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,
Divisions of
* Infectious Diseases,
Experimental Pathology,
Pulmonary and Critical Care, and
Department of Immunology, Mayo Clinic, Rochester, MN 55905
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, it triggers cells to
chemotax, and in some cell types such as neurons, causes cell death. To
elucidate this dual and opposing receptor function, we have
investigated whether CXCR4 activation by its chemokine SDF1 could
lead to the simultaneous activation of both anti- and proapoptotic
signaling pathways; the balance ultimately influencing cell survival.
CXCR4 activation in CD4 T cells by SDF1 led to the activation of the
prosurvival second messengers, Akt and extracellular signal-regulated
protein kinase. Selective inhibition of each signal demonstrated
that extracellular signal-regulated protein kinase is essential for
mediating SDF1-triggered chemotaxis but does not confer an
antiapoptotic state. In contrast, Akt activation through CXCR4 by
SDF1 interactions is necessary to confer resistance to apoptosis.
The proapoptotic signaling pathway triggered by SDF1-CXCR4
interaction involves the Gi protein-independent
activation of the proapoptotic MAPK (p38). Furthermore, other
chemokines and chemokine receptors also signal chemotaxis and
proapoptotic effects via similar pathways. Thus, Gi
protein-coupled chemokine receptors can function as death prone
receptors and the balance between the above signaling pathways will
ultimately mandate the fate of the activated
cell. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and 
, SDF1 is widely
expressed and triggers chemotaxis of monocytes, T cells, and
CD34+ human progenitor cells (5, 6).
SDF1 is the natural ligand of CXCR4, which also serves as the
coreceptor for the X4 HIV envelope (env).
SDF1 can signal two very different outcomes through the same CXCR4
receptor in different cells. Although SDF1 signaling induces
chemotaxis in CD4 T cells, it induces cell death in neurons
(7, 8, 9, 10, 36). SDF1-CXCR4 interactions trigger many
intracellular signals, including increases in
Ca2+ influx (11, 12), extracellular
signal-regulated protein kinase (ERK)1/2 phosphorylation
(13, 14), activation of phosphatidylinositol 3-kinase
(PI3K) and Akt (13, 14, 15), tyrosine phosphorylation of focal
adhesion complex components such as Pyk-2 and Crk, and an increase in
NF-
B activity (13, 16). Among these signals, ERK1/2 and
Akt activation deserve special attention as antiapoptotic signals.
Inhibition of either of these signals results in cell death in various
cell types (17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29). It remains unclear why SDF1
stimulation of CXCR4 does not result in cell death in CD4 T cells, yet
does cause death in other cell types. We hypothesized that the
molecular mechanisms of CXCR4 activation can mediate cell survival or
death via the activation (or lack thereof) of specific signaling
pathways downstream of G protein-coupled chemokine receptors either
with pro- or antiapoptotic features. Using CXCR4 and its ligand SDF1
as a model to study this hypothesis in primary CD4 T cells, we
demonstrate that CXCR4 can induce cell death when engaged by SDF1.
However, this is only observed when the SDF1-CXCR4-dependent
activation of the antiapoptotic PI3K-Akt is inhibited, which in
turn allows for a Gi protein-independent
mitogen-activated protein kinase (MAPK) (p38) dependent signaling
pathway to mediate death of primary CD4 T cells. Interestingly, we
found this model pertained to G protein-coupled chemokine receptors
from both the CXC and CC subtypes. These results demonstrate the
proapoptotic function of chemokine receptors and their role in various
disease processes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PBMCs were isolated by Ficoll-Hypaque from healthy donors and CD4 T cells were purified by negative depletion using the StemCell magnetic column as described in product instructions (StemCell Technologies, Vancouver, British Columbia, Canada), yielding a population of 98% pure CD4 T cells. The CD4 T cells were maintained in RPMI media containing 10% FBS, 10,000 µg/ml penicillin/streptomycin, and 200 mM glutamine.
