Cancer and Metastasis Reviews 22: 337358, 2003.

# 2003 Kluwer Academic Publishers. Manufactured in The Netherlands.

Src family kinases in tumor progression and metastasis

Justin M. Summy and Gary E. Gallick*
The University of Texas M.D. Anderson Cancer Center, Department of Cancer Biology, Houston TX 77030,
USA

Key words: Src, protein tyrosine kinase, tumor progression, angiogenesis, cell survival
Summary
The Src family of non-receptor protein tyrosine kinases plays critical roles in a variety of cellular signal
transduction pathways, regulating such diverse processes as cell division, motility, adhesion, angiogenesis,
and survival. Constitutively activated variants of Src family kinases, including the viral oncoproteins v-Src
and v-Yes, are capable of inducing malignant transformation of a variety of cell types. Src family kinases,
most notably although not exclusively c-Src, are frequently overexpressed and/or aberrantly activated in a
variety of epithelial and non-epithelial cancers. Activation is very common in colorectal and breast cancers,
and somewhat less frequent in melanomas, ovarian cancer, gastric cancer, head and neck cancers,
pancreatic cancer, lung cancer, brain cancers, and blood cancers. Further, the extent of increased Src family
activity often correlates with malignant potential and patient survival. Activation of Src family kinases in
human cancers may occur through a variety of mechanisms and is frequently a critical event in tumor
progression. Exactly how Src family kinases contribute to individual tumors remains to be dened
completely, however they appear to be important for multiple aspects of tumor progression, including
proliferation, disruption of cell/cell contacts, migration, invasiveness, resistance to apoptosis, and
angiogenesis. This review details the evidence for Src family activation in human tumors, and
emphasizes possible consequences to tumor progression. Given the ability of Src and its family members
to participate in so many aspects of tumor progression and metastasis, Src family kinases are attractive
targets for future anti-cancer therapeutics.

Introduction
In 1911, the young pathologist, Peyton Rous,
isolated from a chicken the virus that has
continued to bear his name, Rous Sarcoma Virus
[1]. While Rous was able to fulll all of Kochs
postulates with respect to demonstrating that the
virus was an etiologic agent for sarcomas in these
birds, the full signicance of the work went
unrecognized for decades, and it was not until
1966 that he was to win the Nobel Prize in
Medicine for his accomplishments. As is now
obvious, Rous Sarcoma Virus was the archetypal
retrovirus, which collectively harbor transforming
* Corresponding author.
E-mail: ggallick@mdanderson.org

genes that were to revolutionize our understanding

of signal transduction and cancer biology. Rous
Sarcoma Virus and its transforming gene termed
Src (originally because it induced Sarcomas in
infected birds) have been at the vanguard of
advances in our understanding of signal transduction and malignant transformation. By an elegant
strategy using tumor bearing rabbit serum [2], Src
was the rst transforming protein isolated.
Through then very tedious molecular approaches,
Bishop and Varmus [3] demonstrated that the viral
Src gene (v-src) had as its progenitor a normal
cellular gene (proto-oncogene) c-src, an experiment largely responsible for the awarding of the

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Summy and Gallick

Nobel Prize in Medicine to them in 1989. Src was

also discovered to be the rst gene product with
intrinsic protein tyrosine kinase activity [4].
With such an illustrious history, one would
expect alterations in Src would also play a leading
role in understanding how aberrant activation of
proto-oncogenes was important in human tumorigenesis and tumor progression. However, such
has not been the case. Because Src is rarely
mutated in human tumors, and amplications
and rearrangements of the gene in tumors are even
rarer, establishing a clear role for Src in human
cancers has proven difcult. Nevertheless, as our
knowledge of signal transduction has increased,
and the central role of Src in many signaling
processes continues to be discerned, the concept
has become better established that abnormal
regulation of Src and its family members are
critical in many types of tumors. This review will
rst briey describe Src structure and function,
then focus on the best studied tumors in which
aberrant expression or activity of Src may be
critical to the disease.

The Src family of protein tyrosine kinases

The Src family kinases (SFKs) comprise a subclass of membrane-associated non-receptor tyrosine kinases that are involved in a variety of
cellular signal transduction pathways. There are
nine members of the Src family, including c-Src,
c-Yes, Fyn, Lyn, Lck, Hck, Blk, Fgr, and Yrk.
Most Src family kinases are expressed primarily in
cells of hematopoietic origin. C-Src, c-Yes, and
Fyn, however, display a much more ubiquitous
pattern of expression, with particularly high levels
in platelets, neurons, and some epithelial tissues
[5]. Src family kinases are activated in response to
cellular signals that promote proliferation, survival, motility, and invasiveness, including activation of cytokine receptors, receptor protein
tyrosine kinases, g-protein coupled receptors, and
integrins [5]. Their involvement in these normal
cellular signaling pathways, coupled with the
ability of constitutively active Src family kinases
to induce cell transformation, has sparked a keen
interest in the role Src family kinases may play in
the onset or progression of human cancers.
Indeed, c-Src and c-Yes are overexpressed and/or

hyper-activated in a variety of human epithelial

cancers, while the primarily hematopoietic-specic
SFKs may be involved in the growth and
progression of some leukemias and lymphomas.

Src family kinase structure and regulation

The ability of the avian viral oncoproteins v-Src
and v-Yes to induce broblast cell transformation
suggests that their cellular counterparts, c-Src and
c-Yes, have the potential to contribute to human
carcinogenesis. V-Src and v-Yes are encoded by
avian retroviruses and are capable of inducing
sarcomas in chickens and transforming chicken
embryo broblast cells in culture [6,7]. To understand how these proteins are able to induce cell
transformation, it is important to understand the
functional domain architecture shared by all Src
family kinases, and the role of these domains in
both regulating tyrosine kinase activity and
recruiting additional proteins into signaling complexes. These aspects have been reviewed extensively elsewhere [5,8], and will only be discussed
briey here.
All Src family kinases are comprised of an
amino terminal membrane localization signal, also
known as the Src homology 4 or SH4 domain, a
poorly conserved unique domain, an SH3 domain,
SH2 domain, tyrosine kinase domain, and a
regulatory sequence [8]. Src family kinases are
kept inactive through an elegant series of intramolecular interactions that restrict the accessibility
of the kinase domain active site for ATP and
substrates. The inactive or closed conformation is
attained via phosphorylation of a conserved
tyrosine residue (Y527 in avian c-Src), near the
carboxy terminal tail of the protein, which forms
an intramolecular interaction with the SH2
domain [9,10]. Working cooperatively with the
SH2/tail interaction is an association between the
SH3 domain and the short stretch of amino acids
linking the SH2 and kinase domains [9,10].
Together, these intramolecular interactions not
only limit accessibility of the kinase domain but
also the binding surfaces of the SH3 and SH2
domains, thus further limiting the potential for
these proteins to participate in cellular signaling.
The viral proteins v-Src and v-Yes, through loss
of sequence in their carboxy-terminal tails, are no

Src family kinases in tumor progression and metastasis

longer able to be regulated through intramolecular

interactions and thus are constitutively active and
transformation-competent [6,7]. Mutation of Y527
in c-Src to phenylalanine also results in an active
and transformation competent protein [1113].
However, although there has been at least one
report of a c-Src activating mutation present in
human colon cancer [14], genomic mutation is not
the predominant mechanism of SFK activation in
human cancers. In the absence of mutation, kinase
activity may be augmented through displacement
of the intramolecular interactions via higher
afnity binding between the SH3 and SH2
domains and their cellular ligands and/or through
dephosphorylation of the carboxy-terminal regulatory tyrosine, normally phosphorylated by the
C-terminal Src kinase (Csk) and closely related
kinases [8,15,16]. Src family kinase activation
arises through multiple mechanisms, differing not
only between different cancers, but also within a
particular subclass of cancers. Regardless of the
mechanism, the constitutively high specic activity
of SFKs in a large number of human tumors, even
in the absence of activating mutations suggest that
they may be important in the malignant process.
Further, as discussed throughout this review, the
rarity of activating mutations suggest that SFK
activation may be more critical for tumor progression than tumor initiation.
How then do SFKs contribute to the progression of cancers? The available evidence would
suggest that they are capable of promoting several
aspects of tumor progression and metastasis. The
hallmarks of a metastatic cancer are multi-fold
[17]. Regulation of Src family members has been
implicated in several of these, including aberrant
proliferation; increased motility and invasiveness;
resistance to apoptosis; and angiogenesis. Not
surprisingly, these are normally regulated, in part
by Src family members during development,
differentiation, and homeostasis. In this review,
we will focus on how their aberrant regulation
leads to tumor progression in a variety of human
tumors.

