Semaphorins Biology and Their Significance in Cancer

Review Article

Austin J Clin Pathol. 2014;1(2): 1009.

Semaphorins Biology and Their Significance in Cancer

Yasser Abuetabh1,2, Suchita Tiwari1, Brian Chiu1 and Consolato Sergi1,3

1Department of Lab Medicine and Pathology, University of Alberta, Canada

2Departments of Clinical Laboratory and Blood Bank, Al Imam Abdul Rahman Al Faisal Hospital, Saudi Arabia

3Stollery Children's Hospital, University of Alberta, Canada

*Corresponding author: Consolato Sergi, Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, AB, T6G 2B7, Canada

Received: May 20, 2014; Accepted: June 11, 2014; Published: June 14, 2014

Abstract

Semaphorins are a large family of secreted, membranous and plasma membrane-associated proteins that were initially identified as axon guidance cues. Semaphorins have many receptors which are categorized into two large families: plexins and neuropilins. The plexin family of receptors functions as transmembrane receptors to mediate cell repelling cues for Semaphorins. Neuropilins are semaphorins' receptors that require the binding of class 3 semaphorins which in turn mediates the subsequent binding of plexin. The interactions of Semaphorins with their receptors are involved in many biological functions, including organogenesis, immune responses, vascularization and tumor progression. Recently, several lines of evidence suggest the dual role of semaphorins and their receptors as tumor suppressors or tumor promoters. Moreover, therapies targeting the Semaphorin-plexin complex are under investigation. The focus of this mini-review is to characterize and define the significant roles of semaphorins and its receptors in cell biology and cancer.

Keywords: Semaphorins; Plexin; Neuropilin; Guidance molecules; Tumor progression

Introduction

Semaphorins (Semas), also known as collapsins, have been defined as a large family of secreted, membranous and plasma membrane-associated proteins that were initially identified as factors that mediated axonal guidance [1,2]. Although they have been found mostly in multi-cellular organisms, few viruses-expressing Semas have also been identified. It has been demonstrated that Semas are structurally and functionally conserved throughout species such as in nematode worms and crustaceans. Semas have also been found to have crucial regulatory roles in the morphogenesis and homeostasis in the heart, blood vessel, liver, lung and bone [2]. Greater than twenty five vertebrate, invertebrate and viral Semas have been recognized, and based on their structures, Semas are categorized into eight classes (Table 1) [1,2]. Semas have been demonstrated to act as chemoattractant and chemorepellent. They provide repulsive or attractive cues for axons to move away from non-target regions or to move towards target regions [2]. Therefore, Semas have dual mechanistic roles depending on various extrinsic and intrinsic modularity signals (such as, Ig Cell Adhesion Molecules (IgCAMs), proteoglycans and Rac1) that directly affect its activity or indirectly affecting its association with the plexin and neuropilin family of receptors [2].

Semaphorins structural and functional perspectives

Semas consist of a Sema domain, Plexin-Semaphorin-Integrin (PSI) domain and immunoglobulin domain. The Sema domain is a critical component for semaphorin activities and determines receptor binding specificity [3]. The PSI domain, immediately next to the carboxy-terminal side of the Sema domain, is reportedly highly conserved, and followed by a seven-blade β-propeller at the N-terminus next to the PSI domain [4]. Semaphorins signal via two large family of receptors: plexins and neuropilins (NRP or NPN). Most membranous semaphorins are bound to plexins with the exception of class 3 semaphorins (Table 1) which are recruited to plexins by neuropilins receptors. Class 3 Sema members are highly implicated in mediating attractive and repulsive effects during neuronal development. For instance, it has been reported that Sema3B acts as a chemoattractant instead of chemorepellent when the activity of Focal Adhesion Kinas (FAK) is increased. It has also been demonstrated that Sema5A acts as axon attractant and repellent in the presence of heparin sulfate proteoglycans, and chondroitin sulfate proteoglycans, respectively [2]. Moreover, intrinsic factors such as cyclic nucleotides also switch Sema3A's repulsive cue to an attractive one. In addition, the decrease of Rac1 switches Sema3A from an attractive to a repulsive cue. The repulsive action of Sema3E/plexinD1 is changed to attractive one in presence of NRP-1 [2]. In addition to their expression in neuronal tissues, Sema3s are also expressed in non-neuronal tissues, and the multitude of signals comprising Sema has made the Semas a molecule of interest for organogenesis, angiogenesis, immune responses and cancer progression [1].

