Current Molecular Medicine 2007, 7, 777-789 777
1566-5240/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd.
RAGE and RAGE Ligands in Cancer
Craig D. Logsdon*,1,2, Maren K. Fuentes1,3, Emina H. Huang4 and Thiruvengadam
Departments of Cancer Biology1 and Medical Oncology2, The University of Texas M.D. Anderson Cancer
Center, Houston, Texas 77030, and the Program in Cellular and Molecular Biology3 and the Department of
Surgery4, University of Michigan, Ann Arbor, Michigan 48109, USA
Abstract: The receptor for advanced glycation end-products (RAGE) is a multifunctional receptor with multiple
ligands that is known to play a key role in several diseases, including diabetes, arthritis, and Alzheimer's dis-
ease. Recent evidence indicates that this receptor also has an important role in cancer. RAGE ligands, which
include the S100/calgranulins and high-mobility group box 1 (HMGB1) ligands, are expressed and secreted by
cancer cells and are associated with increased metastasis and poorer outcomes in a wide variety of tumors.
These ligands can interact in an autocrine manner to directly activate cancer cells and stimulate proliferation,
invasion, chemoresistance, and metastasis. RAGE ligands derived from cancer cells can also influence a vari-
ety of important cell types within the tumor microenvironment, including fibroblasts, leukocytes, and vascular
cells, leading to increased fibrosis, inflammation, and angiogenesis. Several of the cells in the tumor microenvi-
ronment also produce RAGE ligands. Most of the cancer-promoting effects of RAGE ligands are the result of
their interaction with RAGE. However, these ligands also often have separate intracellular roles, and some
may interact with other extracellular targets, so it is not currently possible to assign all of their effects to RAGE
activation. Despite these complications, the bulk of the evidence supports the premise that the ligand–RAGE
axis is an important target for therapeutic intervention in cancer.
Keywords: RAGE, advanced glycation end products (AGEs), inflammation, cancer.
The receptor for advanced glycation end-products
(RAGE) is a member of the immunoglobulin superfa-
mily of receptors and has unique properties that make
it a key component in a variety of diseases. RAGE is
expressed in many tissues and cell types, usually at
low levels in homeostasis except in the lung where its
expression is very high even in the apparent absence
of disease [1-3]. Despite its wide-spread distribution,
RAGE-deficient mice develop and function essentially
normally . Physiologically, RAGE seems to have a
role in embryonic neuronal outgrowth . However, in
the adult, RAGE appears to act primarily in pathological
responses, as a receptor for a very broad range of
ligands that fall into the category of damage-associated
molecular pattern molecules (DAMPs). Expression of
these RAGE ligands is elevated in a variety of models
of inflammation and disease and seems to largely de-
termine the activity of this receptor. The most studied
role of RAGE is as a mediator of vascular dysfunction
in diabetes [6,7]. However, RAGE has also been impli-
cated in several other diseases, including arthritis, Alz-
heimer's disease, and cancer [1-3].
Cancer has long been described as a wound that
doesn't heal. The processes of wound healing, includ-
ing inflammation and angiogenesis, are important
*Address correspondence to this author at the Lockton Distinguished
Professor for Pancreatic Cancer Research, Departments of Cancer
Biology and Medical Oncology, The University of Texas M.D. Ander-
son Cancer Center, Unit 953, 1515 Holcombe Blvd., Houston, Texas
77030, USA; Tel: 713 563-3585; Fax: 713 563-8986;
elements of cancer progression, and RAGE plays key
roles in these processes [3,6]. However, the impor-
tance of RAGE in cancer, has only recently begun to
be appreciated. The initial study in this regard indicated
that inhibition of RAGE could reduce the growth, motil-
ity, and invasiveness of natural and implanted tumors
in nude mice . A number of subsequent studies have
broadened the investigation by introducing new ligands
and have raised interesting and important questions
regarding the specificity and targets of RAGE ligands
and anti-RAGE treatments, and are the subject of this
review. This new information suggests that RAGE and
its ligands may play an even larger role in cancer than
originally suggested. RAGE has unique properties that
contribute to several aspects of cancer development.
Several RAGE ligands, including high-mobility group
box-1 (HMGB1, also called amphoterin) and members
of the S100/calgranulin family of proteins, are up-
regulated in both inflammation and cancer. Cancer
cells as well as several other types of cells in the tumor
microenvironment, such as endothelial and smooth
muscle cells, fibroblasts, and leukocytes, express
RAGE. Activation of RAGE initiates a variety of cell
signaling pathways that regulate important cellular
functions, including proliferation, survival, migration,
motility, and invasiveness. Therefore, RAGE and
RAGE ligands are potential targets for new cancer
THE RAGE GENE AND RAGE SPLICE
The RAGE gene is localized on chromosome 6 near
the human leukocyte antigen locus of the MHC III com-
778 Current Molecular Medicine, 2007, Vol. 7, No. 8 Logsdon et al.
plex in humans and mice, in close proximity to the ho-
meobox gene HOX12 and the human counterpart of
the mouse mammary tumor gene int-3 . The basic
structure of RAGE consists of three immunoglobulin-
like regions, one "V"-type domain and two "C"-type
domains, followed by a short transmembrane domain
and a short cytoplasmic tail [2,10] (Fig. 1). Recently,
RAGE splice variants have been detected and appear
to be more numerous under pathological conditions.