Colorectal carcinoma
The activation and functions of Src family kinases
have been more extensively studied in colon cancer

339

than in any other human cancer. The initial studies

of c-Src in colon cancer were largely correlative
and indicated that c-Src protein levels and/or
kinase activity are frequently elevated in colon
carcinomas relative to normal colonic mucosa. In
1986, Rosen and co-workers [18] discovered
elevated c-Src kinase activity in all colon cancer
cell lines studied. Similarly, Bolen et al. [19]
reported elevated c-Src specic kinase activity in
colon carcinoma tissues and cell lines, relative to
normal colonic mucosa. The elevated kinase
activity was not due solely to elevated c-Src
protein expression levels. Furthermore, the elevated kinase activity appeared to be the result of a
post-translational modication, as in vitro translated mRNA from colon tumor cells did not result
in c-Src protein with elevated kinase activity
relative to that from normal colonic mucosa [19].
Similar results were obtained by Cartwright et al.
[20].
Later studies demonstrated that c-Src kinase
activity positively correlated with the malignant
potential of the cells, providing evidence that c-Src
activation contributes to the progression of colon
cancer toward the metastatic phenotype. In colon
cancer, evidence suggests that Src activation might
contribute both to early and later stages of tumor
progression. In 1990, Cartwright and colleagues
determined that c-Src kinase activity was elevated
in adenomatous polyps relative to normal mucosa,
and that adenomas with the greatest malignant
potential, having a villous structure and severe
dysplasia, displayed the highest kinase activity
[21]. Further studies from this laboratory determined that c-Src kinase activity was elevated in
premalignant ulcerative colitis lesions, and that,
again, those lesions with the greatest dysplasia and
thus the greatest potential for progression to
carcinoma, displayed the highest levels of c-Src
activity [22].
Results obtained by Weber et al. [23] indicated
that c-Src activity is highest in moderate to well
differentiated colonic lesions, while poorly differentiated carcinomas displayed c-Src kinase activity
similar to normal colonic mucosa. These studies
have not been pursued further to determine
whether cell composition (tumor versus stromal
cells; necrosis, etc.) might have contributed to this
observation. Talamonti and co-workers [24], in
1993, compared levels of c-Src activity from

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colonic polyps, primary tumor lesions, and liver

metastases. In these studies it was observed that
Src kinase activity was elevated in pre-malignant
polyps, higher still in primary colonic lesions, and
highest in liver metastases. These results again
provide correlative evidence that c-Src activity
may promote progression toward the metastatic
phenotype. Studies by Termuhlen et al. [25]
conrmed these results and indicated that the
increased c-Src activity in hepatic metastases was
specic for colon carcinoma, as non-colon-derived
hepatic metastases displayed little elevation in cSrc activity. However, increased c-Src activity was
not limited to hepatic metastases, as extrahepatic
colonic metastases displayed elevated c-Src activity, which was on average, 5.7 fold higher than
that detected in hepatic metastases [25]. These
results indicate that c-Src activity may contribute
to the metastatic progression of colonic metastases, regardless of the site of metastasis. Interestingly, although the majority of the available data
indicate that c-Src kinase activity increases with
increasing metastatic potential in colon carcinomas, there are some reports that indicate that c-Src
activation occurs primarily in the early stages of
colon cancer progression. Sakai et al. [26] reported
that adenomas displayed stronger immunohistochemical staining for active c-Src than did more
advanced adenocarcinomas. Iravani et al. [27], in
1998, reported that c-Src expression and kinase
activity were highest in adenomatous colon tissue,
relative to normal colonic mucosa, primary
carcinoma lesions, or synchronous metastatic
lesions. These results suggest that c-Src activation
contributes to cancerous progression primarily in
the early stages of carcinoma formation. The
reasons for these discrepancies are unclear; however, it may simply indicate that c-Src activation,
while occurring frequently in the progression of
colonic epithelium toward the metastatic phenotype, is not necessarily a requirement at every stage
of progression. Nevertheless, the majority of
studies using human tissue suggest that c-Src
activation likely contributes to malignant progression of colon cancer. Perhaps the strongest
correlative evidence that Src contributes to tumor
progression was obtained when Allgayer et al. [28]
recently reported that elevated c-Src activity served
as an independent indicator of prognosis at all
stages of carcinoma. The ability of Src activation to

predict tumor cell survival has future implications

in therapeutic treatment of colon cancer.
Although c-Src is frequently activated in human
colon cancer, it is not the only Src family kinase
whose activation corresponds with malignant
progression. C-Yes is also frequently activated in
colon carcinoma. Park and colleagues, in 1993,
demonstrated that c-Yes kinase activity was
elevated in three of ve colon cancer cell lines
and 10 of 21 primary colon carcinomas, relative to
normal colonic mucosa [29]. It was reported in this
study that the elevated c-Yes kinase activity was
largely attributable to elevated protein levels. Pena
et al. [30] reported in 1995 that, similar to c-Src, cYes kinase activity was also elevated in premalignant lesions of the colon and that the degree of cYes activation correlated positively with the likelihood of malignant progression. Adenomas at
highest risk for progression to cancer, those greater
than 2 cm in diameter with severe dysplasia and a
villous architecture, displayed the highest level of
c-Yes kinase activity [30]. In 1996, Alexander and
colleagues demonstrated that c-Yes message levels
were elevated in inammatory bowel disease (IBD)
lesions, relative to normal colon [31]. C-Yes
message levels were higher in IBD patients who
were resected for colon cancer than those who were
not [31]. Interestingly, Han et al. [32] reported that,
similar to c-Src, c-Yes is frequently activated in
colon cancer liver metastases. However, rarely are
both kinases found to be activated in the same
tumor and c-Yes activation generally corresponds
with a worse clinical prognosis than does c-Src
activation in liver metastases.
Given the high homology between c-Src and cYes, it is frequently assumed that they perform
redundant functions. While there is considerable
evidence to support this notion, several studies in
recent years have also indicated specicity in
signaling between c-Src and c-Yes. Thus the
question arises as to whether c-Src and c-Yes are
regulated in the same fashion in colon carcinoma
and whether or not they perform unique or
redundant functions. Unfortunately, very little is
known about the role of c-Yes in colon. It is
known, however, that cells from c-src
/
mice
are decient in several processes that are dependent on the dynamic regulation of the actin
cytoskeleton, including motility, cell spreading,
membrane rufing, and neurite extension [3336].

