuropathologica, vol. 109, no. 1, pp. 93–108, 2005.
[6]
P. C. Burger, B. W. Scheithauer, and W. Paulus, “Pilocytic astrocytoma,” in Pathology and Genetics of Tumours of the Nervous System, P. Kleihues and W. K. Cavenee, Eds., pp. 45–51, International Agency for Research on Cancer, Lyon, France, 2000.
[7]
P. Kleihues and H. Ohgaki, “Primary and secondary glioblastomas: from concept to clinical diagnosis,” Neuro-Oncology, vol. 1, no. 1, pp. 44–51, 1999.
[8]
H. Ohgaki and P. Kleihues, “Genetic pathways to primary and secondary glioblastoma,” American Journal of Pathology, vol. 170, no. 5, pp. 1445–1453, 2007.
[9]
M. Mizoguchi, R. A. Betensky, T. T. Batchelor, D. C. Bernay, D. N. Louis, and C. L. Nutt, “Activation of STAT3, MAPK, and AKT in malignant astrocytic gliomas: Correlation with EGFR status, tumor grade, and survival,” Journal of Neuropathology and Experimental Neurology, vol. 65, no. 12, pp. 1181–1188, 2006.
[10]
A. J. Wong, S. H. Bigner, D. D. Bigner, K. W. Kinzler, S. R. Hamilton, and B. Vogelstein, “Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification,” Proceedings of the National Academy of Sciences of the United States of America, vol. 84, no. 19, pp. 6899–6903, 1987.
[11]
C. J. Wikstrand, R. E. McLendon, A. H. Friedman, and D. D. Bigner, “Cell surface localization and density of the tumor-associated variant of the epidermal growth factor receptor, EGFRvIII,” Cancer Research, vol. 57, no. 18, pp. 4130–4140, 1997.
[12]
A. J. Ekstrand, N. Longo, M. L. Hamid et al., “Functional characterization of an EGF receptor with a truncated extracellular domain expressed in glioblastomas with EGFR gene amplification,” Oncogene, vol. 9, no. 8, pp. 2313–2320, 1994.
[13]
Y. Narita, M. Nagane, K. Mishima, H. J. Su Huang, F. B. Furnari, and W. K. Cavenee, “Mutant epidermal growth factor receptor signaling down-regulates p27 through activation of the phosphatidylinositol 3-kinase/Akt pathway in glioblastomas,” Cancer Research, vol. 62, no. 22, pp. 6764–6769, 2002.
[14]
J. A. Diehl, M. Cheng, M. F. Roussel, and C. J. Sherr, “Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization,” Genes and Development, vol. 12, no. 22, pp. 3499–3511, 1998.
[15]
G. Lammering, K. Valerie, P. S. Lin, T. H. Hewit, and R. K. Schmidt-Ullrich, “Radiation-induced activation of a common variant of EGFR confers enhanced radioresistance,” Radiotherapy and Oncology, vol. 72, no. 3, pp. 267–273, 2004.
[16]
H. C. E. Welch, W. J. Coadwell, L. R. Stephens, and P. T. Hawkins, “Phosphoinositide 3-kinase-dependent activation of Rac,” FEBS Letters, vol. 546, no. 1, pp. 93–97, 2003.
[17]
P. A. Forsyth, H. Wong, T. D. Laing et al., “Gelatinase-A (MMP-2), gelatinase-B (MMP-9) and membrane type matrix metalloproteinase-1 (MT1-MMP) are involved in different aspects of the pathophysiology of malignant gliomas,” British Journal of Cancer, vol. 79, no. 11-12, pp. 1828–1835, 1999.
[18]
A. Guha, M. M. Feldkamp, N. Lau, G. Boss, and A. Pawson, “Proliferation of human malignant astrocytomas is dependent on Ras activation,” Oncogene, vol. 15, no. 23, pp. 2755–2765, 1997.
[19]
G. S. Kapoor and D. M. O'Rourke, “Receptor tyrosine kinase signaling in gliomagenesis: pathobiology and therapeutic approaches,” Cancer Biology and Therapy, vol. 2, no. 4, pp. 330–342, 2003.
[20]
M. M. Feldkamp, N. Lau, and A. Guha, “The farnesyltransferase inhibitor L-744,832 inhibits the growth of astrocytomas through a combination of antiproliferative, antiangiogenic, and proapoptotic activities,” Annals of the New York Academy of Sciences, vol. 886, pp. 257–260, 1999.