The existence of variant RAGE isoforms from the same
gene (co-expressed with the full-length RAGE tran-
script) implies that the pre-mRNA of RAGE can be sub-
jected to alternative splicing under the control of un-
known pathways . The three major RAGE isoforms
are commonly referred to as the full-length RAGE re-
ceptor, expressed secretory RAGE (esRAGE), and N-
truncated RAGE (NtRAGE) [11,12] (Fig. 1). Spliced
variants of RAGE have now been described in several
cell types, including endothelial cells and pericytes ,
brain astrocytes and peripheral blood mononuclear
cells , and lung bronchial epithelial cells . We
have recently observed in pancreatic cancer cells the
expression of RAGE splice variants that are not ex-
pressed in the normal pancreas (unpublished observa-
tion). The function of these variants in normal or cancer
cells is not completely understood.
Expressed Secretory RAGE
Expressed secretory RAGE (esRAGE) mRNA con-
tains the same immunoglobulin domains present in full-
length RAGE receptor mRNA but also contains part of
intron 9, which incorporates a stop codon within the
sequence (Fig. 1). Because of the insertion of this stop
codon, the esRAGE mRNA lacks exons 10 and 11,
which encode the transmembrane domain of RAGE,
resulting in esRAGE not being embedded in the mem-
brane. Rather, esRAGE is efficiently secreted from
cultured cells and is capable of capturing ligands .
For this reason, esRAGE can function as a decoy-type
receptor. Interestingly, before esRAGE was discovered
as a naturally occuring form of RAGE, a synthetic
version of this molecule, termed soluble RAGE
(sRAGE), was produced in a baculovirus expression
system as a means of inhibiting RAGE activation .
The expression of the splice variant esRAGE was in-
vestigated in several normal organs and was found to
be present in a variety of cell types . Serum levels
of esRAGE are altered under various disease states
and higher plasma levels of esRAGE are associated
with a reduced risk of coronary artery disease, hyper-
tension, the metabolic syndrome, arthritis and Alz-
heimer’s disease. Recently, levels of circulating es-
RAGE were found to be greatly reduced or absent in
75% of non-small cell lung cancers (NSCLCs) .
Taken together, these data suggest that esRAGE may
modify the activity of the RAGE signaling system under
various conditions. Further research will be needed to
fully understand the significance of esRAGE at the
level of the tissue and in circulation.
The mRNA for NtRAGE retains intron 1, which like
intron 9 contains a novel stop codon, resulting in the
loss of both exon 1 and exon 2. This truncated version
Fig. (1). Molecular structure of RAGE and its splice variants. Full-length RAGE possesses one V-type and two C-type immuno-
globulin domains. Dominant-negative RAGE (dnRAGE) has lost the cytoplasmic domain responsible for RAGE ligand-mediated
signaling and can interfere with the signaling of the full-length receptor. Expressed secretory RAGE (esRAGE) lacks both the
cytoplasmic domain and the transmembrane domain. This form of the receptor is secreted and can act as an antagonist by
binding RAGE ligands. N-truncated RAGE (ntRAGE) lacks the V-type domain and therefore cannot bind RAGE ligands. How-
ever, all forms of RAGE are thought to be able to interact with Mac-1 on other cells. Activation of full-length RAGE leads to a
variety of intracellular signaling events that ultimately result in important effects on several aspects of cell biology.
RAGE and RAGE Ligands in Cancer Current Molecular Medicine, 2007, Vol. 7, No. 8 779
of full-length RAGE therefore lacks the V-type immu-
noglobulin domain but is otherwise identical to full-
length RAGE and is retained in the plasma membrane
(Fig. 1). As a result of the deletion of the V-type immu-
noglobulin domain, NtRAGE is significantly impaired in
its ability to bind RAGE ligands [12, 13, 17]. Expression
studies with a plasmid bearing the N-truncated cDNA
indicated that it expressed 42kDa protein without N-
linked oligosaccharides, which was localized mainly on
the plasma membrane similar to full-length RAGE, but
it is unclear how it reaches the plasma membrane, as
this variant lacks a signal peptide . Expression of
this non-binding variant did not inhibit AGE-stimulated
effects. Nevertheless, overexpression of NtRAGE in-
hibited endothelial cell migration . This suggests
that NtRAGE can interact with other molecules and
interfere with normal functions that may be independ-
ent of signaling by the typical RAGE ligands. Further
studies are necessary to determine the mechanism
involved in these effects of this unusual splice variant
EFFECTS OF RAGE LIGANDS
RAGE was originally discovered as the cell surface
receptor for the advanced glycation end-products
(AGEs), a heterogeneous population of protein and
lipid adducts that are formed through a post-
translational, non-enzymatic glycoxidation reaction of
sugar ketones or aldehyde groups with free amino
groups [18-20]. These AGEs appear to be very impor-
tant in the vascular complications of diabetes, and
RAGE is involved in these effects. However, RAGE is a
member of the immunoglobulin superfamily, and based
on the biology of this family , it was hypothesized
that RAGE might interact with other ligands in addition
to products of glycoxidation. The first alternative
ligands found for RAGE was a member of the S100
family of molecules . S100 molecules are primarily
known for their roles in inflammation, and therefore, the
observation that an S100 molecule could activate
RAGE broadened the scope of pathologies in which
this receptor might be important . Since then, the
number of RAGE ligands has expanded to include
amyloid-?-peptide and ? fibril sheets, involved in the
development of Alzheimer’s disease, several other
S100 proteins, and HMGB1. In contrast to RAGE itself,
which may or may not be highly expressed in different
cancers, RAGE ligands are generally overexpressed in
most types of cancer. Each of these ligands has been
implicated as being involved in cancer and will be dis-
cussed briefly, with the exception of amyloid-?-peptide
and ? fibril sheets, which are restricted to neurological
disorders and outside the scope of this review.