Immunoblotting
CD4 T cells were left untreated or incubated at 37°C with 200
nM SDF1 (R&D Systems, Minneapolis, MN) for 30 s, unless
otherwise specified. Cells were lysed in a whole-cell lysis buffer
(1 x PBS, 1% Nonidet P-40, 0.1% SDS, 0.5% deoxycholate
with 10 mM sodium othovanadate, 300 µM sodium fluoride, 10 mM
p-nitrophenyl phosphate, and protease inhibitors
leupeptin, aproptopin, and pepstatin). Some CD4 T cells were
preincubated for 1 h at 37°C with 1 µg/ml of pertussis toxin,
100 nM of wortmannin, 10 µM PD9809, 10 µM of SB203580, 20 µM of
Z-Val-Ala-Asp-(OMe)-CH2F (Z-VAD), or the caspase 8
inhibitor Z-LEHD (all obtained from Calbiochem, San Diego, CA) before
adding SDF1. A total of 25 µg of cell lysate protein was run on a
10% SDS-PAGE, and the proteins were transferred by electroblotting
onto polyvinylidene fluoride membrane (Millipore, Bedford, MA).
The blots were probed with Abs specific for ERK1/2 phosphorylation at
Thr202 and Tyr204, Akt
phosphorylation at Ser473, p38 phosphorylation
at Thr180/Tyr182, and c-Jun
amino terminal kinase (JNK) phosphorylation at
Thr183/Tyr185 (obtained
from NEB, Beverley, MA). Membranes were stripped with 6 M guanidine for
5 min at room temperature, washed extensively, and then reblotted with
Abs to ERK2, anti-Akt, anti-p38, or anti-JNK, all obtained
from Santa Cruz Biotechnology (Santa Cruz, CA). Proteins were
visualized using the ECL system (Amersham Pharmacia Biotech,
Piscataway, NJ) after incubating membranes with protein A-conjugated
HRP (Amersham Pharmacia Biotech).
Cell mixing experiments, cell death analysis, and confocal microscopy
CD4 T cells (2 x 106) were untreated
or preincubated with specific inhibitors for 1 h at 37°C, and
then mixed with 200 nM of SDF1, IL-8, or RANTES (R&D Systems) and
then incubated again at 37°C for 2 h. Cells were then counted,
diluted, and plated in 96-well plates at a concentration of 0.5 x
106/ml in 200 µl, and incubated overnight at
37°C. The following day, cells were counted and percentage of cell
death was calculated using trypan blue dye exclusion as follows: 1
- (total number of viable cells on day 2 divided by total number of
viable cells on day 1) x 100. Cell death was also confirmed using
two flow cytometry-based methods: cells with reduced FSC, and cells
with increased hypodiploid DNA content following propidium iodide
staining (30). Experiments for every figure were performed
in duplicate and repeated twice. All measurements are presented as
means with SDs. Statistical comparisons were made between conditions
using Student t test paired observations.
Chemotaxis assays
CD4 T cells (1 x 106), untreated or
treated with Pertussis toxin 1 µg/ml, wortmannin 100 nM (Calbiochem),
or PD98506 30 µM (Calbiochem) for 1 h at 37°C, were plated
(1 x 106 cells in 0.1 ml) in the upper well
of a 24-well transmigration chamber (5 µM pore size; Transwell;
Costar, Cambridge, MA). A total of 100 nM of SDF1, IL-8, or RANTES
in 0.6 ml of media was added to the lower well. Plates were incubated
at 37°C for 2 h, and cells that had migrated to the lower
chamber were counted using Trypan dye exclusion. Percentage of cell
chemotaxis was calculated as: (number of cells that migrated to lower
chamber divided by number of cells originally plated in the upper
chamber) x 100.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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protein signaling reverses
SDF1-triggered chemotaxis and results in CD4 T cell death
SDF1 leads to a Gi-dependent CD4 T
cell chemotaxis upon engagement with CXCR4 (31). To
confirm this, primary resting CD4 T cells were pretreated with the
Gi inhibitor, pertussis toxin, before addition
of SDF1. Subsequently, the percentage of CD4 T cell chemotaxis was
analyzed. As shown in Fig. 1
B,
right panel, and as reported for other cell types (15, 32, 33), pertussis toxin inhibited SDF1-triggered chemotaxis.
To determine whether this inhibition of chemotaxis could be secondary
to cell death, parallel cultures of primary resting CD4 T lymphocytes
were treated under the same conditions and analyzed for cell death
24 h later. As shown in Fig. 1B, left panel,
SDF1 treatment did not cause cell death, except when cells were
preincubated with pertussis toxin. Cell death was apoptotic as
demonstrated by a reduced forward scatter and an increase in
hypodiploid DNA content (Fig. 1C).