[21]
L. Goldberg and Y. Kloog, “A Ras inhibitor tilts the balance between Rac and Rho and blocks phosphatidylinositol 3-kinase-dependent glioblastoma cell migration,” Cancer Research, vol. 66, no. 24, pp. 11709–11717, 2006.
[22]
S. Gupta, A. R. Ramjaun, P. Haiko et al., “Binding of ras to phosphoinositide 3-Kinase p110α is required for ras-driven tumorigenesis in mice,” Cell, vol. 129, no. 5, pp. 957–968, 2007.
[23]
S. Wennstr？m and J. Downward, “Role of phosphoinositide 3-kinase in activation of Ras and mitogen-activated protein kinase by epidermal growth factor,” Molecular and Cellular Biology, vol. 19, no. 6, pp. 4279–4288, 1999.
[24]
P. A. Steck, M. A. Pershouse, S. A. Jasser et al., “Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers,” Nature Genetics, vol. 15, no. 4, pp. 356–362, 1997.
[25]
J. Li, C. Yen, D. Liaw et al., “PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer,” Science, vol. 275, no. 5308, pp. 1943–1947, 1997.
[26]
T. Maehama and J. E. Dixon, “The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate,” The Journal of Biological Chemistry, vol. 273, no. 22, pp. 13375–13378, 1998.
[27]
M. Natarajan, T. P. Hecker, and C. L. Gladson, “FAK signaling in anaplastic astrocytoma and glioblastoma tumors,” Cancer Journal, vol. 9, no. 2, pp. 126–133, 2003.
[28]
J. Gu, M. Tamura, and K. M. Yamada, “Tumor suppressor PTEN inhibits integrin- and growth factor-mediated mitogen-activated protein (MAP) kinase signaling pathways,” Journal of Cell Biology, vol. 143, no. 5, pp. 1375–1383, 1998.
[29]
M. Tamura, J. Gu, T. Takino, and K. M. Yamada, “Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: Differential involvement of focal adhesion kinase and p130Cas,” Cancer Research, vol. 59, no. 2, pp. 442–449, 1999.
[30]
J. Gu, M. Tamura, R. Pankov et al., “Shc and FAK differentially regulate cell motility and directionality modulated by PTEN,” Journal of Cell Biology, vol. 146, no. 2, pp. 389–403, 1999.
[31]
F. B. Furnari, H. Lin, H. J. S. Huang, and W. K. Cavenee, “Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 23, pp. 12479–12484, 1997.
[32]
P. A. Steck, M. A. Pershouse, S. A. Jasser et al., “Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers,” Nature Genetics, vol. 15, no. 4, pp. 356–362, 1997.
[33]
D. Haas-Kogan, N. Shalev, M. Wong, G. Mills, G. Yount, and D. Stokoe, “Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC,” Current Biology, vol. 8, no. 21, pp. 1195–1198, 1998.
[34]
Q. Shi, A. B. Hjelmeland, S. T. Keir et al., “A novel low-molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth,” Molecular Carcinogenesis, vol. 46, no. 6, pp. 488–496, 2007.
[35]
D. Zagzag, M. Nomura, D. R. Friedlander et al., “Geldanamycin inhibits migration of glioma cells in vitro: A potential role for hypoxia-inducible factor (HIF-1α) in glioma cell invasion,” Journal of Cellular Physiology, vol. 196, no. 2, pp. 394–402, 2003.
[36]
D. Zagzag, D. R. Friedlander, B. Margolis et al., “Molecular events implicated in brain tumor angiogenesis and invasion,” Pediatric Neurosurgery, vol. 33, no. 1, pp. 49–55, 2000.
[37]
M. Nakada, J. A. Niska, N. L. Tran, W. S. McDonough, and M. E. Berens, “EphB2/R-ras signaling regulates glioma cell adhesion, growth, and invasion,” American Journal of Pathology, vol. 167, no. 2, pp. 565–576, 2005.
[38]
H. L. Bouterfa, V. Sattelmeyer, S. Czub, D. Vordermark, K. Roosen, and J. C. Tonn, “Inhibition of Ras farnesylation by lovastatin leads to downregulation of proliferation and migration in primary cultured human glioblastoma cells,” Anticancer Research, vol. 20, no. 4, pp. 2761–2771, 2000.