RAGE’s name comes from its ability to bind and be
activated by AGEs. AGEs are known to accumulate in
a variety of circumstances, including during the aging
process , in the presence of hyperglycemia such as
occurs during diabetes , and during the course of
inflammatory diseases, including renal failure . The
most common AGE found in vivo is the N? car-
boxymethylysine (CML), which results from the glyca-
tion of a lysine residue . Very little is known about
the presence or role of AGEs in cancer. However, tu-
mors are generally characterized by increased glucose
uptake and a high rate of glycolysis, so the formation of
AGEs might be expected. This hypothesis was sup-
ported in one study in which specific antibodies were
used to localize CML and other AGEs in a variety of
tumors . In another study, treatment with AGEs in-
duced melanoma cell proliferation, migration, and inva-
sion in vitro, and these effects were completely blocked
by treatment with an antibody against RAGE .
These results suggest that AGEs are involved in the
growth and invasion of melanoma through interactions
with RAGE. However, several other RAGE ligands are
also likely to be expressed and secreted by tumor cells,
so the specific contribution of AGEs is currently un-
known. It has also been suggested recently that AGEs
may not stimulate cellular responses via RAGE but that
contaminants in the preparation of AGEs might contrib-
ute to the apparent activation of RAGE . However,
this study conflicts with a wealth of data showing AGE
activation of RAGE and so must be considered with
HMGB1 was first referred to as amphoterin, be-
cause of its dipolar nature, and was thought to be a
non-histone-binding protein because it was originally
discovered to be bound loosely to chromatin . Since
that time, HMGB1 has been implicated in a variety of
biologically important processes, including transcrip-
tion, DNA repair, differentiation, neural development,
and extracellular signaling, and its potential roles in
cancer have recently been reviewed. As a nuclear pro-
tein, HMGB1 binds to the minor groove of DNA and
facilitates the assembly of site-specific DNA binding
proteins like p53 at their cognate binding sites within
chromatin . However, it is now known that HMGB1
also has an important extracellular function. HMGB1
can be secreted from activated inflammatory cells (e.g.,
monocytes and macrophages ) or released from
necrotic but not apoptotic cells  and act as an ex-
tracellular cytokine . When released from damaged
cells, this molecule has been found to act as a “necrotic
marker” used by the immune system to recognize tis-
sue damage, initiate reparative responses, and pro-
mote maturation of lymphocytes . Extracellular
HMGB1 also acts as a potent pro-inflammatory cyto-
kine, contributing to the pathogenesis of a wide variety
of inflammatory disorders.
HMGB1 has several effects that increase the ag-
gressiveness of cancer. One of its major effects is the
stimulation of metastasis through its effects on the
transcription of many genes involved at different steps
in the metastatic cascade . HMGB1 also affects
cancer cell survival; overexpression of HMGB1 was
associated with reduced levels of pro-apoptotic genes
780 Current Molecular Medicine, 2007, Vol. 7, No. 8 Logsdon et al.
[33, 34] and increased levels of anti-apoptotic genes
. However, there is a conflicting report in which
HMGB1 seems to have a pro-apoptotic effect on some
cells . A growing number of studies support the
idea that HMGB1 is a useful therapeutic target in can-
cer and a number of other important diseases, includ-
ing sepsis, acute respiratory distress syndrome, and
arthritis [8, 27, 36].
RAGE was the first known receptor for HMGB1, as
the two molecules were observed to be co-localized in
the developing rat brain and their interaction was found
to mediate neurite outgrowth . Several studies have
shown, via inhibition of RAGE signaling by approaches
including treatment with soluble RAGE and expression
of dominant-negative RAGE or blocking antibodies,
that HMGB1 acts via RAGE . A key report published
a few years ago demonstrated that blocking the signal-
ing cascade between HMGB1 and RAGE decreased
tumor growth and metastasis in glioma cells . In that
study, rat C6 glioma cells were stably transfected with
RAGE mutated constructs and injected into nude mice.