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-CXCR4 interactions, such as the MAPK ERK1/2 or PI3K-Akt, were
being suppressed by pertussis toxin treatment. To address this
question, CD4 T cells were obtained from the same donor and processed
in parallel to those used in Fig. 1
B. As shown in Fig. 1A, SDF1 triggered the phosphorylation of both the MAPK
ERK1/2 and of Akt. This phosphorylation was not observed in pertussis
toxin-pretreated cells. Moreover, pertussis toxin did not modify the
expression level of CXCR4 by flow cytometry in these cells (untreated
20%, pertussis toxin 19%, p = NS).
Altogether, these results indicate that SDF1 provides a potent
chemotactic signal to resting primary CD4 T cells. Inhibition of
signaling pathways downstream of Gi reverse
the SDF1 triggered chemotaxis and, surprisingly, resulted in cell
death.
Blocking SDF1-triggered ERK1/2 phosphorylation does not lead to
CD4 T cell death
We next questioned whether the
Gi-dependent MAPK or Akt signaling pathways,
activated by SDF1-CXCR4 interactions, are involved in protecting
primary CD4 T cells from undergoing CD4 T cell death when stimulated by
SDF1. First, we addressed the role of MAPK in this process by
inhibiting MAPK kinase (MEK), the upstream regulator of ERK1/2,
with the inhibitor (PD98509) before SDF1 treatment. Two and 24
h later, chemotaxis and cell survival were measured, respectively, as
described in Fig. 1. Although SDF1 did not induce CD4 T cell death
in cells treated with the MEK inhibitor, it significantly inhibited the
SDF1-triggered chemotaxis (Fig. 2B). The specificity and
efficacy of PD98509 as an inhibitor of both ERK1 and 2 was analyzed by
determining ERK1/2 and Akt phosphorylation following SDF1 treatment.
As shown in Fig. 2A, only the SDF1-triggered
phosphorylation of ERK1 and 2, but not of Akt, was abrogated in the
presence of the MEK inhibitor. Furthermore, the PD98509 inhibitor did
not change CXCR4 cell surface expression when analyzed by flow
cytometry (untreated 20%, PD98509 21%, p =
NS).
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mediated
chemotaxis, but is not involved in protecting cells from
SDF1-CXCR4-triggered death.
Blocking SDF1-triggered Akt phosphorylation leads to
CD4 T cell death
Because Akt phosphorylation in primary CD4 T cells was also found
to be Gi-dependent (Fig. 1A), we
next examined the role of Akt and its upstream activator, PI3K, in
SDF1-mediated signaling in primary CD4 T lymphocytes using the PI3K
inhibitor wortmannin. Pretreatment of CD4 T cells with wortmannin
before SDF1 stimulation led to significant cell death. This was not
observed in CD4 T cells treated with either wortmannin or SDF1 alone
(Fig. 3B, left
panel). However, pretreating the cells with wortmannin before
activation of SDF1 did not block chemotaxis (Fig. 3B,
right panel), and did not change cell surface expression of
CXCR4 (untreated 17%, wortmannin 15%, p = NS).
Because the vast majority of CD4 T cells chemotax within 2 h, we
presume the same cells are among those that apoptose at 24 h,
suggesting that the apoptotic and chemotaxis triggering pathways are
unrelated. The specificity of the PI3K inhibitor was demonstrated by
its ability to inhibit Akt, but not ERK1 and 2, phosphorylation
following SDF1 treatment (Fig. 3A). From this
information, we inferred that SDF1-CXCR4 interactions can lead to
the activation of different signaling pathways that result in different
functional outcomes: those involved in chemotaxis (MAPK-dependent), and
those that neutralize presumed proapoptotic pathway(s), such as in the
PI3K-Akt axis.
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for progressively longer
duration to determine the kinetics of SDF1 activation of Akt through
the CXCR4 receptor. As shown in Fig. 3C, Akt phosphorylation
occurred very early and was transient. It peaked 30 s after
SDF1 stimulation and vanished after 10 min, suggesting it maybe a
trigger to other proliferative downstream signals. Therefore, Akt
activation is not only an essential prosurvival signal, but also
appears to be involved in an early cascade of signaling that protects
cells from death up to 24 h later. However, this may be a result
of the sensitivity of the methods used to detect very early cell
death.