[39]
N. Dyson, “The regulation of E2F by pRB-family proteins,” Genes and Development, vol. 12, no. 15, pp. 2245–2262, 1998.
[40]
K. Ueki, Y. Ono, J. W. Henson, J. T. Efird, A. Von Deimling, and D. N. Louis, “CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated,” Cancer Research, vol. 56, no. 1, pp. 150–153, 1996.
[41]
K. L. Burns, K. Ueki, S. L. Jhung, J. Koh, and D. N. Louis, “Molecular genetic correlates of p16, cdk4, and pRb immunohistochemistry in glioblastomas,” Journal of Neuropathology and Experimental Neurology, vol. 57, no. 2, pp. 122–130, 1998.
[42]
A. C. Bellail, S. B. Hunter, D. J. Brat, C. Tan, and E. G. Van Meir, “Microregional extracellular matrix heterogeneity in brain modulates glioma cell invasion,” International Journal of Biochemistry and Cell Biology, vol. 36, no. 6, pp. 1046–1069, 2004.
[43]
A. A. Jarjour, M. Durko, T. L. Luk, et al., “Autocrine netrin function inhibits glioma cell motility and promotes focal adhesion formation,” PLoS ONE, vol. 6, no. 9, Article ID e25408, 2011.
[44]
S. Mertsch, N. Schmitz, A. Jeibmann, J. G. Geng, W. Paulus, and V. Senner, “Slit2 involvement in glioma cell migration is mediated by Robo1 receptor,” Journal of Neuro-Oncology, vol. 87, no. 1, pp. 1–7, 2008.
[45]
G. Neufeld, N. Shraga-Heled, T. Lange, N. Guttmann-Raviv, Y. Herzog, and O. Kessler, “Semaphorins in cancer,” Frontiers in Bioscience, vol. 10, pp. 751–760, 2005.
[46]
M. Reyes-Mugica, K. Rieger-Christ, H. Ohgaki et al., “Loss of DCC expression and glioma progression,” Cancer Research, vol. 57, no. 3, pp. 382–386, 1997.
[47]
J. J. Yiin, B. Hu, M. J. Jarzynka et al., “Slit2 inhibits glioma cell invasion in the brain by suppression of Cdc42 activity,” Neuro-Oncology, vol. 11, no. 6, pp. 779–789, 2009.
[48]
A. Dallol, D. Krex, L. Hesson, C. Eng, E. R. Maher, and F. Latif, “Frequent epigenetic inactivation of the SLIT2 gene in gliomas,” Oncogene, vol. 22, no. 29, pp. 4611–4616, 2003.
[49]
R. G. Correa, R. M. Sasahara, M. H. Bengtson et al., “Human semaphorin 6B [(HSA)SEMA6B], a novel human class 6 semaphorin gene: Alternative splicing and all-trans-retinoic acid-dependent downregulation in glioblastoma cell lines,” Genomics, vol. 73, no. 3, pp. 343–348, 2001.
[50]
J. N. Rich, C. Hans, B. Jones et al., “Gene expression profiling and genetic markers in glioblastoma survival,” Cancer Research, vol. 65, no. 10, pp. 4051–4058, 2005.
[51]
X. Li and A. Y. W. Lee, “Semaphorin 5A and plexin-B3 inhibit human glioma cell motility through RhoGDIα-mediated inactivation of Rac1 GTPase,” The Journal of Biological Chemistry, vol. 285, no. 42, pp. 32436–32445, 2010.
[52]
X. Li, J. W. S. Law, and A. Y. W. Lee, “Semaphorin 5A and plexin-B3 regulate human glioma cell motility and morphology through Rac1 and the actin cytoskeleton,” Oncogene, vol. 31, no. 5, pp. 595–610, 2011.
[53]
L. Tamagnone, S. Artigiani, H. Chen et al., “Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates,” Cell, vol. 99, no. 1, pp. 71–80, 1999.
[54]
J. C. Adams and J. Lawler, “The thrombospondins,” Cold Spring Harbor Perspectives in Biology, vol. 3, no. 10, Article ID a009712, 2011.