Table 1: Classes of Semaphorins and Organogenesis.




  

    
Class No.

    
Potential    actions in organogenesis

    
Protein type

    
Found in

  

  

    
I

    
Sema 1A: axon guidance

    
Membrane bound

    
Invertebrate

  

  

    
II

    
Sema 2A: axon guidance

    
Secreted

    
Invertebrate

  

  

    
III

    
Sema 3A &    3C: heart, lung, bone and tooth development. Axon guidance

    
Secreted

    
Vertebrate

  

  

    
IV

    
Sema 4D: kidney development

    
Membrane bound

    
Vertebrate

  

  

    
V

    
Sema 5C:    olfactory development in nervous system

    
Membrane bound

    
Vertebrate and    Invertebrate

  

  

    
VI

    
Sema 6D: heart & bone development

    
Membrane bound

    
Vertebrate

  

  

    
VII

    
Sema 7A: bone development

    
Membrane bound

    
Vertebrate

  

  

    
VIII

    
Sema VA and Sema VB

    
Secreted

    
Viral

  









Table 1: Classes of Semaphorins and Organogenesis.

Table 2: Semaphorin Receptor Classes and Potential Functions.




  

    
Receptor Classes

    
Subclasses

    
Potential Functions

  

  

    
Plexin A

    
1, 2, 3, 4

    
Plexin A1, A2:    lung and heart morphogenesis

  

  

    
Plexin B

    
1, 2, 3

    
Plexin B1, B2:    kidney development.

  

  

    
Plexin C

    
-

    
Plexin C1: sex    chords and testis development

  

  

    
Plexin D

    
-

    
Plexin D1: heart development

  

  

    
Neuropilin 1

    
-

    
NRP1: heart and nervous system development

  

  

    
Neuropilin 2

    
-

    
NRP 2: Lymphogenesis

  









Table 2: Semaphorin Receptor Classes and Potential Functions.

Accumulating evidence indicates that several semaphorins, the so-called "immune semaphorins" have been shown to play significant roles in both inhibiting and activating immune responses, and the immune-semaphorins and their receptors (including Sema3A, Sema3B, Sema3C, Sema4A, Sema4D and Sema7A) have been identified [5]. For example, Sema3A is involved in inhibition of monocyte migration and inhibition of T-cell activation. Sema7A is involved in activation of monocyte and macrophage, and Sema4D is involved in B-cell activation [5]. Semas and their receptors have also been shown to have crucial roles in the progression as well as suppression of a wide range of tumors. For instance, Sema4D promotes angiogenesis and cell migration; whereas, Sema3A inhibits the same actions. A growing body of evidence indicates that angiogenesis may be, in part, mediated by Semas and its receptors, ultimately contributing to tumor progression and invasiveness [6].

Semaphorin receptors

Semas have unique receptors which fall into one of two large families: plexins and neuropilins (NRP). The plexin family is divided into 4 groups that comprise of nine members (plexin A1-4, plexin B1-3, plexin C and plexin D) (table 2). These receptors interact with specific Sema members to mediate their signaling and to regulate a wide range of essential roles including organogenesis [7]. The conserved cytoplasmic domain of plexins has been shown to have a spilt GTPase-Activating (GAP) sites, and this domain is tyrosine phosphorylated [8]. Therefore, plexins orchestrate the activity of various GTPase such as RHOD, R-Ras, Rnd1 and Rac [9]. It has been also reported that plexins might play a role in cell adhesion and motility. The extracellular domain of plexin is also conserved and contains 500 amino acids Sema domain. In type B plexins, the extracellular domain has sites for furin-like proteases [10]. Most Semas bind directly to plexins; for instance, class 4 and 7 bind to plexins type B and C, respectively. However, some members of class 3 Sema bind to plexin by recruiting other co-receptors such as neuropilins [7].