Src family kinases in tumor progression and metastasis

C-Yes is evidently unable to compensate for the

lack of c-Src in these processes. Regulation of
actin cytoskeleton dynamics is crucial to the
motility, invasiveness, and metastatic spread of
tumor cells, and thus the contributions of c-Yes to
colon carcinoma progression may differ from
those of c-Src. The data from Han et al. [32]
indicate that c-Src and c-Yes may be regulated
differently in colon cancer, and thus may make
unique contributions to colon cancer progression.
Interestingly, a third Src family kinase, Lck, is
also occasionally expressed in human colon
carcinoma cells [37]. This is of note due to the
fact that Lck expression is typically limited to cells
of hematopoietic origin. Lck expression in colon
cancer arises as a result of abnormal activation of
the type 1 Lck promoter, possibly due to the loss
of a transcriptional repressor [38]. The contribution of Lck to colon cancer progression, however,
has not been extensively studied and remains
poorly understood.

Src family kinases contribute directly to colon

tumor growth
The works cited above provide strong, but only
correlative evidence for a role for Src family
kinases in the progression of colon carcinoma
toward the malignant phenotype. Using cell line
models, several studies in recent years, however,
have provided more direct evidence that Src family
kinases play an important role in colon cancer progression. These studies involve ectopic expression
of c-Src or an activated variant or downregulation
of c-Src expression and/or kinase activity.

Ectopic expression of c-Src in colon cancer

In 1997, Irby et al. [39] transfected poorly
metastatic human colon tumor cell lines with a cSrc expression vector, resulting in clones that
expressed 410 fold higher levels of c-Src than
controls. These studies demonstrated that c-Src
overexpression did not affect cell proliferation in
vitro or metastatic spread of the tumor cells when
injected into nude mice, however, the growth of
primary tumors derived from these colon tumor
cells was signicantly enhanced in nude mice,

341

relative to wild type cells. The lack of effect on

metastatic spread of cancer cells in this study may
have been due to the fact that the overexpressed cSrc was not hyper-activated. Pories et al. [40]
demonstrated soft agar growth and increased
invasive potential upon overexpression of c-Src
in rat epithelial cell lines. Both of these studies
indicate that c-Src can contribute to different
aspects of tumor growth and/or progression
toward the metastatic phenotype.

Inhibition of Src family kinase activity in colon

tumor cells
Several methods have been used to downregulate
Src kinase activity, and these have provided
important contributions to the overall knowledge
of the role of Src family kinase activation in colon
cancer. In 1991, Garcia and colleagues [41]
demonstrated that treatment of human colon
tumor cell lines with the tyrosine kinase inhibitor
herbimycin A caused a reduction in c-Src kinase
activity, followed by subsequent reductions in cSrc protein levels and growth of colon tumor cells.
Herbimycin A treatment resulted in 40% growth
inhibition of colon tumor cell lines, as compared
with a 12% growth inhibition of a normal colon cell
line [41]. Kawai et al. [42] recently demonstrated
that herbimycin A treatment of colonic epithelial
cells expressing activated Src inhibited the proinvasive effects of TNF-a in these cells, indicating a
possible role for c-Src or SFK activation in the
progression of colon cells from inammatory
lesions such as ulcerative colitis to a cancerous
state. Interestingly, Novotny-Smith and Gallick
[43] demonstrated that prolonged TNF-a treatment
of TNF sensitive derivatives of the HT-29 colon
carcinoma cell line displayed reduced c-Src kinase
activity and cell proliferation in response to treatment with TNF-a. However, the reduction in cell
proliferation occurred prior to the decrease in c-Src
activity and thus was not likely caused by it.
Another strategy used to downregulate Src family
kinase activity is overexpression of the Src family
negative regulator Csk. Nakagawa et al. [44] utilized
an adenovirus expression system to overexpress Csk
in a mouse colon adenocarcinoma cell line. Cells
expressing Csk were able to form primary tumors in
mice but were decient in metastatic spread and in

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their ability to invade through Matrigel in vitro.

More recently, Boyer et al. [45] produced similar
results, expressing Csk or dominant negative
(kinase dead) Src in a rat carcinoma cell line. These
cells again were decient in their ability to form
metastases when implanted in mice, while still
retaining the ability to form primary tumors.
Overexpression of Csk or dominant negative Src
are useful tools for studying the collective role(s)
of Src family kinases in biologic systems. However,
because these strategies result in inhibition of
multiple Src family members (and often other
signaling molecules as well) they are unable to
provide insights with respect to contributions of
individual family members. To circumvent this
problem, Staley et al. [46] utilized a c-Src antisense
construct to effect exclusive downregulation of
c-Src in the colon cancer cell line HT-29. Clonal
transfectants obtained with the c-Src antisense
construct proliferated more slowly than parental
cells or cells transfected with a sense construct in
vitro. When injected into nude mice, the antisenseexpressing cells formed dramatically slower-growing tumors than did sense-expressing or wild type
HT-29 [46]. Not only do these data indicate the
importance of c-Src in the growth of human colon
tumor cells, but they reveal the importance of
specicity between Src family kinases, as c-Yes
protein expression levels and kinase activity were
not affected by the c-Src antisense construct.

Mechanisms of Src family kinase activation in

colon cancer
The studies discussed above indicate the importance of Src family kinase activation in the
progression of colon tumors; however, they do
not address the question of how Src family kinases
are activated in human colon cancer. The best
current data suggest that multiple mechanisms
contribute to Src activation in colon tumor cells.
Di Domenico and co-workers demonstrated that
both c-Src and c-Yes are activated upon estradiol
stimulation of Caco-2 colon carcinoma cells [47].
The method of activation was not determined;
however, the elevated tyrosine kinase activity
appeared to be important for downstream MAP
kinase activation and cell proliferation. Mao and
colleagues [48], in 1997, demonstrated that highly

metastatic colon cancer cell lines displayed elevated c-Src kinase activity that was further
enhanced upon stimulation with various mitogens.
Specically, stimulation of the EGF receptor,
Her2/Neu, and c-Met were found to induce c-Src
activation. EGFR was demonstrated to associate
with c-Src, indicating a potential SH2 displacement
mechanism for activation of c-Src in response to
these mitogens [48]. C-Src also associates similarly
with the protein tyrosine kinase receptor for
hepatocyte growth factor/scatter factor, c-Met.
We have demonstrated that Src activation resulting
from overexpression of c-Met contributes to the
tumorigenic and metastatic potential of colon
tumor cells (Herynk et al., submitted).
The regulation of Src family kinases by phosphorylation/dephosphorylation of the regulatory
tyrosine residue has been studied in some detail in
human colon cancer. In 1987, DeSeau et al. [49]
reported that despite no detectable differences in
tyrosine phosphatase activity between lysates of
normal colon cells and colon carcinoma cells,
treatment of cells with the phosphatase inhibitor
sodium vanadate resulted in increased c-Src kinase
activity from normal colon cells but not colon
tumor cells. These experiments indicate differences
in c-Src regulation between normal and cancerous
colon cells. Park and Cartwright [50] reported in
1995 that c-Src activity was elevated in colon
cancer cells above normal colonic epithelium and
was further increased 2- to 3-fold during mitosis of
colon carcinoma cells, indicating a potential role
for c-Src in progression through the cell cycle. This
increased activity corresponded with a decrease in
phosphorylation at the regulatory tyrosine residue.
Interestingly, in these cells, c-Yes activity and
protein levels decreased during mitosis, again
indicating differential regulation, and thus potentially differential functions, between c-Src and cYes in colon cancer [50]. Peng and Cartwright [51]
reported that Src and the tyrosine phosphatase
SH-PTP2 (Syp) were capable of co-association and
that this co-association resulted in phosphorylation of Syp by active Src and dephosphorylation of
Src Y527 by Syp, causing activation of both
enzymes. Zheng et al. [52] reported that Src
phosphorylation of PTP alpha at tyrosine 789
results in PTP alpha binding to the Src SH2
domain and dephosphorylation of Src at Y527
[52]. These studies indicate that c-Src may be