[55]
V. Castellani, A. Chédotal, M. Schachner, C. Faivre-Sarrailh, and G. Rougon, “Analysis of the L1-deficient mouse phenotype reveals cross-talk between Sema3A and L1 signaling pathways in axonal guidance,” Neuron, vol. 27, no. 2, pp. 237–249, 2000.
[56]
T. Toyofuku, H. Zhang, A. Kumanogoh et al., “Dual roles of Sema6D in cardiac morphogenesis through region-specific association of its receptor, Plexin-A1, with off-track and vascular endothelial growth factor receptor type 2,” Genes and Development, vol. 18, no. 4, pp. 435–447, 2004.
[57]
J. M. Swiercz, R. Kuner, and S. Offermanns, “Plexin-B1/RhoGEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2,” Journal of Cell Biology, vol. 165, no. 6, pp. 869–880, 2004.
[58]
A. Kumanogoh, C. Watanabe, I. Lee et al., “Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: a novel mechanism for regulating B cell signaling,” Immunity, vol. 13, no. 5, pp. 621–631, 2000.
[59]
A. Kumanogoh, S. Marukawa, K. Suzuki et al., “Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2,” Nature, vol. 419, no. 6907, pp. 629–633, 2002.
[60]
R. H. Xiang, C. H. Hensel, D. K. Garcia et al., “Isolation of the human semaphorin III/F Gene (SEM A3F) at chromosome 3p21, a region deleted in lung cancer,” Genomics, vol. 32, no. 1, pp. 39–48, 1996.
[61]
Y. Sekido, S. Bader, F. Latif et al., “Human semaphorins A(V) and IV reside in the 3p21.3 small cell lung cancer deletion region and demonstrate distinct expression patterns,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 9, pp. 4120–4125, 1996.
[62]
J. Roche, F. Boldog, M. Robinson et al., “Distinct 3p21.3 deletions in lung cancer and identification of a new human semaphorin,” Oncogene, vol. 12, no. 6, pp. 1289–1297, 1996.
[63]
Y. Tomizawa, Y. Sekido, M. Kondo et al., “Inhibition of lung cancer cell growth and induction of apoptosis after reexpression of 3p21.3 candidate tumor suppressor gene SEMA3B,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 24, pp. 13954–13959, 2001.
[64]
E. Castro-Rivera, S. Ran, P. Thorpe, and J. D. Minna, “Semaphorin 3B (SEMA3B) induces apoptosis in lung and breast cancer, whereas VEGF165 antagonizes this effect,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 31, pp. 11432–11437, 2004.
[65]
I. Chabbert-De Ponnat, V. Buffard, K. Leroy et al., “Antiproliferative effect of semaphorin 3F on human melanoma cell lines,” Journal of Investigative Dermatology, vol. 126, no. 10, pp. 2343–2345, 2006.
[66]
F. Wu, Q. Zhou, J. Yang et al., “Endogenous axon guiding chemorepulsant semaphorin-3F inhibits the growth and metastasis of colorectal carcinoma,” Clinical Cancer Research, vol. 17, no. 9, pp. 2702–2711, 2011.
[67]
D. R. Bielenberg, Y. Hida, A. Shimizu et al., “Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype,” Journal of Clinical Investigation, vol. 114, no. 9, pp. 1260–1271, 2004.
[68]
R. E. Bachelder, E. A. Lipscomb, X. Lin et al., “Competing autocrine pathways involving alternative neuropilin-1 ligands regulate chemotaxis of carcinoma cells,” Cancer Research, vol. 63, no. 17, pp. 5230–5233, 2003.
[69]
J. G. Herman and G. G. Meadows, “Increased class 3 semaphorin expression modulates the invasive and adhesive properties of prostate cancer cells,” International Journal of Oncology, vol. 30, no. 5, pp. 1231–1238, 2007.
[70]
M. Martin-Satue and J. Blanco, “Identification of semaphorin E gene expression in metastatic human lung adenocarcinoma cells by mRNA differential display,” Journal of Surgical Oncology, vol. 72, no. 1, pp. 18–23, 1999.
[71]
C. Christensen, N. Ambartsumian, G. Gilestro et al., “Proteolytic processing converts the repelling signal Sema3E into an inducer of invasive growth and lung metastasis,” Cancer Research, vol. 65, no. 14, pp. 6167–6177, 2005.