In vivo, tumor growth and metastasis were markedly
decreased. In vitro, it was shown that blocking the
HMGB1-RAGE interaction decreased cell proliferation,
migration, and invasion. More recently, it has been
suggested that HMGB1 may also activate the Toll-like
receptor (TLR) pathways, specifically TLR2, TLR4
[38,39]. However, this possibility remains controversial,
as one report suggests that bacterial endotoxins may
be contaminants in preparations of HMGB1 and that an
HMGB1 preparation that is endotoxin-free does not
stimulate TLR . More recently HMGB1 and RAGE
have been found to interact with TLR9 . Because
HMGB1 has several effects, acts both intracellularly
and extracellularly, and can potentially interact with
more than one receptor, caution must be used when
attempting to understand the role of RAGE in the ac-
tions of this molecule in disease.
S100 molecules are small, calcium-binding, cell-
signaling molecules of the EF-hand (helix-loop-helix)
type [42,43]. These molecules can interact to form di-
mers or various oligomeric structures and have both
intracellular and extracellular functions. As intracellular
molecules, they are calcium-signaling or calcium-
buffering proteins responsible for assorted roles in the
cell cycle, cell differentiation, and cell motility. However,
several S100 family members, including S100B,
S100A4, S100A8, S100A9, S100A12, S100A13, and
S100P, are secreted and appear to have extracellular
roles. Secreted S100s were long observed to collect at
sites of chronic inflammation, but their role was not un-
derstood. This changed when the extracellular newly
identified RAGE binding protein (EN-RAGE), now
known as S100A12, was discovered, using column
chromatography, as a molecule that bound to and acti-
vated RAGE . (Of interest is the fact that S100A12
is not expressed in mice ). Because of the high de-
gree of similarity among the S100 molecules and the
pattern recognition properties of RAGE binding, it was
predicted that many or all S100s could be RAGE
ligands. This prediction has been generally supported,
as S100A4 , S100B , and S100P  have
been definitively shown to mediate cell functions via
RAGE activation. However, there are also reports sug-
gesting that S100A4 , S100B , and the complex
of S100A8/9  exert important extracellular effects
that are independent of RAGE. Therefore, S100 pro-
teins, like other RAGE ligands, have separate intracel-
lular roles as well as separate receptors in addition to
Of the 20+ members of the S100 family, a handful
have been implicated in cancer . The S100 family
member S100P, which was named after identification
in the placenta , has been shown to directly interact
with RAGE [47,52,53] and to have an important role in
cancer. In animal models, the overexpression or silenc-
ing of S100P in cancer cells forming orthotopic tumors
was directly correlated with increased or decreased
pancreatic cancer tumor growth, respectively [52,53].
Transfection of S100P into a benign, non-metastatic rat
mammary cell line caused an increase in local muscle
invasion and metastasis in a mouse model . Ex-
ogenous treatment of pancreatic cancer cell lines with
S100P stimulated cell proliferation, survival, migration,
and invasion and activated the MAP kinase (Erk 1/2)
and NF?B pathways [47,52,53]. The effects of treat-
ment with extracellular S100P were shown to be medi-
ated by its interaction with RAGE, since blockade of
this interaction prevented the effects of exogenous
S100P on cell functions . S100A4 is often consid-
ered a metastasis-inducing molecule, and this function
has been recently reviewed . S100B is a potential
cancer biomarker, as it is highly expressed in mela-
noma . However, not all S100s appear to promote
cancer. S100A2 is often found to be inversely related to
S100A4 , and an anti-tumorigenic, mechanistic role
for S100A2 has been described in squamous cell car-
cinoma . Therefore, although the roles of several
members of the S100 family in cancer remain unclear,
some of them have been shown to directly interact with
RAGE EXPRESSION IN TUMORS
RAGE is expressed in a variety of human tumors,
including ovarian, breast, colonic, brain, lung, prostate,
lymphoma, and melanoma . In most pathologic
conditions in which it plays an important role, RAGE
levels are found to be elevated. This phenomenon has
been well documented in diabetes [7, 60], arthritis ,
and Alzheimer's disease . The increased expres-
sion of RAGE is thought to be due to a positive-
feedback regulation of the RAGE promoter through
RAGE activation of NF?B . This phenomenon has
been shown to amplify and prolong inflammatory sig-
nals . Therefore, it might be expected that RAGE
levels would be elevated in cancer. Indeed, increased
levels of RAGE have been reported in several cancers,
including prostate , colon , and gastric tumors
RAGE and RAGE Ligands in Cancer Current Molecular Medicine, 2007, Vol. 7, No. 8 781
. However, others have not observed elevated
RAGE levels in colon cancer  or pancreatic cancer.