The second important receptor for Semas is neuropilin family which has two types, neuropilin 1 (NRP1) and Neuropilin 2 (NRP2). Structurally, neuropilins consist of two Complement Binding (CUB) domains (designated as a1 and a2 domains), two coagulation factor V/VIII domains (designated as b1 and b2 domains), and MAM domain (designated as c domain) [11,12]. The secreted semaphorins belonging to the Sema3 subfamily do not bind to the plexins but instead bind to the NRP1 or NRP2. The NRPs form complexes with members of the plexin family and function as the semaphorin binding elements and the plexins function as the signal transducing elements [6,11,12]. NRP1 has also been found to bind with a wide range of different factors such as, Vascular Endothelial Growth Factor (VEGF), and Placental Growth Factor-2 (PIGF-2) [13,14]. Moreover, NRP1 has been identified to be present in two forms both in a monomeric and dimeric form. It has been demonstrated that the monomeric form of NRP1 binds with VEGF165 and inhibits the signaling of VEGF receptor-1 (VEGFR-1) which is important for vascular development [15]. On the other hand, the dimeric form of NRP1 has been demonstrated to promote the phosphorylation of VEGFR-2 [15]. NRP2 was identified based on its sequence homology to NRP1. The amino acid sequence of its CUB, FV/FVIII and MAM domains is 45%, 48% and 35% similar to the corresponding domains of NRP1 respectively. NRP1 has essential roles in development of the nervous and cardiovascular system, while NRP2 plays an important role in neurogenesis and lymphogenesis [16].

Semaphorin-like protein, polyductin

There was speculation that semaphorin-like proteins, such as polyductin, have significant roles in tumorigenesis. Polyductin (also known as fibrocystin) is the main product of polycystic kidney and hepatic disease 1 (PKHD1) gene [17]. PKHD1 mutations have been found to be responsible for most Autosomal Recessive Polycystic Diseases (ARPKDs) which are characterized by abnormal formation of the bile duct, cyst formation, and bile duct dilation [17,18]. ARPKD is one of the major renal and hepatic-related deaths among infants and newborns [19]. Structurally, Polyductin (PD) is suggested to have a single transmembrane-spanning domain near its carboxyl terminus, an extracellular domain with repeated immunoglobulin-like plexin-transcription-factor domains, and short cytoplasmic domain [17,18,20]. It shares some features with members of the Sema family of proteins, but lacks several key domains of the Semas [21]. Several short segments of PD have weak homology to other proteins whose functions are known, including Hepatocyte Growth-Factor Receptor (HGFR) and several plexins. This supports the notion that PD may function as a receptor, similar to hepatocyte growth factor receptor and plexins [19-21]. It has been believed that PD, as well as polycystin-1 and polycystin-2 (the Autosomal Dominant Polycystic Kidney Disease (ADPKD) proteins) may play a significant role of cilia formation of different epithelial cells, and cholangiocytes [17,18]. Absence of PD has been linked with ciliary dysfunction, which is associated with cystogenesis [22]. Moreover, PD has been found to be expressed by a variety of tissues, such as liver, kidney and pancreas. Interestingly, PD has also been demonstrated to play a central role in the development of the primitive intrahepatic biliary system [23]. Intense immunohistochemical staining of PD has been identified in abnormal development of biliary system (also known as ductal plate malformation), as well as in Cholangiocellular Carcinoma (CCA), but not in HCC [23]. Furthermore, Kaimori et al [24] have shown that PD undergoes a complicated pattern of Notch-like proteolytic processing. Cleavage at a probable pro-protein convertase site produces a large extracellular domain that is tethered to the C-terminus. Both the predictable structures and potential functions either as a receptor, a ligand or possibly both, are supportive evidence that suggest PD to be a "close" member of the Sema family. The role of polyductin in regards to its role in the transforming effect on cholangiocytes is still poorly understood and requires further investigation.

Semaphorins and their receptors in cancer

As reviewed by Gu et al. there is accumulating evidence indicating that Semas and their receptors control tumor progression, indirectly, by modulating angiogenesis and the functions of other cell types in the tumor microenvironment, including immune cells and tumor associated macrophages and fibroblasts, or, by directly affecting the behavior of tumor cells [16].