SDF1-mediated CD4 T cell death is a caspase-independent process
Previous work from our laboratory and others has demonstrated that
CXCR4 activation can lead directly to CD4 T cell death when engaged by
X4 HIV env, highlighting the ability of this chemokine
receptor to mediate CD4 T cell death (8, 9, 10). Because X4
env-CXCR4-triggered CD4 T cell death is not mediated by the
caspase pathway (10), we questioned whether the
SDF1-triggered CD4 T cell death, via CXCR4 activation, in
Akt-inhibited cells is also caspase-independent. For this, we studied
resting CD4 T cells in which Akt or Gi were
inhibited and were then treated with SDF1 in the presence of the
pan-caspase inhibitor, Z-VAD. As shown in Fig. 4, the SDF1-triggered death of CD4 T
cells, in which Gi (pertussis toxin) or Akt
(wortmannin) were inhibited, was not reduced in the presence of Z-VAD.
The functional ability of Z-VAD was verified by demonstrating that this
peptide blocked the death of CD4 T cells from the same donor following
CD4 cross-linking alone or in conjunction with anti-Fas
cross-linking Abs (Fig. 4B) (34). The
caspase-independent nature of SDF1-induced CD4 T cell death was
further verified by using a peptide inhibitor of caspase 8, the caspase
most proximal to death domain containing receptors such as Fas. Caspase
8 inhibition also did not block the SDF1-mediated death (data not
shown). Taken together, these data show that the death signal that is
triggered by SDF1 in resting CD4 T cells in which the prosurvival
PI3k-Akt pathway is blocked was not reversed by a number of caspase
inhibitors, analogous to the case of X4 HIV
env-CXCR4-mediated CD4 T cell death
(8, 9, 10).
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-triggered CD4 T cell death is a p38-mediated process and
independent of Gi chemokine receptor signaling
We next sought to identify the signaling pathway whereby
SDF1-CXCR4 interactions lead to CD4 T cell death in the presence of
a blocked PI3K-Akt axis. A number of studies point to the potential
involvement of kinases of the stress-activated pathway such as JNK and
p38 in mediating apoptosis in a caspase-independent manner in a variety
of cells. These kinases are stimulated by cellular stresses such as
heat shock, UV irradiation, or inflammatory cytokines, including
TNF- and IL-1 (20). In addition, both JNK and p38 are
reported to be activated by X4 HIV env in neurons and by
SDF1 in other cells (35), respectively. Therefore, we
investigated whether JNK and/or p38 are activated and may participate
in the SDF1-triggered CD4 T cell death. As shown in Fig. 5A, p38 but not JNK 1 or 2 was
phosphorylated following SDF1 activation. In addition, p38
phosphorylation was decreased in the presence of the specific p38
inhibitor SB203580. CXCR4 surface expression was not changed by flow
cytometry analysis after SB203580 treatment (untreated 19%, SB203580
16%, p = NS). Furthermore, SDF1-induced p38
activation was not blocked by the Gi
inhibitor, pertussis toxin (Fig. 5A). We next investigated
whether p38 was involved in mediating CD4 T cell death following
SDF1 treatment of cells in which Akt was inhibited. As shown in Fig. 5B, blocking the PI3K Akt axis with wortmannin enabled
SDF1 to cause CD4 T cell death. However, this cell death was not
observed when wortmannin and SDF1-treated cells were incubated in
the presence of the p38 inhibitor SB203580 (Fig. 5B). The
SDF1-mediated CD4 T cell death as a result of PI3K inhibition was
mediated by p38, as shown in a dose-dependent manner with the p38
inhibitor SB203580 (Fig. 5B). Therefore, p38 appears to
mediate the pro-death signal triggered by SDF1 and is independent of
the Gi signaling of the chemokine receptor.