Furthermore, in lung cancer, RAGE levels are signifi-
cantly decreased [68-70]. These observations seem to
call into question the role of RAGE in cancer. However,
RAGE ligands are elevated in nearly all tumors. Fur-
thermore, the story has been made more complex by
the discovery of important splice variants of RAGE. For
example, in non-small cell lung cancer along with a
decrease in full-length RAGE, there is also a decrease
in a splice variant that acts as a natural antagonistic
form of the receptor (sRAGE) . Thus, to fully under-
stand the role of RAGE in cancer it is necessary to take
into account differences in the levels of RAGE, its
splice variants, and its ligands.
RAGE AND RAGE LIGANDS IN SPECIFIC
The role of RAGE in lung tumors has recently been
reviewed . Lung cancer is unique in that there is
conflicting evidence concerning RAGE and RAGE
ligands in this disease. Reduced levels of RAGE have
been observed in NSCLC compared with the normal
lung [68-70]. Down-regulation of RAGE also correlated
with higher tumor stages . Furthermore, overex-
pression of full-length human RAGE in lung cancer
cells (NCI-H358) resulted in diminished tumor growth
compared to that in dominant-negative RAGE-
expressing cells in vivo . Recently, it was found that
esRAGE, the splice variant that is secreted and acts as
an antagonist, is also down-regulated in NSCLC .
The balance of full-length RAGE and esRAGE may
influence the ability of the cells to respond to endoge-
nous ligands and is an example of the complexities of
the role of RAGE in cancer. Furthermore, several
RAGE ligands are highly expressed in the lung, includ-
ing S100A12 and HMGB1 . These ligand levels are
critical determinants of RAGE function.
Other ligands are also expressed in lung cancer.
The RAGE ligand S100P is overexpressed in NSCLC
and associated with poor survival [73, 74]. Further-
more, forced expression of S100P in an NSCLC cell
line increased its transendothelial migration .
S100A4 is also up-regulated in NSCLC tissue and as-
sociated with poor patient survival . A recent study
has shown that reduced E-cadherin expression com-
bined with higher S100A4 expression is associated
with poor prognosis due to increased metastasis in
pulmonary adenocarcinoma . At present, there is
no specific information available about the role of other
RAGE ligands, such as S100A8 and -A9, HMGB1, and
AGEs, in lung cancer, and further study is needed to
fully understand the role of RAGE and its ligands in this
aggressive cancer pathology.
Little is known about the levels of RAGE or RAGE
splice variants in breast cancer. On the other hand,
breast cancer has been a source of considerable in-
formation about RAGE ligands. In particular, S100A4
plays a crucial role in breast cancer growth. A direct
correlation has been observed between S100A4 ex-
pression and mean vessel density in breast tumors
. In one study, the long-term survival rate was much
higher in S100A4-negative patients compared to
S100A4-positive patients (80% vs 11%, median follow-
up 19 years) . S100A4 has also been shown to be
an independent predictor of patient survival and a
marker for early metastasis . S100P also plays an
important role in breast cancer progression from initial
tumorigenesis to invasive carcinoma. S100P is specifi-
cally expressed in breast cancer tissue . Immuno-
histochemical analysis of S100P in 303 breast cancer
patients followed up for up to 20 years has shown that
the survival duration of patients with S100P-positive
carcinomas was significantly worse—by about 7-fold—
than that for those with S100P-negative staining .
Moreover, patients with tumors that stained positively
for both S100P and S100A4 had significantly shorter
survival compared to patients with tumors positive for
either S100 protein alone, suggesting that the combina-
tion of S100P and S100A4 is the most significant inde-
pendent risk factor for death in this group of patients
. S100P seems to be increased early in tumori-
genesis, as it is expressed in non-transformed breast
epithelial cell lines after immortalization and also in hy-
perplastic ductal tissues . Expression of another
RAGE ligand, S100A9, was associated with poor dif-
ferentiation in breast cancer tissues . High levels of
HMGB1 have also been observed in human primary
breast carcinoma , and this expression was further
enhanced by estrogen [34, 83]. Taken together, there
is considerable evidence for the importance of RAGE
ligands in breast cancer; however, it is currently un-
clear which of these effects are mediated by RAGE.
Both RAGE and RAGE ligands have been reported
to be elevated in prostate cancer. The RAGE ligands
S100A8 and S100A9 are overexpressed in human
prostate cancer, and these proteins were co-localized
with RAGE in cancer cells and secreted by prostate
cancer cells . The addition of these S100s induced
activation of NF?B, phosphorylation of p38, and MAP
kinase (Erk1/2) activity and increased the migration of
benign prostate cells in vitro . S100A9 serum levels
were also found to be significantly elevated in patients
with prostate cancer compared with those with benign
prostatic hypertrophy or healthy individuals, and it was
suggested that S100A9 could be a serum marker like
prostate-specific antigen . HMGB1 also appears to
be involved in prostate cancer development . High
levels of RAGE and HMGB1 have been observed in
untreated prostate cancer tissue, hormone-refractory
prostate cancer tissue, and a hormone-independent
prostate cancer cell line compared to levels in normal
prostate tissue . HMGB1-RAGE expression was
also found to be elevated in PC-3 cells, and in these
782 Current Molecular Medicine, 2007, Vol. 7, No. 8 Logsdon et al.
cells, androgen deprivation increased HMGB1 secre-
tion and cancer cell invasion .