Many cancer cells express abnormal levels of semaphorins and their receptors (Table 3) [16,25,26]. The pro-tumorigenic semaphorins, including Sema3C, 3E, 4D, 5A, 5B and 6D, have been found to be upregulated in multiple cancers. The overexpressions of these Semas contribute to multiple mechanisms sustaining tumor progression, invasion and metastasis and pro-angiogenic properties. On the other hand, the anti-tumorigenic semaphorins, including Sema 3A, 3B, 3F, and 3G, are often downregulated in cancers. Interestingly, some semaphorins have been found to be downregulated or deleted in one cancer type, but overexpressed in several cancers, suggesting that these Semas may have both an anti-tumoral and pro-tumoral role in different tumors [27-29].

Table 3: Semaphorins and Tumorigenic Mechanisms in Cancer.




  

    
Semas

    
Aberrant gene    expression in cancers

    
Pro- or    anti-tumorigenic mechanisms of Semas

    
References

  

  

    
SEMA3A

    
    
      
  • D/R in breast    cancer
    • 
    

    
-Inhibits    migration of breast cancer

      
-Inhibits    branching of lung development

    
[46]

  

  

    
SEMA3B

    
    
      
  • D/R in breast,    lung cancers
    • 
    

    
-Inhibits    tumor formation

      
-Induces    apoptosis of lung & breast cancers

    
[46,47]

  

  

    
SEMA3C

    
    
      
  • O/E in breast,    lung cancers
    • 
    

    
-Promotes    tumor growth

      
-Promotes    branching of lung development

    
[48,49]

  

  

    
SEMA3D

    
    
      
  • D/R in glioma
    • 
    

    
-Induces tumor    angiogenesis and invasiveness

    
[50]

  

  

    
SEMA3E

    
    
      
  • O/E in    ovarian, colo-rectal cancers
    • 
    

    
-Promotes    metastasis of tumor cells in breast cancer

    
[51]

  

  

    
SEMA3F

    
    
      
  • D/R in lung    cancer
    • 
    

    
-Inhibits    spreading of breast cancer

      
-Suppresses    lung cancer cell growth

    
[52]

  

  

    
SEMA4D

    
    
      
  • D/R in    non-Hodgkin lymphoma
    • 
      
  • O/E in head    and neck cancer
    • 
    

    
-Induces tumor    angiogenesis and tumour invasiveness

    
[27-29]

  









Table 3: Semaphorins and Tumorigenic Mechanisms in Cancer.

Semas and their receptors have also been investigated in prostate cancer. For instance, Sema4D has been demonstrated to be up-regulated, and its receptor, plexin B1, is mutated in prostate cancer [30,31]. Blanc et al. investigated the expression of Semas and their receptors in prostate cancer cell lines as well as tissues. By quantitative Real Time-Polymerase Chain Reaction (RT-PCR) and immunohistochemistry procedures, they indicated that all (Sema3A, B, C, F; Sema4D; plexinA1, A2, A3; plexinB1, B3; plexinD1; NRP1 and NRP2) were expressed at variable levels. In particular, Sema3E-plexinD1 complex was significantly over-expressed and correlated to prostate cancer progression and metastasis [32].

The expressions of Semas class 3 in hypoxic conditions have also been investigated as Sema3s have a significant role in angiogenesis. Blanc V et al. found that the expression of Sema 3B and Sema3C were gradually increased; whereas the expression of Sema3E and 3A were decreased. Therefore, induced angiogenesis may be mediated by some members of Sema family as well as their appropriate receptors [32]. NRP1 and NRP2 are described as receptors for angiogenic factors, such as VEGF and Hepatocyte Growth Factor (HGF). Both NRP1 and NRP2 have been demonstrated to be expressed during artery and vein development, respectively [33]. To this end, over-expression of NRP1 in prostate cancer has been highly correlated with the degree of invasiveness and tumor angiogenesis [34-36]. NRPs are frequently overexpressed and often associated with poor prognosis or advanced disease, while inhibition of NRP1 is associated with suppression of lung cancer progression [37]. Consistently, methylation of Sema3B and Sema3F inactivate their tumor suppressor functions in lung cancers [38,39]. Sema3C, Sema4B, Sema4D and PlexinB1 are significantly up-regulated and associated with metastasis and angiogenesis in lung cancer [28,40-42]. Dysregulated expressions of NRP1 and NRP2 have also been implicated in lung cancer progression and invasiveness [43,44].