Src family kinases in tumor progression and metastasis

activated through both SH2 displacement and

Y527 dephosphorylation.
Phosphorylation of Y527, a critical aspect of
regulation of Src, is accomplished by Csk and its
family members. Cam and colleagues [53] demonstrated a mild reduction in Csk message levels,
protein levels, and kinase activity in colon
carcinoma tissues and cell lines, relative to normal
colon cells, and this correlated inversely with c-Src
protein levels and kinase activity, which were
elevated in the cancerous cells.
There has been one report of mutational
activation of c-Src in colon cancer. In 1999, Irby
et al. [14] reported a truncating mutation at residue
531 that resulted in an activated and transformation-competent c-Src variant in 12% of advanced
human colon cancers tested. However, this mutation has not been detected by other groups in
subsequent studies [5456]. Thus, while mutations
in Src that directly contribute to metastasis
provide a very important demonstration of the
role of Src in tumor progression, they do not
appear to represent a common mechanism of c-Src
activation in human colon cancer.
Finally, Rajala et al. [57] provided evidence that
c-Src protein levels and kinase activity may be
regulated in part by N-myristoyltransferase activity. These studies demonstrated that N-myristoyltransferase activity is higher in colonic epithelial
neoplasms than normal colonic tissue and that this
corresponds with increased levels of c-Src and
decreased expression of the N-myristoyltransferase
inhibitory protein (NIP71). Collectively, these data
suggest that, in most colon tumor cells, Src
activation is secondary to a variety of epigenetic
events (e.g. overexpression of growth factor
receptors, changes in integrin composition/function, changes in Csk regulation) that occur during
colon tumor progression. However, once activated, Src further contributes to the process.

Functions of Src family kinases in colon

cancer progression
Src family kinases in colon cancer motility,
invasiveness, and detachment
The above mentioned studies by Staley et al. [46]
and Irby et al. [14,39] indicate that c-Src activity is

343

important for proliferation and growth of primary

tumors derived from human colon cancer cells.
Aside from the role of c-Src in proliferation,
several recent studies indicate that Src contributes
to the motility and invasiveness of colon cancer
cells. It has long been known that c-Src plays an
important role in the dynamic regulation of the
actin cytoskeleton, and processes dependent on
this regulation, including cell motility, cell/matrix
adhesion, and cell/cell adhesion [8]. Brunton et al.
[58] demonstrated that during the adenoma to
carcinoma transition of colonic epithelia, levels of
EGF receptor and FAK were increased. Furthermore, EGF induced movement of the cells into the
basement membrane, coinciding with increased cSrc kinase activity, redistribution of c-Src to the
cell periphery, and enhanced phosphorylation of
FAK.
C-Src or Src family kinases may also contribute
to the invasiveness of colon carcinoma cells
through upregulated expression of matrix proteases that facilitate the degradation of the basement membrane necessary for tumor invasiveness.
Allgayer et al. [59] demonstrated that activated cSrc can induce transcription of the urokinase
plasminogen activator receptor, and transcription
of the gene for this receptor is blocked by
inhibitors of Src family kinases. Additionally,
Nakagawa et al. [44] demonstrated that overexpression of Csk in colon tumor cells results in
reduced expression of the matrix metalloprotease
MMP-2.
Another important event in the progression of
colon cancer to the metastatic phenotype is the
disruption of cadherin-mediated cell/cell contacts.
Studies in other systems have indicated that Src
family kinase activity will disrupt cell/cell junctions mediated by cadherins [8,60]. Irby and
Yeatman [61] recently demonstrated that expression of active c-Src in colon cancer cell lines
resulted in up to a 7-fold decrease in cell/cell
adhesion, accompanied by cadherin phosphorylation and loss of cadherin/catenin association.
Expression of dominant negative Src or incubation
with a Src family kinase inhibitor restored adhesion, demonstrating that the effect was specic for
activated Src family kinases. In a recent study,
Avizienyte et al. [62] went a step further and
attempted to determine whether it was the kinase
activity of activated c-Src or the enhanced avail-

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ability of the SH3 and SH2 domains that was

responsible for de-regulation of the E-cadherin
system in colon cancer cells. In this study, they
demonstrated that elevated c-Src activity caused
several of the components of adherens junctions to
re-distribute to integrin-based adhesion complexes, formed upon expression of active Src.
Additionally, they showed that while the noncatalytic domains were sufcient for formation of
integrin-adhesion complexes, they were not sufcient to induce disruption of E-cadherin containing cell/cell contacts [62].
For cells to metastasize, they must detach from
the primary tumor and surrounding cellular
matrix. This loss of attachment in normal cells
results in a form of programmed cell death termed
anoikis. Windham et al. [170] recently demonstrated that c-Src activation contributes to anoikis
resistance in colon carcinoma cells, through the
phosphatidylinositol 3-kinase (PI3K)/Akt pathway. In these studies, inhibiting Src family kinase
activity or downregulation of c-Src specically
through an antisense construct increased the
susceptibility of HT29 cells to anoikis. Conversely,
overexpression of activated c-Src in colon cancer
cells that express low levels of endogenous c-Src
enhanced the resistance of these cells to anoikis.
Increased c-Src expression/activity resulted in
increased Akt phosphorylation, but not that of
Erk 1/2.

decreased VEGF expression in HT29 colon

carcinoma cells, but the ability of hypoxia to
induce VEGF expression was decreased by over 50
fold in the c-Src antisense cells. Tumors formed by
these cells in nude mice showed a signicant
decrease in vascularity, in comparison to parental
cells, thus indicating that c-Src specically may
play an important role in the angiogenesis of colon
cancer cells in which it is activated. These data
suggest a biologic mechanism by which Src
activation might contribute to tumor progression,
as increased activity of Src would contribute to
angiogenesis in the growing tumor.
In a nal note on the role of c-Src in colon
cancer progression, Malek et al. [66] recently used
gene chip technology to compare the expression of
genes in human colon cancer cells to those induced
in Src-transformed rat broblasts. Several genes
were found to be transcriptionally activated in
both the Src-transformed broblasts and the colon
tumor cells, including cell cycle proteins, cytoskeletal proteins, and transcription factors. Technology such as this may help provide a more detailed
understanding of genes that are transcribed downstream of activated c-Src in colon carcinoma cells.
Such knowledge would certainly be useful in
improving the understanding of the roles of c-Src
and related proteins in the progression of colon
carcinoma.

Src family kinases in colon cancer angiogenesis

Breast carcinoma

The role of SFKs in colon cancer angiogenesis has

come under more intense investigation in recent
years. A critical study of Mukhadopathyay [63]
demonstrated that Src, but not its family members,
was critical to hypoxia-induced expression of
vascular endothelial growth factor (VEGF) in
broblasts. Thus, given the above studies demonstrating the importance of Src in tumorigenic
growth, and the slow rate of growth of tumor cells
resulting from Src reduction, the possibility that
Src may be exerting its effect, at least in part
through VEGF expression has been investigated.
Fleming et al. [64] demonstrated that levels of
vascular endothelial growth factor, an important
angiogenic factor, varied directly with c-Src levels.
Ellis et al. [65] demonstrated that not only did
antisense-mediated c-Src downregulation result in

Although the functions of Src family kinases in

breast cancer have not been studied to the extent
that they have in colon cancer, considerable data
support a role for SFKs in the progression of this
cancer as well. In 1983, Jacobs and Rubsamen [67]
demonstrated elevated c-Src kinase activity in
breast carcinoma tissue, in comparison to normal
breast epithelium. In 1986, Rosen et al. [18]
reported similar ndings. In 1989, Lehrer and
colleagues [68] attempted to determine if elevated
c-Src kinase activity was associated with any
clinical parameters. Their studies indicated that
tumors expressing the progesterone receptor generally displayed higher c-Src kinase activity than
those that did not. Koster et al. [69] demonstrated
that 2530% of breast cancer specimens studied
displayed signicant expression of at least one

Src family kinases in tumor progression and metastasis

proto-oncogene, including c-src, erbB, raf1, lck,

and H-ras. In the rst comprehensive study of
human breast tumors, Ottenhoff-Kalff et al. [70]
reported in a study of 72 breast cancer specimens,
that all tumor samples displayed elevated tyrosine
kinase activity relative to normal controls and that
70% of this tyrosine kinase activity could be
attributed to c-Src. In 1996, Verbeek and coworkers [71] utilized immunohistochemical staining, along with in vitro kinase assays and western
blots, to demonstrate that c-Src protein expression
and kinase activity were elevated in breast cancer
tissue, relative to normal breast tissue. Similar
results were obtained by Reissig and colleagues
[72]. In both studies, c-Src protein levels and
kinase activity were found to be elevated relative
to non-cancerous tissue.