[72]
J. R. Basile, R. M. Castilho, V. P. Williams, and J. S. Gutkind, “Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 24, pp. 9017–9022, 2006.
[73]
S. Kato, K. Kubota, T. Shimamura, et al., “Semaphorin 4D, a lymphocyte semaphorin, enhances tumor cell motility through binding its receptor, plexinB1, in pancreatic cancer,” Cancer Science, vol. 102, no. 11, pp. 2029–2037, 2011.
[74]
O. G. W. Wong, T. Nitkunan, I. Oinuma et al., “Plexin-B1 mutations in prostate cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 48, pp. 19040–19045, 2007.
[75]
A. Rody, T. Karn, E. Ruckh？berle et al., “Loss of plexin B1 is highly prognostic in low proliferating ER positive breast cancers—results of a large scale microarray analysis,” European Journal of Cancer, vol. 45, no. 3, pp. 405–413, 2009.
[76]
J. J. Gómez Román, G. O. Garay, P. Saenz et al., “Plexin B1 is downregulated in renal cell carcinomas and modulates cell growth,” Translational Research, vol. 151, no. 3, pp. 134–140, 2008.
[77]
G. M. Argast, C. H. Croy, K. L. Couts et al., “Plexin B1 is repressed by oncogenic B-Raf signaling and functions as a tumor suppressor in melanoma cells,” Oncogene, vol. 28, no. 30, pp. 2697–2709, 2009.
[78]
M. Dhanabal, F. Wu, E. Alvarez et al., “Recombinant Semaphorin 6A-1 ectodomain inhibits in vivo growth factor and tumor cell line-induced angiogenesis,” Cancer Biology and Therapy, vol. 4, no. 6, pp. 659–668, 2005.
[79]
X. Y. Zhao, L. Chen, Q. Xu, and Y. H. Li, “Expression of semaphorin 6D in gastric carcinoma and its significance,” World Journal of Gastroenterology, vol. 12, no. 45, pp. 7388–7390, 2006.
[80]
G. A. Scott, L. A. McClelland, A. F. Fricke, and A. Fender, “Plexin C1, a receptor for semaphorin 7a, inactivates cofilin and is a potential tumor suppressor for melanoma progression,” Journal of Investigative Dermatology, vol. 129, no. 4, pp. 954–963, 2009.
[81]
D. D. Roberts, “Regulation of tumor growth and metastasis by thrombospondin-1,” FASEB Journal, vol. 10, no. 10, pp. 1183–1191, 1996.
[82]
A. Sadanandam, M. L. Varney, S. Singh et al., “High gene expression of semaphorin 5A in pancreatic cancer is associated with tumor growth, invasion and metastasis,” International Journal of Cancer, vol. 127, no. 6, pp. 1373–1383, 2010.
[83]
A. Sadanandam, E. G. Rosenbaugh, S. Singh, M. Varney, and R. K. Singh, “Semaphorin 5A promotes angiogenesis by increasing endothelial cell proliferation, migration, and decreasing apoptosis,” Microvascular Research, vol. 79, no. 1, pp. 1–9, 2010.
[84]
G. Q. Pan, H. Z. Ren, S. F. Zhang, X. M. Wang, and J. F. Wen, “Expression of semaphorin 5A and its receptor plexin B3 contributes to invasion and metastasis of gastric carcinoma,” World Journal of Gastroenterology, vol. 15, no. 22, pp. 2800–2804, 2009.
[85]
G. Pan, H. Lv, H. Ren et al., “Elevated expression of semaphorin 5A in human gastric cancer and its implication in carcinogenesis,” Life Sciences, vol. 86, no. 3-4, pp. 139–144, 2010.
[86]
T. P. Lu, M. H. Tsai, J. M. Lee et al., “Identification of a novel biomarker, SEMA5A, for non-small cell lung carcinoma in nonsmoking women,” Cancer Epidemiology Biomarkers and Prevention, vol. 19, no. 10, pp. 2590–2597, 2010.
[87]
A. Balakrishnan, J. Y. Penachioni, S. Lamba et al., “Molecular profiling of the "plexinome" in melanoma and pancreatic cancer,” Human Mutation, vol. 30, no. 8, pp. 1167–1174, 2009.
