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[Frontiers in Bioscience 10, 751-760, January 1, 2005]
751
SEMAPHORINS IN CANCER
Gera Neufeld, Niva Shraga-Heled, Tali Lange, Noga Guttmann-Raviv, Yael Herzog, And Ofra Kessler
Cancer and Vascular Biology Research Center, Rappaport Research Institute in the Medical Sciences, The Bruce Rappaport
Faculty of Medicine, Technion, Israel Institute of Technology, 1 Efron St., P.O. Box 9679, Haifa, 31096, Israel
TABLE OF CONTENTS
1. Abstract
2. Introduction
3. The semaphorin gene family
4. Semaphorin receptors
4.1. Plexins
4.2. Neuropilins
4.3. Additional semaphorin receptors
5. Semaphorin induced signal transduction
6. Semaphorins as modulators of tumor progression
6.1. Class-3 semaphorins in tumorigenesis and tumor progression
6.2. Class 4 semaphorins and their role in tumor progression
6.3. Class 5 and 6 semaphorins and their role in tumor progression
7. Conclusions
8. Acknowledgements
9. References
1. ABSTRACT
The semaphorins are the products of a large
family of genes currently containing more than 30
members. These genes are divided into eight classes of
which classes 1, 2 and 8 contain invertebrate and viral
semaphorins, while classes 3–7 contain the vertebrate
semaphorins. The semaphorins have been implicated in
diverse developmental processes such as axon guidance
during nervous system development and regulation of cell
migration. Plexin receptors function as binding and signal
transducing receptors for all semaphorins except for the
class-3 semaphorins which bind to neuropilins which
subsequently activate signaling through associated plexins.
The class-3 semaphorins semaphorin-3B (s3b) and
semaphorin-3F (s3f) function additionally as potent
inhibitors of tumor development in small cell lung
carcinoma. Recent evidence indicates that these
semaphorins modulate the adhesive and migratory
properties of responsive malignant cells. S3f as well as
semaphorin-3A (s3a) were also found to function as
inhibitors of angiogenesis, and it was shown that the anti-
angiogenic properties of s3f contribute significantly to its
anti-tumorigenic properties. In contrast with these
inhibitory semaphorins, there is some evidence indicating
that semaphorins such as semaphorin-3C (s3c),
semaphorin-3E (s3e), semaphorin-4D (s4d), semaphorin-
5C (s5c) semaphorin-6A (s6a) and semaphorin-6b (s6b)
may contribute to tumorigenesis or to tumor progression. In
this review we discuss the semaphorins, their receptors and
their signal transduction mechanisms, and evidence linking
semaphorins to the control of tumorigenesis and tumor
progression.
2. INTRODUCTION
The semaphorins and their receptors, the
neuropilins and the plexins, were originally characterized
as constituents of the complex regulatory system
responsible for the guidance of growing axons to their
targets during the development of the central nervous
system. However, a growing body of evidence indicates
that the semaphorins and their receptors are implicated in
the regulation of additional developmental processes such
as the migration of neural crest cells and heart development
to name but a few examples (1,2). In addition, there is a
growing body of evidence suggesting that the semaphorins
and their receptors may play a regulatory role in
tumorigenesis and in the process of tumor formation. This
evidence is reviewed in the following sections.
3. THE SEMAPHORIN GENE FAMILY
The semaphorin family consists of more than 30 genes
divided into 8 classes, of which the first two classes are
derived from invertebrates, classes 3-7 are the products of
vertebrate semaphorins, and the 8
th
contains viral
semaphorins (3) (Figure 1). In the literature the
semaphorins are often referred to by an array of confusing
designations. This situation was clarified several years ago
by the adoption of a unified nomenclature for the
semaphorins (3). The semaphorins are characterized by the
presence of a conserved sema domain which is ~500
amino-acids long and is usually located at their N-terminal.
The sema domain is essential for semaphorin signaling and
determines receptor binding specificity (4). The sema
domains of two different semaphorins were recently
characterized at an atomic resolution revealing beta
propeller topology (5-6). In addition, semaphorins contain
additional structural motifs such as immunoglobulin like
domains (classes 2-4 and 7), thrombospondin repeats (class
5) and basic domains (class 3). The semaphorins are
produced either as secreted proteins as in the case of the
class-3 semaphorins or as membrane anchored or trans-
Semaphorins in Cancer
752
Figure 1. The main classes of the semaphorins and their structure. The heavy black line represents the cell membrane.
membrane proteins that can be further processed into
soluble proteins. The active forms of the class-3 and class 4
semaphorins s3a and s4a are homo-dimeric (7,8), and it is
therefore reasonable to assume that the active forms of the
other class-3 and class-4 semaphorins also form
homodimers. Semaphorins have been mainly characterized
as axon guidance factors that function primarily in the
developing nervous system (9). In recent years it was
realized that semaphorins play a role in many
developmental processes outside of the nervous system, in
particular as regulators of cell migration (10), immune
responses (11) and organogenesis (2). It is therefore not
surprising that some of the semaphorins have been recently
found to play important roles in tumor development and
progression.