Mechanisms of Src family kinase activation in

breast cancer
As with colon cancer, multiple mechanisms lead to
SFK activation in breast carcinomas. Breast
cancer cells frequently overexpress members of
the EGFR family of receptor tyrosine kinases,
including EGFR and Her2/Neu [73]. As SFKs are
known to be activated downstream of receptor
tyrosine kinases via displacement of the tail
phosphotyrosine from the SH2 domain with
higher afnity phosphotyrosine residues on the
receptor [7478], this may represent an important
mechanism of SFK activation in breast cancer
cells. Luttrell et al. [79] demonstrated that the cSrc SH2 domain associated with activated EGFR
and Neu from breast cancer cell lines. Additionally, endogenous c-Src was shown to associate
with the activated EGFR. In 1994, Oude Weernink et al. [80] demonstrated EGF-dependent
enhanced c-Src kinase activity from cells overexpressing EGFR. Meanwhile, Muthuswamy and
co-workers [81,82] found evidence for c-Src
activation downstream of Neu in a mouse model
system. In this system, transgenic mice develop
mammary tumors as a result of Neu expression
under the control of the mouse mammary tumor
virus promoter/enhancer. C-Src activity was
shown to be 6 to 8 fold higher in tumors than
the surrounding mammary epithelium, and c-Src

345

formed a stable complex with Neu, indicating that

c-Src activation was likely due to an SH2
displacement mechanism [82]. Muthuswamy and
Muller [83] later demonstrated that c-Src association with Neu was dependent on tyrosine phosphorylation of Neu, and was likely dependent on
the c-Src SH2 domain. Interestingly, in their
system, c-Src did not associate with EGFR, and
EGF stimulation of cell lines overexpressing
EGFR resulted in transphosphorylation of Neu
and co-association of Neu and c-Src. This same
group of investigators later reported that c-Yes
was also activated in Neu-induced mouse mammary tumors and this activation correlated with
the ability of c-Yes to associate with Neu in an
SH2-dependent fashion [84]. Biscardi et al. [85]
found that c-Src and EGFR co-associate in an
EGF-dependent fashion in breast cancer cell lines
and tumor samples which overexpress both
proteins. Discrepancies in the ndings on the coassociation between c-Src and EGFR may be due
to differences in the model systems used in the
various studies. It is also possible that c-Src may
interact with the EGFR indirectly through an
intermediary protein. In support of this latter
possibility, Li et al. [86] demonstrated that the
mucin-like transmembrane glycoprotein MUC1
constitutively associates with EGFR in breast
carcinoma cells. Activation of EGFR in these cells
results in phosphorylation of MUC1 on tyrosine
and subsequent SH2-dependent binding of c-Src to
MUC1.
In recent years, several studies have indicated
that SFKs may be activated in breast cancer via
tyrosine phosphatase-dependent dephosphorylation of the regulatory tyrosine. Egan et al. [87]
observed that c-Src kinase activity from breast
cancer cells was elevated 5.6 fold above that
detected in normal control cells and that this
elevated activity could be suppressed when the
cells were grown in the presence of the phosphatase inhibitor sodium vanadate. Furthermore, a
tyrosine phosphatase activity capable of dephosphorylating the regulatory tyrosine was detected
in membrane fractions from breast tumor cells.
This phosphatase was later identied as proteintyrosine phosphatase 1 B (PTP1B). In this study,
Bjorge and colleagues [88] demonstrated further
that overexpression of PTP1B in 293 cells resulted
in a 2-fold increase in c-Src activity. It should be

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Summy and Gallick

noted again that SH2 displacement and dephosphorylation of the regulatory tyrosine are not
mutually exclusive and both may contribute to
SFK activation in breast cancer cells.

Contributions of SFKs to breast cancer

progression
As with colon cancer, activation of SFKs in breast
cancer does not guarantee a signicant contribution to the biological progression of these tumors.
However, substantial data exist to indicate that
this is indeed the case. The transgenic mouse
model has been important in determining the
importance of SFKs in mammary tumorigenesis.
Webster and colleagues utilized transgenic mice to
express an activated c-Src specically in mouse
mammary glands, under the transcriptional control of the mouse mammary tumor virus long
terminal repeat [89]. Further, female mice expressing active c-Src frequently developed epithelial
hyperplasias, which occasionally progressed to full
neoplasias [89]. In an alternative mouse model,
mice harboring the polyomavirus (PyV) middle T
antigen under the control of a mammary-specic
promoter invariably develop mammary tumors.
However, when mice lacking the c-src gene express
PyV middle T, mammary tumor formation occurs
less frequently and at a delayed rate [90]. These
results indicate an important role for c-Src in the
formation of mammary tumors in this system.
Interestingly, mice lacking the c-yes gene develop
PyV middle T-induced mammary tumors at a
normal rate; however, middle T is decient in
transformation of endothelial cells in the absence
of c-Yes [90]. These results indicate that c-Yes may
not be important for mammary tumorigenesis, at
least in this model system, and further illustrate
the lack of absolute functional redundancy between
c-Src and c-Yes, despite their signicant homology.

Src family kinases in breast cancer cell growth and

survival
While the transgenic mouse model is useful,
extrapolation of results obtained in this system
to human breast cancer can be problematic.
Several studies, however, have focused on the

importance of c-Src and SFKs in the growth and

survival of human breast cancer cells. As mentioned above, breast tumors with elevated c-Src
activity frequently express the progesterone receptor, raising the possibility that SFK may contribute to hormone-dependent cell growth
signaling [68]. In support of this possibility,
Arnold et al. [91] demonstrated that the human
estrogen receptor was phosphorylated by c-Src in
vitro. This group determined also that tyrosine
phosphorylation of the human estrogen receptor
was necessary for dimerization of the receptor and
binding to the estrogen receptor response element
[92]. Migliaccio et al. [93] demonstrated that c-Src
is activated downstream of the estradiol receptor
in a hormone-dependent fashion, leading to
subsequent activation of the mitogen activated
protein kinase (MAPK) pathway. This same group
later demonstrated that progestins acting through
the progesterone receptor can induce activation of
c-Src, and subsequent MAPK pathway activation,
through cross-talk with the estrogen receptor [94].
However, Boonyaratanakornkit et al. [95] demonstrated that the progesterone receptor was capable
of directly activating SFKs, through displacement
of the SH3 domain/linker intramolecular interaction, in response to progestin. Thus, while SFK
activation is evidently necessary for progesterone
receptor cell signaling, the mechanism of SFK
activation downstream of hormone stimulation is
unclear and may vary from system to system.
In estradiol-stimulated MCF-7 cells, SFK activity is necessary for activation of PI3K and Akt,
leading to subsequent cyclin D1 transcription and
cell cycle progression [96]. Furthermore, Tsai and
colleagues demonstrated that estrogen receptornegative breast cancer cell lines were still capable
of inducing Akt activation upon estrogen stimulation in a SFK-dependent fashion [97]. Collectively,
these results suggest that c-Src or SFKs may be
important for breast cancer cell growth and
survival stimulated by multiple hormones.
Enhanced expression of c-Src in cells expressing
elevated levels of EGFR resulted in increased
DNA synthesis, soft agar growth and tumor
formation in nude mice [98]. Shefeld and
colleagues demonstrated that activation of c-Src
in mammary epithelial cells overexpressing ErbB2
and further showed that inhibition of c-Src activity
reduced the ability of these cells to grow in soft