[88]
J. Rieger, W. Wick, and M. Weller, “Human malignant glioma cells express semaphorins and their receptors, neuropilins and plexins,” GLIA, vol. 42, no. 4, pp. 379–389, 2003.
[89]
L. Karayan-Tapon, M. Wager, J. Guilhot et al., “Semaphorin, neuropilin and VEGF expression in glial tumours: SEMA3G, a prognostic marker?” British Journal of Cancer, vol. 99, no. 7, pp. 1153–1160, 2008.
[90]
T. Bagci, J. K. Wu, R. Pfannl, L. L. Ilag, and D. G. Jay, “Autocrine semaphorin 3A signaling promotes glioblastoma dispersal,” Oncogene, vol. 28, no. 40, pp. 3537–3550, 2009.
[91]
V. Barresi, E. Vitarelli, and S. Cerasoli, “Semaphorin3A immunohistochemical expression in human meningiomas: correlation with the microvessel density,” Virchows Archiv, vol. 454, no. 5, pp. 563–571, 2009.
[92]
A. Shimizu, A. Mammoto, J. E. Italiano et al., “ABL2/ARG tyrosine kinase mediates SEMA3F-induced RhoA inactivation and cytoskeleton collapse in human glioma cells,” The Journal of Biological Chemistry, vol. 283, no. 40, pp. 27230–27238, 2008.
[93]
S. Coma, D. N. Amin, A. Shimizu, A. Lasorella, A. Iavarone, and M. Klagsbrun, “Id2 promotes tumor cell migration and invasion through transcriptional repression of semaphorin 3F,” Cancer Research, vol. 70, no. 9, pp. 3823–3832, 2010.
[94]
X. Zhou, L. Ma, J. Li, et al., “Effects of SEMA3G on migration and invasion of glioma cells,” Oncology Reports, vol. 28, no. 1, pp. 269–275, 2012.
[95]
B. Hu, P. Guo, I. Bar-Joseph et al., “Neuropilin-1 promotes human glioma progression through potentiating the activity of the HGF/SF autocrine pathway,” Oncogene, vol. 26, no. 38, pp. 5577–5586, 2007.
[96]
Y. Sasaki, C. Cheng, Y. Uchida et al., “Fyn and Cdk5 mediate semaphorin-3A signaling, which is involved in regulation of dendrite orientation in cerebral cortex,” Neuron, vol. 35, no. 5, pp. 907–920, 2002.
[97]
J. Y. Ahn, Y. Hu, T. G. Kroll, P. Allard, and K. Ye, “PIKE-A is amplified in human cancers and prevents apoptosis by up-regulating Akt,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 18, pp. 6993–6998, 2004.
[98]
R. Liu, B. Tian, M. Gearing, S. Hunter, K. Ye, and Z. Mao, “Cdk5-mediated regulation of the PIKE-A-Akt pathway and glioblastoma cell invasion,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 21, pp. 7570–7575, 2008.
[99]
K. V. Lu, S. Zhu, A. Cvrljevic et al., “Fyn and Src are effectors of oncogenic epidermal growth factor receptor signaling in glioblastoma patients,” Cancer Research, vol. 69, no. 17, pp. 6889–6898, 2009.
[100]
H. G. Vikis, W. Li, Z. He, and K. L. Guan, “The semaphorin receptor plexin-B1 specifically interacts with active Rac in a ligand-dependent manner,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 23, pp. 12457–12462, 2000.
[101]
J. M. Swiercz, R. Kuner, J. Behrens, and S. Offermanns, “Plexin-B1 directly interacts with PDZ-RhoGEF/LARG to regulate RhoA and growth cone morphology,” Neuron, vol. 35, no. 1, pp. 51–63, 2002.
[102]
V. Perrot, J. Vázquez-Prado, and J. Silvio Gutkind, “Plexin B regulates Rho through the guanine nucleotide exchange factors leukemia-associated Rho GEF (LARG) and PDZ-RhoGEF,” The Journal of Biological Chemistry, vol. 277, no. 45, pp. 43115–43120, 2002.
[103]
J. Aurandt, H. G. Vikis, J. S. Gutkind, N. Ahn, and K. L. Guan, “The semaphorin receptor plexin-B1 signals through a direct interaction with the Rho-specific nucleotide exchange factor, LARG,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 19, pp. 12085–12090, 2002.