4. SEMAPHORIN RECEPTORS
4.1 Plexins
The best characterized semaphorin receptors are
encoded by the genes belonging to the plexin family. The
plexins are segregated into four sub-families containing 9
vertebrate plexins. The plexins are transmembrane proteins
containing a cytoplasmic SP domain that includes putative
tyrosine phosphorylation sites but no known enzymatic
activity. Their extracellular domain is distinguished by the
presence of a sema domain, by the presence of a Met
related sequence (MRS) domain and by glycine-proline (G-
P) rich motifs which the plexins share with the tyrosine-
kinase receptors belonging to the Met family of receptors
(Figure 2)(12). Some vertebrate semaphorins belonging to
the 4-7 classes have been shown to bind directly to plexins
and to activate plexin mediated signal transduction as a
result. For example, semaphorin-4D (s4d) binds to plexin-
B1 (13) and semaphorin-6D (s6d) binds to plexin-A1 (14).
In addition, semaphorin-7A as well as several viral
semaphorins were found to bind to plexin-C1 which is
itself a virally encoded plexin like receptor (Table 1) (15).
Plexin-B1 can form a complex with the
hepatocyte growth factor receptor MET. Following s4d
binding to plexin-B1, the MET tyrosine kinase is activated
resulting in the phosphorylation of both receptors (13).
Likewise, s6d potentiates the effects of VEGF as a result of
complex formation between plexin-A1 and VEGF receptor-
2 (Table 1) (14). Plexins were found to associate with
additional types of cell surface receptors. Plexin-A1
associates with the Off-Track (OTK) receptor (16) and the
plexin-A1 ligand s6d induces OTK mediated signaling(14).
4.2. Neuropilins
Class-3 semaphorins differ from other types of
semaphorins by their inability to bind directly to plexins.
The six members of this semaphorin class bind instead to
neuropilin-1 (np1) or to the neuropilin-2 (np2) homo-
dimeric receptors or to heterodimers of these two
neuropilins (17-20). Structurally, these two receptors are
related although the overall homology is only 44% (19).
Semaphorins in Cancer
753
Table 1. The receptors of some selected semaphorins.
Semaphorin
High affinity binding
receptor
Low affinity binding
receptor
Functional receptor References
S3a Np1 Np1/np1/plexin-A(1-2) 24
S3c Np1,Np2 (Np1/Np2)(?)/Plexin-A(?), plexin-D1 20,27, 24
S3f Np2 Np1 Np2/plexin-A(1-2) 24
S4a TIM-2 38
S4b Plexin-B1 Plexin-B1/MET CD-72 13,37
S5A Plexin-B3 Plexin-B3/MET 105
S6d Plexin-A1 Plexin-A1/VEGFR-2 14
Figure 2. The general structure of the neuropilins and their plexin co-receptors.
Their general structure is shown in Figure 2. Although it
was demonstrated that np1 is required for s3a induced
collapse of axonal growth cones, deletion of the
cytoplasmic domain of np1 did not inhibit s3a activity,
suggesting the existence of an independent signal
transducing moiety (21). It was subsequently found that the
four type-A plexins can form complexes with neuropilins in
which the plexins serve as the signal transducing partners
(15,22-24). Plexins belonging to the other three plexin
subfamilies may also be able to form complexes with
neuropilins, as demonstrated in the case of plexin-B1 and
np1 (15,25), and recent data indicates that plexin-D1 can
also transduce signals of class-3 semaphorins (Table-1)
(26,27).