Src family kinases in tumor progression and metastasis

agar [99]. In 1998, Amundadottir and Leder [100]

reported that inhibition of SFK activity with the
Src family inhibitor PP1 disrupted anchorageindependent growth of a TGF-a induced mammary tumor cell line. c-Src is also activated
downstream of broblast growth factor-2 (FGF2) signaling in the human breast cancer cell line
MCF-7 [101]. In this system, c-Src activation led to
the tyrosine phosphorylation of the cell cycle
mediator cyclin D2. Recently Belsches-Jablonski
et al. [102], demonstrated overexpression and coassociation of Her2/Neu and c-Src in human
breast cancer cell lines and tumor samples. In
these studies, heregulin treatment stimulated
anchorage-independent growth, and inhibition of
SFK activity with the inhibitor PP1 resulted in
reduced anchorage-dependent and anchorageindependent growth and triggered apoptosis,
indicating a role for SFKs in both growth and
survival of breast carcinoma cells. Disruption of
SFK activity in several human cancer cell lines,
including those of breast cancer origin, induced a
mitotic block that occurred after chromosome
condensation and before spindle assembly [103].
A cooperative effect of activated c-Src and Stat3
in the transcriptional activation of the gene for
hepatocyte growth factor (HGF), also known as
scatter factor has been demonstrated [104]. HGF/
c-Met signaling facilitates cell growth, motility,
and survival [105], and thus represents another
system wherein c-Src activation may contribute to
the metastatic progression of human breast cancer
cells. In human breast cancer cell lines expressing
elevated EGFR and c-Src kinase activities, Stat3 is
constitutively activated in a SFK and JAKdependent fashion [106]. SFK inhibition resulted
in a reduction of Stat3 DNA binding, growth
inhibition, and initiation of apoptosis. Olayioye et
al. [107] recently demonstrated that SFK activity is
essential for EGF and neuregulin induced MAPK
activation in multiple breast carcinoma cell lines.
Bougeret and colleagues [108] reported that the
Csk homologous kinase Chk, when transfected
into MCF-7 breast carcinoma cells, inhibits heregulin induced activation of c-Src and Lyn and
delays mitotic entry. It was subsequently shown
that Chk expression inhibits migration of T47D
breast cancer cells, presumably due again to
inactivation of SFKs [109]. Thus, Src may be a
critical regulator of a variety of protein tyrosine

347

kinase receptors aberrantly expressed and/or

activated in breast cancer.

Src family kinases in breast cancer angiogenesis

As with colon cancer, c-Src is important in the
induction of VEGF transcription in breast cancer
cells. Expression of the antisense c-Src vector
described by Pal and co-workers resulted in
decreased VEGF transcription in breast cancer
cells. Interestingly, VEGF expression and c-Src
activation were inhibited under hypoxic conditions
by the tumor suppressor p53. Taken together,
these results suggest an important role for c-Src in
a variety of signaling pathways involved in breast
cancer cell growth, survival, and angiogenesis.

Src family kinases in detachment, motility, and

invasiveness of breast carcinoma
c-Src is necessary for hyaluronan mediated motility (RHAMM) motility of cells [36]. It has been
demonstrated previously that RHAMM is
required for breast cancer motility, and thus cSrc may likewise be essential for motility in breast
cancer cells [111]. In a study of RAFTK function
in breast cancer cells, [112] Zrihan-Licht and
colleagues demonstrated that after HRG stimulation, RAFTK associated with p190 RhoGAP,
RASGAP, and ErbB-2, and is required for
phosphorylation of p190 RhoGAP by Src. Association of RAFTK with ErbB-2 was abolished by
mutation of the Src binding site, as was the
stimulation of invasion normally detected upon
expression of wild type RAFTK in breast cancer
cells [112]. These results indicate that c-Src, in
conjunction with RAFTK may play a pivotal role
in the invasion of breast cancer cells. Src family
kinases may also contribute to motility through
shedding of the L1 adhesion molecule [113]. These
studies demonstrated that upon pervanadate
treatment or EDTA-mediated cell detachment,
the SFK Fyn was activated, and the cytoplasmic
tail of L1 was subsequently tyrosine phosphorylated. Incubation with the SFK inhibitor PP2
blocked cell rounding and detachment from the
substrate. The authors proposed that, as soluble
L1 binds to the proteoglycan neurocan, L1

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Summy and Gallick

shedding may support integrin-mediated cell

migration and adhesion [113]. As discussed above,
Hung and Elliott [104] demonstrated that continuous activation of c-Src, in conjunction with Stat3,
can result in elevated HGF expression, and
subsequent activation of autocrine HGF/c-Met
signaling. In addition to promoting tumor cell
growth, this signaling pathway may contribute to
the motility and invasiveness of breast cancer cells.
In support of this idea, Rahimi et al. [114]
demonstrated that c-Src is activated in response
to HGF stimulation of breast carcinoma cells and
breast epithelial cells and that this activation
corresponds with co-association between c-Met
and c-Src. Expression of dominant negative Src in
these cells disrupted HGF-induced motility and
soft agar growth but did not affect cell proliferation on a plastic substratum. SFKs may also play a
role in downregulation of E-cadherin mediated cell
aggregation in breast cancer cells, as PP2 stimulated aggregation of breast cancer cells in their
studies [115]. Finally, it was recently demonstrated
that treatment of breast cancer cells with the SFK
inhibitor PP1 or expression of a dominant negative
Src vector signicantly reduced CD99-induced cell
motility [116]. Taken together these data indicate
that not only do SFKs likely contribute to the
growth and survival of breast cancer cells, but also
to motility, invasiveness, and thus metastatic
potential.

c-Yes activation in human melanoma

In comparison to breast and colon cancer, much
less is known about the roles of SFKs in other
human cancers; however, the results of several
studies suggest that they may be involved in a
variety of human epithelial and non-epithelial
cancers. Human melanoma is one of the few
cancers in which c-Yes has been more strongly
implicated than c-Src. Increased expression and
kinase activity of c-Yes has been demonstrated in
human melanoma cell lines, relative to normal
melanocytes [117]. No differences were detected in
the expression and activation of c-Src between the
melanoma cells and melanocytes. Later, Marchetti
et al. [118] showed that c-Yes tyrosine kinase
activity was further elevated in brain metastatic
melanoma cell lines. Furthermore, they demon-

strated that c-Yes was activated upon stimulation

with the neurotrophin nerve growth factor (NGF),
while c-Src activity was unaffected. Further
supporting the potential link between c-Yes
activity and metastatic progression, the degree of
c-Yes activation in response to NGF stimulation
correlated with the invasiveness of the melanoma
cells [118]. These studies again indicate specicity
in signaling between c-Src and c-Yes in human
cancers and suggest that c-Yes may make a more
signicant contribution than c-Src to the progression of human melanoma.