In colon cancer, RAGE expression has been re-
ported to increase as colon cancer progresses, as indi-
cated by Dukes’ classifications . However, in other
studies, no increase in RAGE expression was noted in
colon tumors compared to surrounding normal tissue
. The expression and distribution of RAGE splice
variants have not been investigated in this cancer. Im-
munohistochemical studies have indicated that RAGE
has three patterns of staining in colon cells: cytosolic,
luminal, and membranous. A relationship between the
RAGE staining pattern and atypia has also been re-
ported; as atypia becomes more severe, RAGE local-
ization moves from the cytosol to the membrane, sug-
gesting that RAGE could be used for predicting malig-
nant potential .
RAGE appears to be involved in the interface be-
tween inflammation and carcinogenesis in the colon.
The multiple intestinal neoplasia (MIN+/-) mouse is the
murine corollate of the human condition familial ade-
nomatous polyposis (FAP). The phenotype of this
model typically includes 20–50 adenomatous polyps,
predominantly in the small bowel. Administration of
sRAGE intraperitoneally from weaning to 20 weeks of
age led to a significant decrease in the number of pol-
yps (personal communication, E. Huang). RAGE has
also been documented to play a role in the inflamma-
tory neoplastic model of the IL-10 null mouse. In this
transgenic model, the incidence of chronic inflamma-
tory enterocolitis is as high as 60% in some environ-
ments, with an incidence of dysplastic lesions of up to
30% . Furthermore, breeding the MIN+/- mouse
with the IL-10 null mouse caused a dramatic increase
in both inflammation and colonic polyps, supporting a
role for inflammation in neoplasia . The administra-
tion of sRAGE was able to ameliorate the inflammation
observed in the IL-10 null mouse model . There-
fore, RAGE antagonism, by ameliorating inflammation,
may be useful in cancer prevention as well as in cancer
S100P also seems to be involved in the inflamma-
tion-to-carcinogenesis progression that occurs in colon
cancer. S100P is elevated in the chronic inflammatory
conditions of ulcerative colitis and Crohn's disease,
which both increase the risk of colon cancer up to 10-
fold . S100P was also overexpressed in flat ade-
nomas of the colon, which are associated with a higher
potential for malignancy compared to other adenomas
. S100P was found to be overexpressed in colon
cancer tissue compared to matched normal counter-
parts . In that study, S100P treatment increased
proliferation and migration and activated the MAP
kinase pathway (Erk1/2) and NF?B in SW480 colon
cancer cells, and inhibiting the S100P/RAGE interac-
tion blocked these biological effects . As in pancre-
atic cancer, silencing S100P decreased tumor growth
in a xenograft model of colon cancer (unpublished ob-
servations). Doxorubicin-resistant colon cancer cell
lines expressed higher levels of S100P when com-
pared with their sensitive counterparts . S100A4 is
also expressed in colon cancer and is associated with
invasive potential, as it has been found to be specifi-
cally overexpressed in invasive carcinoma rather than
adenoma or normal tissue [93,94]. In another study,
S100A4 levels correlated with colon cancer patient sur-
vival . S100A4 overexpression in colon cancer
samples has also been associated with gene hy-
pomethylation . Little is known about the role of
AGEs in colon cancer, but AGEs were shown to stimu-
late MAP kinase (Erk1/2) activation in one colon cancer
cell line .
HMGB1 has been associated with invasion and me-
tastasis of colon cancer , and it has also been stud-
ied in colon cancer cell lines in vitro. Colon cancer cell
lines with reduced endogenous HMGB1 levels had de-
creased growth, migration, invasion, and activation of
various cell signaling pathways, and these effects were
reversed when cells were treated with conditioned me-
dium containing HMGB1 . Immunohistochemical
studies have also linked RAGE with its ligand HMGB1
in colon cancer progression, as co-expression of RAGE
and HMGB1 is closely associated with the invasion and
metastasis of colorectal cancer .