The neuropilins form complexes with additional
cell surface molecules. Np1 was reported to form
complexes with L1, an adhesion molecule which seems to
be required under certain circumstances for s3a signal
transduction (28,29). Both np1 and np2 were also found to
function as receptors for specific heparin binding splice
forms of the angiogenic factor vascular endothelial growth
factor (VEGF) (30,31). Both neuropilins were observed to
form complexes with the VEGF tyrosine-kinase receptor
VEGFR-1 (32,33). The interaction with VEGFR-1 is
apparently required for np1 mediated repulsion of
migrating neuronal progenitor cells by s3a (34). Likewise,
it was reported that np1 forms complexes with VEGFR-2
(35,36). The formation of such complexes probably
accounts for the potentiation of VEGF induced cell
migration mediated via activation of VEGFR-2 (30).
4.3. Additional semaphorin receptors
S4d and semaphorin-4A (s4a) were recently
found to play important roles in immune responses (11).
CD-72, a membrane bound calcium dependent protein
belonging to the lectin super-family was found to function
as a s4d receptor in the immune system (37). Likewise,
Semaphorins in Cancer
754
TIM-2, a member of the T-cell immunoglobulin and mucin
domain proteins was found to function as a semaphorin-4A
(s4a) receptor in T cells (38).
5. SEMAPHORIN INDUCED SIGNAL
TRANSDUCTION
Activation of plexins by semaphorins, either
directly or indirectly via neuropilins, leads to diverse
biological responses. One of the best studied responses is
the s3a induced repulsion of axonal growth cones. The
repulsion is apparently triggered by local changes in cell
adhesion and actin cytoskeleton organization. Activation of
the plexins, results in phosphorylation of tyrosine residues
in the cytoplasmic domain of the plexins and subsequent
activation of signal transduction. Plexins can be
phosphorylated as a result of complex formation with
tyrosine-kinase receptors as recently demonstrated in the
case of plexin-B1 which is phosphorylated by the
hepatocyte growth factor receptor MET in response to s4d
(13). Complex formation with tyrosine-kinase receptors
also allows s4d to phosphorylate MET and to induce
invasiveness by activation of this receptor. Similarly,
complex formation between the s6d receptor plexin-A1 and
the VEGF receptor VEGFR-2 enables s6d induced
autophophorylation of VEGFR-2 and induction of VEGFR-
2 mediated signaling (14). Phosphorylation of plexins can
also be the result of semaphorin induced recruitment of
cytosolic tyrosine kinases. The binding of s3a to np1
induces the association of the tyrosine-kinase Fes/Fps with
plexin-A1 leading to plexin-A1 phosphorylation. In growth
cones of s3a responsive nerve cells Fes/Fps forms a
complex with the brain specific collapsin response
mediator protein-2 (CRMP-2) and with CRMP associated
molecule (CRAM). These two proteins are required for s3a
signaling to the actin cytoskeleton in responsive nerve cells
and are also phosphorylated by Fes/Fps in response to s3a
although their exact role is still unclear (39). Another
cytosolic tyrosine-kinase that was found to associate with
the intra-cellular part of plexin-A1 as well as plexin-A2 is
fyn. Fyn phosphorylates plexin-A2 in response to s3a and
attracts the cdk5 kinase, which is also phosphorylated by
Fyn. Activation of cdk5 by fyn was also found to be
essential for s3a mediated growth cone repulsion (40).
Another class of intracellular signal transducing
proteins that interact with plexins was found in studies
which utilized the genetic tools available in the drosophila
fruit fly system. It was found that plexin-A, a drosophila
plexin receptor, binds the MICAL-1 protein in response to
the drosophila semaphorin s1a. MICALs interact with
intermediate filaments and actin on the one hand, and are
putative flavoprotein monooxygenases on the other hand.
The oxidative activity of the MICALs may be important for
semaphorin signaling since monooxygenase inhibitors
inhibit MICAL mediated trunsduction of s3a signals
(41,42).
To affect the organization of the actin
cytoskeleton, semaphorin receptors modulate the activity of
the small GTPases RhoA, Rnd1, Rac1 and CDC42.
Activation of Rac and CDC42 usually triggers the
formation of lamellipodia and filopodia, respectively. In
contrast, activation of the Rho family members Rho1 and
Rnd1 leads to the formation of stress fibers. In neuronal
cells the responses are a bit different. RhoA activation
induces neurite retraction and Rac1 activation induces
neurite extension (43). Activation of Plexin-B1 by s4d
inhibits Rac1 signaling while simultaneously activating
Rho thus resulting in the collapse of growing growth cones
(44,45). These responses may well depend on the relative
cytoplasmic concentrations of the GTPases, as recently
demonstrated in the case of the C. elegans Rac1
homologue. In that case it was shown that changes in Rac1
concentration in neuronal cells can turn repulsion into
attraction and vice-versa (46). In contrast to plexin-B1,
plexin-A1 was not observed to bind Rac1 directly even
though Rac1 is known to play a crucial regulatory role in
the induction of s3a induced growth cone collapse (47). Out
of the Rho family GTPases tested only RhoD and Rnd1
were found to bind to plexin-A1. Interestingly, Rnd1
binding to plexin-A1 leads to a collapse of the actin
cytoskeleton even in the absence of s3a. RhoD on the other
hand antagonizes the effects of Rnd1 even though both
GTPases belong to the Rho family of GTPases (48).