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C demonstrated that SDF1 activated p38 in a rapid
and sustained manner. Peak activation was seen by 10 s after
SDF1 ligation and continued for 24 h. Although the p38
pro-death signal was present immediately, cell death was not detectable
until 24 h after stimulation. Which again may be a result of the
sensitivity of the methods used to determine cell death, or indicate
that p38 begins a series of signals that requires hours before the cell
eventually dies. The activation of Akt and p38 by other G protein-coupled chemokine receptors will also dictate the fate of a CD4 T cell
We next questioned whether the other CXC and CC G protein-coupled
chemokine receptors have the ability to mediate death or survival
similar to CXCR4 via the Akt-p38 balance. To investigate this, primary
resting CD4 T cells were treated with media, IL-8, another CXC
chemokine known to signal through CXC receptors, or RANTES, a CC
chemokine known to signal through CCR receptors. Chemotaxis was
measured 2 h later. Both CXC and CC chemokines induced chemotaxis
in resting CD4 T cells (Fig. 6A). However, when CD4 T cells
were pretreated with the Akt inhibitor wortmannin, CD4 T cell death was
observed, following the addition of IL8 or RANTES (Fig. 6B).
Such death was abrogated by the p38 inhibitor SB203580. Therefore, the
p38 mechanism of cell death in Akt-inhibited CD4 T cells appears to be
mediated by all G protein-coupled chemokine receptors.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and other CXC and CC chemokines, should be considered apoptotic
inducing ligands in cells in which antiapoptotic second messengers are
not functional or unable to overcome the activation of pro-death
signals by SDF1-CXCR4 interactions. Lastly, we have highlighted the
fine balance that exists between p38 and Akt activation within these
cells, controlling cell survival. The role that different signal transduction molecules play in determining cell survival is an area of active investigation. Overall, there are two important pathways that are associated with cell survival, the ERK1/2 kinases and Akt, the downstream effector protein of PI3K. Inhibiting ERK has been shown to cause cell death in lymphocytes (20, 37) and neuronal cell lines (17). In another series of experiments by Yujiri et al. (18), disrupting the MEK kinase 1 gene in cells caused diminished ERK activation and resulted in apoptosis. The pivotal role of Akt in cell survival has been demonstrated in many cell systems as well (22, 23, 24, 25, 26, 27, 28, 29). Pharmacological inhibitors of Akt activation result in cell death (29). When Akt activation is inhibited with plasmids expressing a dominant negative mutant of Akt, cell death results. Conversely, when a plasmid overexpressing activated Akt is replaced into the cell, the cell survives (22, 24). Other ways of activating Akt, such as treating cells with growth factor, lithium, or insulin, also protects cells from apoptosis (23, 25, 27, 28). In particular, insulin has been shown to induce Akt activation and phosphorylation in neurons and protect the neurons from cell death as a result of different noxious stimuli (24, 28).
Blocking a prosurvival signal in isolation does not cause cell death without a concomitant pro-death signal. The stress-activated kinase cascades, including JNK and p38, are pivotal in many forms of apoptosis. Simply activating JNK and p38 by overexpressing MAP kinase kinases 3/6 causes a decrease in ERK phosphorylation and results in cell death in PC-12 cell. Moreover, overexpressing the p38 dominant negative mutant is enough to protect the cells from the programmed cell death (17). The interaction between prosurvival signals such as ERK phosphorylation and pro-death signals JNK or p38 has been shown to determine the fate of T cell lines as well (19, 20). Hence, a balance seems to exist in a number of systems between a prosurvival and pro-death signal that determines the fate of the cell in response to different stimuli.
Herein, we have focused on the survival and death signals chemokines
send cells through Gi protein-coupled
chemokine receptors, and propose a model of SDF1-induced
intracellular signaling depicted in Fig. 7. Our experiments demonstrate that
treating a CD4 T cell with chemokines causes the cell to chemotax, but
not die. If Akt, but not ERK1/2, phosphorylation is inhibited before
the cell is treated with the chemokine, the cell dies. In contrast,
chemotaxis is ERK1/2, but not Akt, phosphorylation-dependent.
Therefore, Akt activation is the crucial prosurvival signal triggered
by interactions of the chemokine with its receptor. This newly
described "chemokine-mediated" death results from the blockade of a
prosurvival signal in primary lymphocytes and is a caspase-independent
process. This process is similar to the death signal previously
described in which X4 HIV env signals CD4 T cells to
apoptose through CXCR4 (8, 10, 38). In addition, we
demonstrated that the simultaneous pro-death signal SDF1 sends
through CXCR4 (which is also the coreceptor for X4 HIV env)
to the CD4 T cell is p38 phosphorylation-dependent, yet is independent
of Gi protein signaling. Because SDF1
signaling did not activate JNK in our model, we assume that JNK is not
involved in this system. Consequently, these studies indicate that
chemokines such as SDF1 can signal CD4 T cell death if the delicate
balance between Akt and p38 activation is tipped in favor of the
Gi protein-independent, phosphorylation
mediated p38 pro-death signal.