There is no direct evidence showing that RAGE is
overexpressed in pancreatic tumors, as neither quanti-
tative reverse transcription polymerase chain reaction
nor western blotting indicated differences between
pancreatic tumor samples and normal controls (unpub-
lished observation). However, RAGE is expressed by
pancreatic cancer cells, and the expression levels of
RAGE in pancreatic cancer cell lines were reported to
correspond with metastatic potential . Also, RAGE
exists as multiple splice variants in pancreatic cancer
but as a single, full-length mRNA in the normal pan-
creas (unpublished observation). In contrast to RAGE
itself, RAGE ligands are overexpressed in pancreatic
cancer, as revealed by microarray and tissue array
analysis of pancreatic cancer tissues [100-103]. In par-
ticular, the molecule S100P has been found to be
overexpressed in pancreatic cancer [100,103,104]. This
expression is specific to pancreatic cancer and was not
observed in samples of chronic pancreatitis, an in-
flammatory disease with similar abundant desmoplastic
features . As was observed in breast cancer,
S100P seems to be an early marker of premalignancy,
as S100P expression has been shown to increase dur-
ing pancreatic cancer progression from precursor
PanIN lesions to invasive adenocarcinoma . The
overexpression of S100P in pancreatic cancer has
been suggested to be due to hypomethylation of its
gene in pancreatic cancer . S100P was found to
be secreted from pancreatic cancer cell lines and to act
extracellularly through RAGE . Moreover, expres-
RAGE and RAGE Ligands in Cancer Current Molecular Medicine, 2007, Vol. 7, No. 8 783
sion of S100P increased pancreatic orthotopic tumor
growth and metastasis in vivo, and silencing of S100P
had the opposite result. S100A4 has also been found
to be involved in pancreatic cancer. S100A4 expres-
sion correlated significantly with higher pathological
stage and poorer prognosis in an immunohistochemical
analysis of tumor samples, and combining the analysis
of S100A4 with that of E-cadherin improved the prog-
nostic value of each marker . Similar to S100P,
overexpression of S100A4 in pancreatic cancer was
related to gene methylation status . Other RAGE
ligands have not been investigated in pancreatic can-
ORAL SQUAMOUS CELL CARCINOMA
Multivariate analysis showed high levels of RAGE to
be an independent prognostic factor for disease-free
survival in OSCC . In this study, RAGE expression
was examined by immunohistochemistry and com-
pared with clinicopathological parameters including
clinical stage, invasive depth, nodal metastasis, dis-
ease recurrence and disease-free survival in patients
with OSCC. In another study by the same group,
RAGE levels were also been shown to be closely as-
sociated with angiogenesis in OSCC . RAGE ex-
pression also appears to be closely associated with the
invasiveness of oral squamous cell carcinoma, as si-
lencing RAGE protein expression using an anti-sense
oligomer reduced cancer cell migration and invasion of
oral carcinoma cells in an animal model . The
RAGE ligand S100P has been identified as a gene
highly expressed in oral squamous cell carcinoma
In a variety of other cancers there is evidence that
RAGE and/or RAGE ligands may be important. In
melanoma, RAGE was detected in the cytoplasm of
human melanoma cells (G361 and A375), and these
cells were stimulated to proliferate and migrate after
treatment with AGEs . Furthermore, anti-RAGE an-
tibody inhibited tumor formation, reduced invasion, and
increased survival in an animal model in vivo . In
melanoma, it has also been reported that AGEs were
present in the beds of human melanoma tumors,
whereas they were nearly undetectable in normal skin
. HMGB1 is also up-regulated in malignant mela-
noma cells . In biliary cancer, RAGE expression
was associated with invasive potential in three cell lines
in vitro . In gastric cancer, RAGE immunoreactivity
correlated with increased lymph node metastasis, and
HMGB1 was also observed to be increased . The
same study also found that RAGE expression corre-
lated with the invasiveness of gastric cancer cells in
vitro and anti-sense oligomers against RAGE inhibited
cell invasion . AGEs were shown to increase the
proliferation of renal cell carcinoma cells . HMGB1
has been found to be associated with gastrointestinal
stromal tumors , hepatocellular carcinoma ,
and osteosarcoma . Taken together, these data
support the assertion that RAGE and RAGE ligands
are involved in nearly all malignancies.
HOW DOES RAGE INFLUENCE CANCER?
Direct Effects of RAGE Activation on Cancer Cells
Activation of RAGE has been shown to influence
cell proliferation [8, 47], survival [47, 52], migration, and
invasion in vitro [8, 47, 52, 66] and metastasis in vivo
[8, 36,52]. These effects are likely the result of RAGE
activating the cellular signaling pathways that regulate
these functions. RAGE is known to stimulate multiple
signaling pathways crucial for cell proliferation, includ-
ing MAP kinase (Erk1/2) [8,47]. RAGE also activates
signaling pathways thought to regulate cell migration,
such as the Ras-extracellular signal-regulated kinase
kinase/c-Jun-NH2-terminal kinase, and p38 mitogen-
activated protein kinase pathways . Stimulation of
RAGE also leads to the activation of the transcription
factor NF?B [47, 121]. This pathway may explain some
of the effects of RAGE activation on cell survival, as a
number of anti-apoptotic genes, including IAPs, Bcl-XL,
and Bcl-2, are also influenced by activation of NF?B
. Furthermore, several transcriptional targets of
RAGE signaling, such as vascular cell adhesion mole-
cule 1  and tissue factor , likely contribute to
the interaction between tumor cells and vascular endo-
thelium that may be involved in stimulating metastasis.
Although activation of various intracellular signaling
pathways can be seen in response to stimulation with
different ligands, no adaptor protein for the transduction
of intracellular signals by RAGE has been identified.
One study has suggested a direct interaction between
the cytoplasmic domain of RAGE and MAP kinase
(Erk1/2) . However, the interaction domains be-
tween these two molecules have not been mapped,
and this work has not been replicated. Therefore, much
remains to be discovered about the cellular mecha-
nisms activated by this important molecule.