Src family kinases in pancreatic cancer

In 1996, Visser et al. [119] utilized a rat experimental exocrine pancreatic carcinogenesis model
system to demonstrate that c-Src protein expression and kinase activity were elevated in azaserine
treated rat pancreas, with respect to untreated
controls. c-Src overexpression was observed in 13/
13 pancreatic carcinoma cell lines, in comparison
to normal pancreatic specimens and elevated c-Src
kinase activity in 14/17 pancreatic carcinoma cell
lines, when compared to normal pancreatic cells
[120]. In these studies, c-Src kinase activity did not
correlate with protein expression levels or expression of Csk. MacMillan-Crow et al. [121] recently
demonstrated that c-Src was subject to tyrosine
nitration in pancreatic carcinoma cells, and that
this correlated with a greater than two fold
increase in c-Src kinase activity and association
between c-Src and cortactin. Tyrosine nitration
may occur in the presence of oxidative stress as a
result of increased levels of the reactive nitrogen
species peroxynitrite [121]. This study indicates
that tyrosine nitration may contribute to c-Src
activation, and subsequent downstream growth
and survival signals in the face of oxidative stress.
Activated c-Src expression in pancreatic carcinoma cells results in elevated expression of the
insulin-like growth factor 1 (IGF-1) receptor [122].
Upregulation of the IGF-1 receptor in response to
Src may occur as a result of Akt activation
downstream of Src [123]. Elevated expression of
the IGF-1 receptor leads to increased IGF-1dependent cell proliferation, thus indicating
another potential mechanism by which c-Src may
contribute to pancreatic cell growth and progres-

Src family kinases in tumor progression and metastasis

sion. As with breast and colon cancer, c-Src

activation not only contributes to pancreatic
cancer growth but also to invasion and metastasis.
The growth of pancreatic carcinoma cell lines with
high metastatic potential on type III collagen
results in reduced E-cadherin expression,
decreased cellcell adhesion, and enhanced migration [124]. These results were also obtained upon
overexpression of activated c-Src. E-cadherin
downregulation in response to collagen could be
suppressed by treatment with the SFK inhibitors
PP1 and herbimycin A [124]. These studies indicate
a potentially important role for c-Src or SFKs in
the growth and progression of human pancreatic
cancer.

Src family kinases in ovarian cancer

As with colon and breast cancer, expression of an
antisense c-src vector in human ovarian cancer
cells indicates that c-Src may play a specic and
vital role in human ovarian cancer. Antisense c-src
vector expression in a human ovarian cancer cell
line resulted in decreased anchorage-independent
growth, decreased tumor growth in a mouse
model, and decreased VEGF expression and
tumor vascularization [125]. These results indicate
that c-Src may be important for several different
aspects of ovarian cancer growth and progression.
c-Src activity appears important for Shc phosphorylation and Erk1/2 activation downstream of
CXCR-1/2 receptor stimulation [126]. Finally, the
importance of Src was demonstrated in hyaluronic
acid-dependent ovarian cell tumor migration, as
overexpression of active Src stimulates HAdependent tumor cell migration, while expression
of dominant negative Src abrogates the tumorigenic phenotype [127].

349

(EMT) of bladder cancer cells was demonstrated

[129]. Overexpression of c-Src results in EMT or
sensitization to growth factor-mediated EMT.
Additionally, overexpression of dominant negative
Src inhibits growth factor induced cell scattering
that occurs concomitantly with EMT [129]. More
recently, utilizing human bladder carcinoma cell
lines, SFK inhibition was demonstrated to block
EMT [130], thus suggesting a potentially important role for SFKs in the progression of bladder
cancer cells to an invasive phenotype.

Src family kinases in gastric cancer

Takekura and colleagues [131], in 1990, demonstrated that c-Src kinase activity was elevated in 8
of 16 gastric carcinoma tissues, in comparison to
normal mucosa samples. The levels of kinase
activity did not necessarily correlate with levels
of c-Src protein expression.

Src family kinases in head, neck, and esophageal

cancers
In 1992, Jankowski et al. [132] detected c-Src
expression in Barretts esophagus (BE) and esophageal adenocarcinoma, but not in normal
mucosa. c-Src kinase activity was elevated three
to 4 fold in BE and 6 fold higher in esophageal
adenocarcinoma than normal control tissues [133].
Dephosphorylation of c-Src at the regulatory
tyrosine was detected in BE tissue. c-Src is
overexpressed in hyperproliferating regions of
head and neck squamous cell carcinoma, dysplastic epithelium, benign papillomas, and inamed
normal tissue [134].

Src family kinases in lung cancer

Src family kinases in bladder cancer
In 1992 Fanning and colleagues [128] demonstrated c-Src kinase activity was elevated in a panel
of human bladder carcinomas over normal tissue
and that increased kinase activity was associated
primarily with low grade bladder lesions. In a rat
bladder carcinoma model the importance of
c-Src in the epithelium-to-mesenchyme transition

In 1990, Kiefer et al. [135] demonstrated expression of v-src-related mRNA in a panel of nonsmall-cell lung cancer (NSCLC) lines, with elevated expression detected in one adenocarcinoma
cell line. In a panel of lung cancers Src expression
was found in 20 of 33 small cell lung cancer and
NSCLC samples but not in histologically normal
lung tissue [136]. In the NSCLC samples, 6080%

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Summy and Gallick

of adenocarcinomas and bronchiolo-alveolar cancers and 50% of squamous cell carcinomas

displayed c-Src protein expression. C-Src expression was detected more frequently in poorly
differentiated squamous cell carcinomas than in
moderately or well differentiated samples [136].
Consistent with these observations, c-Src was
found to be activated in NSCLC cell lines [137].
While relatively little is known of the contributions of SFKs to lung cancer growth and progression, in comparison to other cancers of epithelial
origin, recent studies have begun to shed light on
this issue. Lck and c-Yes kinase activities were
shown to be elevated in a small cell lung cancer cell
line downstream of stem cell factor (SCF)mediated Kit stimulation [138]. Inhibition of
SFK activity with PP1 resulted in a complete
block of SCF-mediated cell growth [138]. It was
later demonstrated that Lck was required for SCFmediated MAPK activation; however, this pathway was dispensable for cell growth in the absence
of Rb [139]. Finally, evidence of a role for SFKs in
hypoxic growth and angiogenesis of human lung
cancer cells has been described [140]. Under
hypoxic conditions, the lung adenocarcinoma cell
line A549 resulted in transcriptional upregulation
of the endothelial PAS domain protein-1 (EPAS-1)
in a SFK-dependent fashion. EPAS-1, in turn,
upregulates its own expression and that of VEGF
[140]. These data indicate that SFKs may be
involved in the regulation of signaling pathways
that govern multiple aspects of lung cancer
progression.

Src family kinases in brain and neuronal tumors

Given the high expression levels of SFKs, including c-Src, Fyn, and c-Yes, in cells of neuronal
origin, it might be expected that they play an
important role in the growth and progression of
brain and neuronal tumors. While not as extensively studied as colon and breast cancer, the
expression and activation of c-Src in brain cancers
has been examined in a number of studies since
the mid-1980s. In 1985, Takenaka and colleagues
[141] demonstrated c-Src protein expression in
human astrocytomas but not normal brain tissues.
A 20 to 40 fold elevation in c-Src kinase activity
was observed in human neuroblastoma cell lines,

in comparison to glioblastomas or normal human

broblasts [142]. Later work demonstrated that
the abundance of c-Src in neuroendocrine tumors
varied with the neuronal differentiation state of
the cells and that the specic kinase activity of
c-Src from neuroblastoma cells, when normalized
against protein levels, was similar to that from
human glioblastoma cells [143]. In other studies,
c-Src kinase activity was elevated in neuroendocrine-derived neuroblastoma and small-cell lung
carcinoma cells, relative to non-neurocrine cells
[144], and c-Src protein levels and kinase activity
correlate with the differentiation state of neuroendocrine-derived tumors [145]. c-Src is expressed in
childhood neuroblastoma and retinoblastoma,
with the neuronal c-Src splice variant (c-SrcN)
being more highly expressed than c-Src in tumors
associated with good clinical prognosis [146].
Expression of v-Src under the control of the glial
brillary acidic protein (GFAP) regulatory elements in transgenic mice resulted in the formation
of astrocytomas in the brain and spinal cord [147].
As the tumors progressed, they became highly
proliferative and demonstrated greater malignancy. The tumors were also highly vascularized
in areas, resembling human glioblastomas [147].
VEGF expression occurs early in development of
these tumors preceding vascularization, and likely
contributes to the progression of these Srcinduced tumors [148]. While data on how c-Src
or SFKs may contribute to the growth and
progression of brain and neuronal tumors is still
relatively sparse, a recent study indicates that
activated and co-associated focal adhesion kinase
(FAK) and c-Src may contribute to the proliferation of anaplastic astrocytoma cells through
ERK2 activation and induction of cyclin D and
E expression [149].