Summary and Future Directions

In summary, semaphorins have originally been identified as axon guidance cues and only been implicated in nervous system development. Recent evidence identifies semaphorins and their receptors (plexins and neuropilins) as key players of many biological functions, including immune responses, angiogenesis and tumor progression. The dual roles of semaphorins and their receptors may suggest that some semaphorins may be used as "replacement therapy" to compensate for the loss of anti-tumorigenic Semas (Table 3). Other Semas that are pro-tumorigenic may represent targets for the development of anti-tumorigenic drugs targeting these Semas or their receptors [26]. Furthermore, a growing body of evidence supports the concept that normalization of tumour blood vessels may represent a novel therapeutic approach [45]. Sema3s are newly identified endogenous angiogenesis inhibitors that significantly extend the vascular normalization window [45]. Antibodies targeting the VEGF-A/C binding sites on NRP1 and NRP2 have been engineered and show promising results on blocking tumor angiogenesis, lymphangiogenesis and metastasis in rodents [37]. Finally, Semas also play a role in the tumor micro-environment and the modulation by "immune semaphorins". Further investigations are needed to better characterize the roles of the Semas and their receptors in modulating tumor progression and to better understand the molecular mechanisms of actions in order to develop new therapeutic drugs.

References

  1. Yazdani U, Terman JR. The semaphorins. Genome Biol. 2006; 7: 211.
  2. Zhou Y, Gunput RA, Pasterkamp RJ. Semaphorin signaling: progress made and promises ahead. Trends Biochem Sci. 2008; 33: 161-170.
  3. Koppel AM, Feiner L, Kobayashi H, Raper JA. A 70 amino acid region within the semaphorin domain activates specific cellular response of semaphorin family members. Neuron. 1997; 19: 531-537.
  4. Gherardi E, Love CA, Esnouf RM, Jones EY. The sema domain. Curr Opin Struct Biol. 2004; 14: 669-678.
  5. Kumanogoh A, Kikutani H. Semaphorins and their receptors: novel features of neural guidance molecules. Proc Jpn Acad Ser B Phys Biol Sci. 2010; 86: 611-620.
  6. Neufeld G, Kessler O. The semaphorins: versatile regulators of tumour progression and tumour angiogenesis. Nat Rev Cancer. 2008; 8: 632-645.
  7. Tamagnone L, Artigiani S, Chen H, He Z, Ming GI, Song H, et al. Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell. 1999; 99: 71-80.
  8. Oinuma I, Ishikawa Y, Katoh H, Negishi M. The Semaphorin 4D receptor Plexin-B1 is a GTPase activating protein for R-Ras. Science. 2004; 305: 862-865.
  9. Tong Y, Chugha P, Hota PK, Alviani RS, Li M, Tempel W, et al. Binding of Rac, Rnd, and RhoD to a novel Rho GTPase interaction motif destabilizes dimerization of the plexin-B1 effector domain. J Biol Chem. 2007; 282: 37215-37224.
  10. Artigiani S, Barberis D, Fazzari P, Longati P, Angelini P, van de Loo JW, et al. Functional regulation of semaphorin receptors by proprotein convertases. J Biol Chem. 2003; 278: 10094-10101.
  11. He Z, Tessier-Lavigne M. Neuropilin is a receptor for the axonal chemorepellent Semaphorin III. Cell. 1997; 90: 739-751.
  12. Chen H, Chédotal A, He Z, Goodman CS, Tessier-Lavigne M. 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.
  13. Trusolino L, Comoglio PM. Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer. 2002; 2: 289-300.