[104]
M. H. E. Driessens, C. Olivo, K. I. Nagata, M. Inagaki, and J. G. Collard, “B plexins activate Rho through PDZ-RhoGEF,” FEBS Letters, vol. 529, no. 2-3, pp. 168–172, 2002.
[105]
M. Hirotani, Y. Ohoka, T. Yamamoto et al., “Interaction of plexin-B1 with PDZ domain-containing Rho guanine nucleotide exchange factors,” Biochemical and Biophysical Research Communications, vol. 297, no. 1, pp. 32–37, 2002.
[106]
J. Aurandt, W. Li, and K. L. Guan, “Semaphorin 4D activates the MAPK pathway downstream of plexin-B1,” Biochemical Journal, vol. 394, no. 2, pp. 459–464, 2006.
[107]
W. Li, H. Chong, and K. L. Guan, “Function of the rho family GTPases in Ras-stimulated Raf activation,” The Journal of Biological Chemistry, vol. 276, no. 37, pp. 34728–34737, 2001.
[108]
D. Barberis, A. Casazza, R. Sordella et al., “p190 Rho-GTPase activating protein associates with plexins and it is required for semaphorin signalling,” Journal of Cell Science, vol. 118, no. 20, pp. 4689–4700, 2005.
[109]
K. Wennerberg, M. A. Forget, S. M. Ellerbroek et al., “Rnd proteins function as RhoA antagonists by activating p190 RhoGAP,” Current Biology, vol. 13, no. 13, pp. 1106–1115, 2003.
[110]
I. Oinuma, H. Katoh, A. Harada, and M. Negishi, “Direct interaction of Rnd1 with Plexin-B1 regulates PDZ-RhoGEF-mediated Rho activation by Plexin-B1 and induces cell contraction in COS-7 cells,” The Journal of Biological Chemistry, vol. 278, no. 28, pp. 25671–25677, 2003.
[111]
I. Oinuma, Y. Ishikawa, H. Katoh, and M. Negishi, “The Semaphorin 4D receptor Plexin-B1 is a GTPase activating protein for R-Ras,” Science, vol. 305, no. 5685, pp. 862–865, 2004.
[112]
I. Oinuma, H. Katoh, and M. Negishi, “Molecular dissection of the semaphorin 4D receptor Plexin-B1-stimulated R-Ras GTPase-activating protein activity and neurite remodeling in hippocampal neurons,” Journal of Neuroscience, vol. 24, no. 50, pp. 11473–11480, 2004.
[113]
T. Toyofuku, J. Yoshida, T. Sugimoto et al., “FARP2 triggers signals for Sema3A-mediated axonal repulsion,” Nature Neuroscience, vol. 8, no. 12, pp. 1712–1719, 2005.
[114]
B. M. Marte, P. Rodriguez-Viciana, S. Wennstr？m, P. H. Warne, and J. Downward, “R-Ras can activate the phosphoinositide 3-kinase but not the MAP kinase arm of the Ras effector pathways,” Current Biology, vol. 7, no. 1, pp. 63–70, 1997.
[115]
M. Osada, T. Tolkacheva, W. Li et al., “Differential roles of Akt, Rac, and Ral in R-Ras-mediated cellular transformation, adhesion, and survival,” Molecular and Cellular Biology, vol. 19, no. 9, pp. 6333–6344, 1999.
[116]
P. J. Keely, E. V. Rusyn, A. D. Cox, and L. V. Parise, “R-Ras signals through specific integrin α cytoplasmic domains to promote migration and invasion of breast epithelial cells,” Journal of Cell Biology, vol. 145, no. 5, pp. 1077–1088, 1999.
[117]
I. Oinuma, H. Katoh, and M. Negishi, “Semaphorin 4D/Plexin-B1-mediated R-Ras GAP activity inhibits cell migration by regulating β1 integrin activity,” Journal of Cell Biology, vol. 173, no. 4, pp. 601–613, 2006.
[118]
I. Oinuma, Y. Ito, H. Katoh, and M. Negishi, “Semaphorin 4D/Plexin-B1 stimulates PTEN activity through R-Ras GTPase-activating protein activity, inducing growth cone collapse in hippocampal neurons,” The Journal of Biological Chemistry, vol. 285, no. 36, pp. 28200–28209, 2010.