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as described by Kaul
et al. (35), the pro-death signal dominates. We infer that
either the p38 MAPK activation overcomes a feeble Akt activation, or
the latter is not activated at all in neurons following CXCR4 ligation
by SDF1.
Another area of interest is the dichotomy of cell fate upon CXCR4
ligation by SDF1 vs HIV X4 env. When SDF1
ligates CXCR4, CD4 T cells chemotax, whereas when HIV X4 env
ligates CXCR4, CD4 T cells die. We speculate that X4
env-CXCR4 interaction may not lead to Akt activation, as
compared with SDF1-CXCR4 interactions. Studies are underway to
determine this. Alternatively, it is possible that SDF1, and not X4
env, leads to the association of CXCR4 with other receptors
that could per se lead to Akt activation. There are reports that CXCR4
and the TCR colocalize after SDF1 treatment (39).
Furthermore, CD4 and CXCR4 are preferentially located on cell surface
microvilli in T cells (40). Thus, SDF1 engagement of
CXCR4 could lead to TCR or CD4 activation, and thereby PI3K (41, 42), causing an effect distinct from that induced by binding to
CXCR4 alone as occurs in neurons. It is interesting that the Akt
prosurvival, but not the p38 pro-death signal, is dependent on
Gi protein signaling. Because we observed that
pertussis toxin inhibited Akt phosphorylation,
Gi protein activity could be required for the
colocalization of CXCR4 to other receptors.
Precedent exists for cross talk between anti- and proapoptotic signaling pathways as shown in the present study. Cross talk between the prosurvival signal ERK and pro-death signal JNK has been described in other cell systems (19, 20, 37). In these systems, blocking the prosurvival signal ERK1/2 phosphorylation resulted in an increase in the pro-death signal JNK/p38 phosphorylation. Whether Akt inhibits p38 activation will require further in depth investigation.
Therefore, our results demonstrate that the prosurvival and pro-death signals chemokines send through their G protein-coupled receptors will determine the fate of the cell. If the chemokine predominantly induces Akt activation, the cell will survive. However, if the chemokine predominantly activates p38, the cell will die. Presumably, a better understanding of the mechanism by which p38 induces death and Akt prevents death will lead to therapies that are able to promote cell survival.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Carlos V. Paya, Division of Infectious Diseases, Mayo Clinic, 200 First Street Southwest, Guggenheim 501, Rochester, MN 55905. E-mail address: paya{at}mayo.edu
3 Abbreviations used in this paper: SDF1, stromal cell-derived factor; env, envelope; ERK, extracellular signal-regulated protein kinase; PI3K, phosphatidylinositol 3-kinase; MAPK, mitogen-activated protein kinase; JNK, c-Jun amino terminal kinase; MEK, MAPK kinase; Z-VAD, Z-Val-Ala-Asp-(OMe)-CH2F.
Received for publication March 11, 2002. Accepted for publication September 4, 2002.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 N. Cabioglu, J. Summy, C. Miller, N. U. Parikh, A. A. Sahin, S. Tuzlali, K. Pumiglia, G. E. Gallick, and J. E. Price CXCL-12/Stromal Cell-Derived Factor-1{alpha} Transactivates HER2-neu in Breast Cancer Cells by a Novel Pathway Involving Src Kinase Activation Cancer Res., August 1, 2005; 65(15): 6493 - 6497. [Abstract] [Full Text] [PDF]
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 M. Kucia, R. Reca, K. Miekus, J. Wanzeck, W. Wojakowski, A. Janowska-Wieczorek, J. Ratajczak, and M. Z. Ratajczak Trafficking of Normal Stem Cells and Metastasis of Cancer Stem Cells Involve Similar Mechanisms: Pivotal Role of the SDF-1-CXCR4 Axis Stem Cells, August 1, 2005; 23(7): 879 - 894. [Abstract] [Full Text] [PDF]
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