  14. Migdal M, Huppertz B, Tessler S, Comforti A, Shibuya M, Reich R, et al. Neuropilin-1 is a placenta growth factor-2 receptor. J Biol Chem. 1998; 273: 22272-22278.
  15. Yamada Y, Oike Y, Ogawa H, Ito Y, Fujisawa H, Suda T, et al. Neuropilin-1 on hematopoietic cells as a source of vascular development. Blood. 2003; 101: 1801-1809.
  16. Gu C, Giraudo E. The role of semaphorins and their receptors in vascular development and cancer. Exp Cell Res. 2013; 319: 1306-1316.
  17. Onori P, Franchitto A, Mancinelli R, Carpino G, Alvaro D, Francis H, et al. Polycystic liver diseases. Dig Liver Dis. 2010; 42: 261-271.
  18. Fischer DC, Jacoby U, Pape L, Ward CJ, Kuwertz-Broeking E, Renken C, et al. Activation of the AKT/mTOR pathway in autosomal recessive polycystic kidney disease (ARPKD). Nephrol Dial Transplant. 2009; 24: 1819-1827.
  19. Mangolini A, Bogo M, Durante C, Borgatti M, Gambari R, Harris PC, et al. NF-kappaB activation is required for apoptosis in fibrocystin/polyductin-depleted kidney epithelial cells. Apoptosis. 2010; 15: 94-104.
  20. Al-Bhalal L, Akhtar M. Molecular basis of autosomal recessive polycystic kidney disease (ARPKD). Adv Anat Pathol. 2008; 15: 54-58.
  21. Onuchic LF, Furu L, Nagasawa Y, Hou X, Eggermann T, Ren Z, et al. PKHD, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats. Am J Hum Genet. 2002; 70: 1305-1317.
  22. Kim I, Li C, Liang D, Chen XZ, Coffy RJ, Ma J, et al. Polycystin-2 expression is regulated by a PC2-binding domain in the intracellular portion of fibrocystin. J Biol Chem. 2008; 283: 31559-31566.
  23. Dorn L, Menezes LF, Mikuz G, Otto HF, Onuchic LF, Sergi C. Immunohistochemical detection of polyductin and co-localization with liver progenitor cell markers during normal and abnormal development of the intrahepatic biliary system and in adult hepatobiliary carcinomas. J Cell Mol Med. 2009; 13: 1279-1290.
  24. Kaimori JY, Nagasawa Y, Menezes LF, Garcia-Gonzalez MA, Deng J, Imai E, et al. Polyductin undergoes notch-like processing and regulated release from primary cilia. Hum Mol Genet. 2007; 16: 942-956.
  25. Rehman M, Tamagnone L. Semaphorins in cancer: biological mechanisms and therapeutic approaches. Semin Cell Dev Biol. 2013; 24: 179-189.
  26. Neufeld G, Sabag AD, Rabinovicz N, Kessler O. Semaphorins in angiogenesis and tumor progression. Cold Spring Harb Perspect Med. 2012; 2: a006718.
  27. Dorfman DM, Shahsafaei A, Nadler LM, Freeman GJ. The leukocyte semaphorin CD100 is expressed in most T-cell, but few B-cell, non-Hodgkin's lymphomas. Am J Pathol. 1998; 153: 255-262.
  28. Basile JR, Castilho RM, Williams VP, Gutkind JS. Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis. Proc Natl Acad Sci U S A. 2006; 103: 9017-9022.
  29. Sun Q, Zhou H, Binmadi NO, Basile JR. Hypoxia-inducible factor-1-mediated regulation of semaphorin 4D affects tumor growth and vascularity. J Biol Chem. 2009; 284: 32066-32074.
  30. Conrotto P, Corso S, Gamberini S, Comoglio PM, Giordano S. Interplay between scatter factor receptors and B plexins controls invasive growth. Oncogene. 2004; 23: 5131-5137.
  31. Wong OG, Nitkunan T, Oinuma I, Zhou C, Blanc V, Brown RS, et al. Plexin-B1 mutations in prostate cancer. Proc Natl Acad Sci U S A. 2007; 104: 19040-19045.
  32. Blanc V, Nariculam J, Munson P, Freeman A, Klocker H, Masters J, et al. A role for class 3 semaphorins in prostate cancer. Prostate. 2011; 71: 649-658.
  33. Herzog Y, Kalcheim C, Kahane N, Reshef R, Neufeld G. Differential expression of neuropilin-1 and neuropilin-2 in arteries and veins. Mech Dev. 2001; 109: 115-119.