Various guanine nucleotide exchange factors (GEFs) and
GTPase activating proteins (GAPs), which function as
regulators of GTPases, also modulate the activity of plexin
binding GTPases (49,50). The GTPases in turn regulate the
activity of downstream effectors such as the LIM kinase
which in turn regulates the phosphorylation state of cofilin,
an actin binding/cleaving protein that is required for s3a
induced growth cone collapse (51).
6. SEMAPHORINS AS MODULATORS OF TUMOR
PROGRESSION
The biological properties of the semaphorins
have been studied extensively with regard to their effects
on axon guidance and nervous system development.
However, it is now clear that their effects are not limited to
the nervous system. Many cell types in addition to nerve
cells express neuropilins and plexins indicating that
semaphorins may be able to affect their behavior. Cell
types expressing neuropilins include neural crest derived
cells (1), immune cells such as dendritic cells and T-cells
(52), neuro-endocrine cells (53,54), Mesothelial cells (55),
endothelial cells (30,56), and bone marrow stromal cells
(57) to name but a few. Plexins are also widely expressed
and are found in endothelial cells (58,59), in bone marrow
cells (60), in epithelial cells of the lung (61) as well as in
many additional types of non-neuronal cells. These
observations suggest that semaphorins may also affect the
behavior of cancer cells derived from cell types that
express semaphorin receptors. Indeed, several semaphorins
have now been found to affect tumor progression and
tumorigenesis.
6.1. Class-3 semaphorins in tumorigenesis and tumor
progression
The discovery of splice form specific vascular
endothelial growth factor receptors on endothelial cells (62)
and their subsequent identification as products of the np1
and np2 genes (30,63), has lead to the identification of both
Semaphorins in Cancer
755
neuropilin receptors as essential regulators of
vasculogenesis (64). These findings suggested that
semaphorins may also function as regulators of
angiogenesis. Since tumor expansion and tumor spread
depend upon tumor angiogenesis (65), it follows that some
class-3 semaphorins may also be able to modulate tumor
progression by modulating tumor angiogenesis. VEGF165
and s3a compete for an overlapping binding site located in
the extra-cellular domain of np1. S3a was indeed able to
inhibit VEGF165 induced migration of endothelial cells as
well as VEGF165 induced in-vitro angiogenesis,
presumably by inhibiting the effects of VEGF (66).
Subsequent experiments have shown that s3a can also
inhibit developmental angiogenesis in chick embryos, a
finding which suggests that s3a should also be able to
inhibit tumor angiogenesis (67,68). However, an effect of
s3a on tumor angiogenesis has not yet been demonstrated.
The effects of s3a may not be limited to the modulation of
tumor angiogenesis. Neuropilins are expressed by tumor cells
derived from prostate cancer (69,70), colon cancer (71),
Melanoma (72), pancreatic carcinoma (73) and breast cancer
(74,75) to name a few examples. MDA-MB-231 breast cancer
cells express large amounts of np1 and plexin-A1 and their
migration and spreading are inhibited by s3a (74,75).
VEGF165 competed with s3a for binding to np1 on these cells
and abrogated the inhibitory effects of s3a, indicating that
semaphorins such as s3a have the potential to function as anti-
metastatic agents, and that by this mechanism VEGF165 may
exert effects that are not dependent upon the presence of the
tyrosine-kinase coupled VEGF receptors (75). S3a was also
found to function as an inducer of neuronal apoptosis (76), a
process that seems to be mediated by MAP kinases (77). This
property may also represent another potential mechanism by
which s3a could affect tumor development and progression.