[119]
Y. Saito, I. Oinuma, S. Fujimoto, and M. Negishi, “Plexin-B1 is a GTPase activating protein for M-Ras, remodelling dendrite morphology,” EMBO Reports, vol. 10, no. 6, pp. 614–621, 2009.
[120]
N. Lau, E. J. Uhlmann, F. C. Von Lintig et al., “Rap1 activity is elevated in malignant astrocytomas independent of tuberous sclerosis complex-2 gene expression,” International journal of oncology, vol. 22, no. 1, pp. 195–200, 2003.
[121]
J. Laterra, E. Rosen, M. Nam, S. Ranganathan, K. Fielding, and P. Johnston, “Scatter factor/hepatocyte growth factor expression enhances human glioblastoma tumorigenicity and growth,” Biochemical and Biophysical Research Communications, vol. 235, no. 3, pp. 743–747, 1997.
[122]
R. Abounader, S. Ranganathan, B. Lal et al., “Reversion of human glioblastoma malignancy by U1 small nuclear RNA/ribozyme targeting of scatter factor/hepatocyte growth factor and c-met expression,” Journal of the National Cancer Institute, vol. 91, no. 18, pp. 1548–1556, 1999.
[123]
R. Abounader, B. Lal, C. Luddy et al., “In vivo targeting of SF/HGF and c-met expression via U1snRNA/ribozymes inhibits glioma growth and angiogenesis and promotes apoptosis,” The FASEB Journal, vol. 16, no. 1, pp. 108–110, 2002.
[124]
S. Giordano, S. Corso, P. Conrotto et al., “The semaphorin 4D receptor controls invasive growth by coupling with Met,” Nature Cell Biology, vol. 4, no. 9, pp. 720–724, 2002.
[125]
P. Conrotto, S. Corso, S. Gamberini, P. M. Comoglio, and S. Giordano, “Interplay between scatter factor receptors and B plexins controls invasive growth,” Oncogene, vol. 23, no. 30, pp. 5131–5137, 2004.
[126]
L. Stevens, L. McClelland, A. Fricke, M. Williamson, I. Kuo, and G. Scott, “Plexin B1 suppresses c-met in melanoma: a role for plexin B1 as a tumor-suppressor protein through regulation of c-met,” Journal of Investigative Dermatology, vol. 130, no. 6, pp. 1636–1645, 2010.
[127]
J. M. Swiercz, T. Worzfeld, and S. Offermanns, “ErbB-2 and met reciprocally regulate cellular signaling via plexin-B1,” The Journal of Biological Chemistry, vol. 283, no. 4, pp. 1893–1901, 2008.
[128]
J. Schlegel, G. Stumm, K. Brandle et al., “Amplification and differential expression of members of the erbB-gene family in human glioblastoma,” Journal of Neuro-Oncology, vol. 22, no. 3, pp. 201–207, 1994.
[129]
K. Ochi, T. Mori, Y. Toyama, Y. Nakamura, and H. Arakawa, “Identification of Semaphorin3B as a direct target of p53,” Neoplasia, vol. 4, no. 1, pp. 82–87, 2002.
[130]
D. Basto, V. Trovisco, J. M. Lopes et al., “Mutation analysis of B-RAF gene in human gliomas,” Acta Neuropathologica, vol. 109, no. 2, pp. 207–210, 2005.
[131]
J. Jeuken, C. van de Broecke, S. Gijsen, S. Boots-Sprenger, and P. Wesseling, “RAS/RAF pathway activation in gliomas: the result of copy number gains rather than activating mutations,” Acta Neuropathologica, vol. 114, no. 2, pp. 121–133, 2007.
[132]
Y. Lyustikman, H. Momota, W. Pao, and E. C. Holland, “Constitutive activation of raf-1 induces glioma formation in mice,” Neoplasia, vol. 10, no. 5, pp. 501–510, 2008.
[133]
H. Davies, G. R. Bignell, C. Cox et al., “Mutations of the BRAF gene in human cancer,” Nature, vol. 417, no. 6892, pp. 949–954, 2002.
[134]
C. Walker, D. G. Du Plessis, K. A. Joyce et al., “Phenotype versus genotype in gliomas displaying inter- or intratumoral histological heterogeneity,” Clinical Cancer Research, vol. 9, no. 13, pp. 4841–4851, 2003.