  34. Latil A, Bièche I, Pesche S, Valéri A, Fournier G, Cussenot O, et al. VEGF overexpression in clinically localized prostate tumors and neuropilin-1 overexpression in metastatic forms. Int J Cancer. 2000; 89: 167-171.
  35. Miao HQ, Lee P, Lin H, Soker S, Klagsbrun M. Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression. FASEB J. 2000; 14: 2532-2539.
  36. Pan Q, Chanthery Y, Liang WC, Stawicki S, Mak J, Rathore N, et al. Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell. 2007; 11: 53-67.
  37. Potiron VA, Roche J, Drabkin HA. Semaphorins and their receptors in lung cancer. Cancer Lett. 2009; 273: 1-14.
  38. Roche J, Boldog F, Robinson M, Robinson L, Varella-Garcia M, Swanton M, et al. Distinct 3p21.3 deletions in lung cancer and identification of a new human semaphorin. Oncogene. 1996; 12: 1289-1297.
  39. Tomizawa Y, Sekido Y, Kondo M, Gao B, Yokota J, Roche J, 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 U S A. 2001; 98: 13954-13959.
  40. Banu N, Teichman J, Dunlap-Brown M, Villegas G, Tufro A. Semaphorin 3C regulates endothelial cell function by increasing integrin activity. FASEB J. 2006; 20: 2150-2152.
  41. Martín-Satué 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.
  42. Nagai H, Sugito N, Matsubara H, Tatematsu Y, Hida T, Sekido Y, et al. CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells. Oncogene. 2007; 26: 4025-4031.
  43. Hong TM, Chen YL, Wu YY, Yuan A, Chao YC, Chung YC, et al. Targeting neuropilin 1 as an antitumor strategy in lung cancer. Clin Cancer Res. 2007; 13: 4759-4768.
  44. Kawakami T, Tokunaga T, Hatanaka H, Kijima H, Yamazaki H, Abe Y, et al. Neuropilin 1 and neuropilin 2 co-expression is significantly correlated with increased vascularity and poor prognosis in nonsmall cell lung carcinoma. Cancer. 2002; 95: 2196-2201.
  45. Serini G, Bussolino F, Maione F, Giraudo E. Class 3 semaphorins: physiological vascular normalizing agents for anti-cancer therapy. J Intern Med. 2013; 273: 138-155.
  46. Staton CA, Shaw LA, Valluru M, Hoh L, Koay I, Cross SS, et al. Expression of class 3 semaphorins and their receptors in human breast neoplasia. Histopathology. 2011; 59: 274-282.
  47. 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 U S A. 2004; 101: 11432-11437.
  48. Martín-Satué 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.
  49. Galani E, Sgouros J, Petropoulou C, Janinis J, Aravantinos G, Dionysiou-Asteriou D, et al. Correlation of MDR-, nm23-H1 and H Sema E gene expression with histopathological findings and clinical outcome in ovarian and breast cancer patients. Anticancer Res. 2002; 22: 2275-2280.
  50. Sabag AD, Bode J, Fink D, Kigel B, Kugler W, Neufeld G. Semaphorin-3D and semaphorin-3E inhibit the development of tumors from glioblastoma cells implanted in the cortex of the brain. PLoS One. 2012; 7: e42912.
  51. Christensen C, Ambartsumian N, Gilestro G, Thomsen B, Comoglio P, Tamagnone L, et al. Proteolytic processing converts the repelling signal Sema3E into an inducer of invasive growth and lung metastasis. Cancer Res. 2005; 65: 6167-6177.
  52. Bielenberg DR, Hida Y, Shimizu A, Kaipainen A, Kreuter M, Kim CC, et al. Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. J Clin Invest. 2004; 114: 1260-1271.

Citation: Abuetabh Y, Tiwari S, Chiu B and Sergi C. Semaphorins Biology and Their Significance in Cancer. Austin J Clin Pathol. 2014;1(2): 1009. ISSN : 2381-9170