The genes encoding s3b and s3f have been
originally identified as genes that are lost in small cell lung
carcinoma, and have been therefore characterized as
potential tumor suppressor genes (78-80). It was shown that
the loss of s3b function resulting in tumor development can
also be due to epigenetic reasons such as de-novo promoter
methylation (81). Expression of s3f in small cell lung
carcinoma cells inhibited colony formation in soft agar and
expression of s3f in MCF-7 breast cancer cells inhibited
their adhesion and spreading (82). Over-expression of
either s3b or s3f in small cell lung carcinoma cells inhibits
their in-vivo tumor forming ability (83-85). The
localization of s3f in expressing tumor cells may be
important, as it was shown that in lung tumors cytoplasmic
localization of s3f is correlated with high VEGF expression
levels and increased tumorigenicity, suggesting that failure
to secrete s3f may promote tumor progression (86). In the
case of S3b, it was shown that s3b expression is induced by
the cell cycle gate-keeper gene p53. Thus, external signals
that induce p53 expression and inhibit the entry of cells into
the cell cycle such as UV irradiation also up-regulate s3b,
indicating that s3b may play a role in regulating the
entrance of cells into the cell cycle as part of the p53
associated machinery (87).
S3f functions as an agonist of the np2 receptor
(19,88) suggesting that s3f may also function as an
inhibitor of angiogenesis. In contrast with s3a, which
inhibits VEGF
165
binding to np1, s3f binding to np2 was
not inhibited by VEGF
165
(63). Nevertheless, s3f inhibited
both VEGF and bFGF induced endothelial cell proliferation
and angiogenesis, as well as the development of tumors
from tumor cells whose proliferation in cell culture was not
inhibited by s3f (58). These experiments suggest that s3f
interferes with the activities of these growth factors using a
mechanism that does not require competition with pro-
angiogenic factors for binding to shared receptors. Rather, the
experiments suggest that s3f inhibits VEGF and bFGF function
downstream of the receptor level, possibly by generating an
inhibitory intracellular signal that counteracts the signals
conveyed by these growth factors in endothelial cells.
S3a, s3b and s3f, have either been shown to
inhibit tumor development, or are expected to inhibit tumor
development based upon experiments suggesting that they
possess anti-angiogenic or anti-tumorigenic properties. The
data regarding other class-3 semaphorins is scant, but
indicates that some of these other class-3 semaphorins may
promote tumor progression rather than inhibit tumor
progression. Thus, S3c expression was found to be up-
regulated in cis-diamminedichloroplatinum (II) (CDDP)-
resistant ovarian cancer TYKnuR cells, in metastatic
human lung adenocarcinoma cells, and in malignant
melanoma cells indicating that up-regulation of s3c
expression may be linked to tumor progression (89-91).
Likewise, high level expression of s3e had been observed
in several metastatic cell lines originating from mouse
mammary adenocarcinoma tumors, indicating that high s3e
expression levels are linked to tumor progression (92).
6.2. Class 4 semaphorins and their role in tumor
progression
The membrane anchored class 4 semaphorin s4d
has recently become a focus of intensive research as a
result of its recently discovered role in immune recognition
(93), and as a result of its newly discovered role as a
regulator of tumor cell invasiveness. HGF/SF (hepatocyte
growth factor/scatter factor) induces scattering, invasion,
proliferation and branching morphogenesis, and plays a
role as a regulator of invasiveness and tumor spread in
many types of tumors (94,95). The HGF/SF tyrosine-kinase
receptor MET as well as MET like receptors such as the
RON receptor for macrophage stimulating protein contain a
conserved sema domain, and were recently found to
associate and form complexes with several types of
receptors belonging to the plexin-B subfamily. When a plexin-
B1/MET complex is challenged with s4d, the tyrosine-kinase
activity of MET is activated, just as if it were activated by
HGF/SF, leading to the phosphorylation of both MET and
plexin-B1. This in turn results in the stimulation of invasive
growth (13,96). These observations implicate s4d as a potential
inducer of tumor invasiveness and tumor progression, although
this has yet to be demonstrated experimentally. HGF/SF also
functions as an inducer of angiogenesis (97,98), indicating that
s4d may also be able to induce angiogenesis via a similar
mechanism.
Recently, the tyrosine-kinase receptor ErbB-2
was also found to form complexes with plexin-B1 and to be
Semaphorins in Cancer
756
phosphorylated in response to s4d (99). Mutations in ErbB-
2 are known to play a role in the induction of tumorigenesis
in breast cancer as well as in other types of cancer (100).
These observations suggest that activating mutations in
plexin-B1 may perhaps be able to induce activation of
ErbB2 and MET in the absence of any ligand and thereby
contribute to tumorigenesis. These possibilities will have to
be tested in the future.