Src family kinases in leukemias, lymphomas, and

myelomas
Given that the majority of SFKs are expressed
predominantly in cells of the hematopoietic lineage
and that SFKs are commonly involved in the
signaling pathways that regulate cell growth and
division, it might be reasonable to assume that
SFKs may be involved in the growth and
progression of cancers arising from cells of

Src family kinases in tumor progression and metastasis

hematopoietic origin. Interestingly, however, there

is relatively little evidence to denitively implicate
SFK activity in these processes, possibly due to the
absolute requirement for SFKs in the function of
these cells. The SFK Lyn is predominantly
expressed in B lymphocytes and monocytes/
macrophages, and several reports in the literature
are suggestive of a role for Lyn in cancers derived
from these cells. Lyn kinase activity, as opposed to
those of Fyn, Yes, or Hck, was specically
activated in myeloid leukemia cell lines in response
to IL-3, an important promoter of growth and
survival [150]. These results indicate that Lyn may
be involved in IL-3 dependent signal transduction
in human myeloid leukemia. Lyn may also be
involved in IL-6 mediated cell proliferation, as
activation of Lyn downstream of IL-6 stimulation
was demonstrated in multiple myeloma cells [151].
More recently, expression of a Lyn antisense
oligonucleotide or incubation with a SFK-specic
tyrosine kinase inhibitor reduced IL-6-dependent
proliferation of CD45 myeloma cells [152]. Lyn
also appears to be preferentially expressed in
human malignant lymphomas of B cell origin
[153]. When complexed with CD19 at the plasma
membrane of B cell lymphomas, Lyn may be an
important regulator of cell survival [154]. Lyn,
Raf-1, and MAP kinases are activated upon crosslinking of the intercellular adhesion molecule 1
(ICAM-1) in a B cell lymphoma line [155].
Katagiri et al. [156] demonstrated that Lyn, in
conjunction with fellow SFK Fgr, may be important for the prevention of apoptosis during
granulocytic differentiation of a promyelocytic
leukemia cell line, as inhibitors of tyrosine kinase
activity or antisense oligonucleotides induced
premature apoptotic cell death during retinoic
acid-induced differentiation. Expression of a Lyn
antisense oligonucleotide resulted in reduced proliferation of a myeloid leukemia cell line in
response to granulocyte/macrophage colony stimulating factor (GM-CSF) [157]. These results
were mirrored by incubation with the SFK
inhibitor PD166285, which also inhibited the
growth of leukemic cell lines. Expression of a
dominant negative Lyn (Y397F) in erythroleukemic cells had a negative effect on the development
of erythroleukemias in vivo, resulting in a reduced
mortality rate and a lengthened latency period
[158]. Finally, Ptasznik et al. [159] uncovered

351

evidence that Lyn may contribute to BCR/ABLdependent cell motility. Lyn is normally activated
downstream of stromal-derived factor 1 (SDF-1)
stimulation of its receptor CXCR4, as part of a
signaling cascade regulating the migration of
progenitor cells [159]. In leukemic cells expressing
Bcr/Abl, Lyn is constitutively active as a result of
association with Bcr/Abl, and is not responsive to
SDF-1 stimulation. Inhibition of Lyn results in
disruption of Bcr/Abl induced cell motility [159].
Importantly, overexpression of Lyn has been
recently observed to be one mechanism by which
Bcr/Abl positive CML cells become resistant to the
inhibitor STI571 (Donato et al., [171]). Hck also
associates with Bcr/Abl and expression of dominant negative Hck resulted in suppression of
cytokine-independent growth of Bcr/Abl expressing myeloid leukemia cells [160]. In total, the
reports summarized here suggest that Lyn may be
involved in the growth, survival and motility of
multiple human cancers of hematopoietic cell
origin.
The Lck tyrosine kinase is expressed primarily
in T lymphocytes, where it is thought to play an
important role in T cell hematopoiesis, proliferation, and receptor signaling [161164]. However,
Lck expression has been detected in other
leukocytes as well. Expression of lck mRNA has
been observed in B cell chronic lymphocytic
leukemia in 1991 [165]. Lck is associated with
the CD19 receptor in B lineage acute lymphoblastic leukemia (ALL) cells and is activated upon
engagement of the CD19 receptor, suggesting a
potential role for Lck in regulation of apoptosis in
B-lineage ALL cells [166]. Lck may contribute to
the induction of cell proliferation by human T cell
leukemia virus type 1 (HTLV-1) [167]. In these
studies the viral oncoprotein p40tax-1 alone was
unable to stimulate cell proliferation in the
absence of cytokines. However, P40tax-1was able
to induce cytokine-independent proliferation in
the presence of constitutively activated Lck [167].
Lck is expressed in B cell chronic lymphocyte
leukemia (CLL) and CD5 B-1cells, a self-renewing subpopulation of B cells that may represent
the normal precursors of CLL cells [168]. Thus,
despite its predominant expression in T lymphocytes, Lck may be involved in the growth and
survival of cancers originating from multiple
blood cell lineages.

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Conclusion
In summary, there is a wealth of data available
that indicate the importance of SFKs in the
growth and progression of human cancers. While
much of that work has focused on the role of cSrc, and to a lesser extent c-Yes, in breast and
colon cancers, SFKs have been implicated in many
different epithelial and non-epithelial cancers.
Their contributions to the biology of these cancers
are likely due to both elevated kinase activity and
increased availability of the functional domains
for intermolecular interactions.

Key unanswered questions

A key issue to be resolved in the future will be the
viability of SFK targeting in anti-tumor therapy.
With the remarkable success of the relatively
selective protein tyrosine kinase inhibitor STI 571
in treatment of Chronic Myelogenous Leukemia
patients, interest in developing selective inhibitors
of other protein tyrosine kinases continues to
grow. Concerted efforts are being made to develop
Src inhibitors, and Metcalf et al. [169] estimate
that Src inhibitors will reach the clinic within two
years. Due to their importance to several different
aspects of cancer progression, including cell
growth, survival, motility, invasion, and angiogenesis, SFKs may represent ideal candidates for
targeted anti-cancer therapeutics. Further, due to
the normal role of Src in bone resorption, Src
inhibitors may hold great promise for inhibiting
progression of tumors with a propensity to
metastasize to the bone, such as prostate and
breast cancer, as well as multiple myeloma.
However, the best use of such inhibitors still
requires a basic understanding of the role of Src
activation in tumor progression. While considerable progress has been made, much remains to be
learned about a class of enzymes that play such
key intermediary roles in signal transduction.

Acknowledgements
This work was supported by NIH 2 R01 CA65527,
NIH 1 U54 CA090810, the Gillson Longenbaugh

Foundation, and the Lockton Fund for Pancreatic

Research.

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