6.3. Class 5 and 6 semaphorins and their role in tumor
progression
Class-5 semaphorins are anchored to cell
membranes and are characterized by seven type 1
thrombospondin repeats functionally important for
tumorigenicity and metastasis (Figure 1) (101). Deletion of
the drosophila lethal giant larvae gene leads to the
generation of highly invasive and widely metastatic tumors
on transplantation into adult flies. Random A p-element
insertion screen was used to identify genes that modulate
tumor progression and tumorigenicity. One of the genes
identified in this screen was the drosophila homologue of
s5c. S5c inactivation was found to inhibit tumor formation
in lethal giant larvae mutants, suggesting that it is required
for tumorigenesis. Further experiments indicate that s5c
probably associates, via its thrombospondin repeats, with
the TGF-β like ligand DPP somehow modulating DPP
induced signal transduction (102).
Vertebrates possess three s5c homologues (s5a,
s5b and s5d) (103,104), indicating that these homologues
may play a role in the development and progression of
human tumors too, although this hypothesis still requires
experimental proof. Recently, this assumption was
strengthened by experiments that have shown that s5a
activates plexin-B3, a receptor that also forms complexes
with the MET tyrosine-kinase receptor. As a result MET
undergoes autophosphorylation and phosphorylates plexin-
B3 (105). This is therefore one more example of a
semaphorin that interacts directly with a B type plexin and
activates as a result the MET tyrosine-kinase receptor
which had been previously shown to play a role in tumor
progression.
S6b belongs to the class-6 membrane anchored
semaphorins. S6b may also be linked to tumor progression
as it was found to be expressed in two different human
glioblastoma cell lines, and its levels were down-regulated
by trans-retinoic acid, an anti-tumorigenic, differentiation
promoting agent (106). In addition, recent evidence has
implicated s6d as a possible regulator of angiogenesis. It is
not known whether tumor cells express s6d, but the fact
that its receptor, plexin-A1 was found to form complexes
with the VEGF receptor VEGFR-2 and to affect
angiogenesis suggests that s6d may have the potential to
affect tumor angiogenesis (14).
7. CONCLUSIONS
During the complex process in which normal
cells turn into malignant cancer cells the tumorigenic cells
acquire an invasive character, become less adhesive and
induce angiogenesis as well as lymphangiogenesis. Normal
cells are also capable of invasive migration and under
appropriate conditions will induce angiogenesis and
lymphangiogenesis. However, in normal tissues there are
multiple regulatory mechanisms that limit and channel
these activities. It is the breakdown of the regulatory
mechanisms that is a hallmark of the tumor tissue formed
by malignant cells. The semaphorins are now emerging as
key regulators of these key processes of tumor progression.
The scanty data that we already have indicates that the
various semaphorins are critical regulators of these
processes, and that the evasion or subversion of semaphorin
mediated regulation of these processes can play a key role
in tumor progression. We have so far only touched the tip
of the iceberg as far as our understanding of the role of the
semaphorins in tumor progression is concerned. The next
few years will likely result in a flood of information, out of
which it is hoped that new and efficient cancer therapies
will emerge.
8. ACKNOWLEDGEMENTS
This work was supported by grants from the
Israel Science Foundation (ISF), By a grant from the
Ministry of Science, Joint program with Germany
(Deutsches Krebsforschungszentrum), By a grant from the
Germany-Israel science Foundation (GIF) and by the
Rappaport Family Institute for Research in the Medical
Sciences of the Faculty of Medicine at the Technion, Israel
Institute of Technology (to G. Neufeld). The costs of
publication of this article were defrayed in part by the
payment of page
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Abbreviations: The names of all semaphorins are
abbreviated according to the following rules: S always
appears as the first denoting a semaphorin. The number
after the S designates the semaphorin to a specific class,
and the final letter designates its place within the class.
Thus, S3F means semaphorin-3F while S4D means
semaphorin-4D.
Key Words: Tumor progression, tumorigenesis,
semaphorin, review, neuropilin, plexins, angiogenesis,
metastasis, invasion, Review
Send correspondence to: Dr Gera Neufeld, Cancer and
Vascular Biology Research Center, Rappaport Research
Institute in the Medical Sciences, The Bruce Rappaport
Faculty of Medicine, Technion, Israel Institute of
Technology, 1 Efron St., P.O. Box 9679, Haifa, 31096,
Israel, Tel: 972-4-8523672, Fax:972-4-8523947, E-mail:
gera@techunix.technion.ac.il
http://www.bioscience.org/current/vol10.htm