RAGE Effects within the Cancer Microenvironment
It is becoming increasingly clear that cancer cells
depend upon interactions with the cells within the can-
cer microenvironment . The cells that reside within
the tumor microenvironment or are recruited to this en-
vironment are affected by and, in turn, affect cancer
cells. Important cells in the tumor microenvironment
include those that compose the microvasculature, in-
cluding endothelial cells and pericytes; those that pro-
duce the abundant extracellular matrix that makes up
the bulk of the stroma, including fibroblasts and myofi-
broblasts; and cells of the immune system, including a
variety of leukocytes such as macrophages. Most of
these cells are known to express RAGE; therefore,
RAGE ligands generated by cancer cells are likely to
influence the tumor microenvironment. Likewise, cells
of the tumor microenvironment also produce RAGE
784 Current Molecular Medicine, 2007, Vol. 7, No. 8 Logsdon et al.
ligands that can interact with RAGE on cancer cells
(Fig. 2). While there are obviously many other factors
involved in the crosstalk between the microenvironment
and cancer cells, it seems likely that RAGE and RAGE
ligands play a significant role.
Fig. (2). RAGE is expressed by cancer cells and cells in the
tumor microenvironment, including leukocytes, endothelial
cells, and fibroblasts. RAGE ligands secreted from cancer
cells or leukocytes can interact with RAGE and other recep-
tors to influence tumor progression.
One of the most important ways in which RAGE
may affect cancer, beyond its effects on cancer cells
themselves, is through its ability to influence angio-
genesis. Tumor growth depends upon the ability of the
cancer cells to receive adequate oxygenation and nu-
trients . Tumors develop a blood supply both by
commandeering local vessels and by developing new
vessels. The development of new vessels, involves the
proliferation and migration of endothelial cells as well
as pericytes. A variety of RAGE ligands have been
shown to influence endothelial cells, including AGEs
and HMGB1 . It was reported that the inhibition of
HMGB1 expression in colon cancer inhibited angio-
genesis . Activation of RAGE increases endothe-
lial cell number and induces expression of vascular
endothelial growth factor (VEGF), a potent angiogenic
factor . RAGE ligands have been found to induce
other angiogenic factors, such as IL-8, through activa-
tion of NF?B . Activation of RAGE also influences
the vasculature by increasing endothelial permeability
to macromolecules , which is a condition com-
monly observed in tumors . Thus, it is likely that
RAGE and RAGE ligands participate in the develop-
ment and the properties of the tumor microvasculature.
Another influence of RAGE and RAGE ligands in
cancer may be mediated through their effects on fibro-
blasts. The role of fibroblasts in cancer is a matter of
increasing study, and there is considerable interest in
understanding the differences between normal stroma
and reactive tumor stroma. One primary role of fibro-
blasts is the elaboration of the prominent extracellular
matrix composing the tumor stroma. However, it is be-
coming increasingly recognized that fibroblasts play
other important roles in cancer . Fibroblasts are
associated with cancer cells during cancer develop-
ment and progression, and their structural and func-
tional contributions to this process are beginning to be
appreciated. Fibroblasts produce growth factors,
chemokines, and extracellular matrix molecules that
facilitate the angiogenic recruitment of endothelial cells
and pericytes. There appear to be important differ-
ences between fibroblasts in healthy tissues and those
found in tumors. In particular, the fibroblasts found in
tumors are called "activated fibroblasts", also some-
times referred to as myofibroblasts. The possibility that
RAGE regulates fibroblasts is supported by studies
showing that skin fibroblasts respond to AGEs by in-
creasing their expression of RAGE and the cytokine
TNF? . Activation of RAGE on synovial fibroblasts
has been found to increase MCP-1 synthesis, which
was sufficient to induce the chemotaxis of monocytes
. RAGE activation was also found to lead to myo-
fibroblast transdifferentiation of mesothelial cells in the
kidney . RAGE may also influence fibroblasts
through the up-regulation of important fibroblast growth
factors, such as connective tissue growth factor .
Thus, while the specific role of RAGE in the activation
of fibroblasts within the tumor microenvironment has
not been well defined, this should be an important topic
for future investigation.
Other cellular targets of RAGE activity likely to be
important in cancer are macrophages. Macrophages
and their precursors, monocytes, respond to RAGE
ligands , and macrophages are also producers of
RAGE ligands . Macrophages can act differently
depending upon the circumstances, and a clear distinc-
tion needs to be made between normal macrophages
and tumor-associated macrophages (TAMs). Macro-
phages derived from healthy or inflamed tissues ap-
pear to act primarily in an anticancer manner, as they
can directly lyse tumor cells and also induce an im-
mune response against cancer cells. The immune
modulatory effects of macrophages include their ability
to present tumor-associated antigens to T cells as well
as express immunostimulatory cytokines that increase
the proliferation and anti-tumor functions of T cells and
natural killer cells. TAMs show greatly reduced levels of
these activities and rather appear to facilitate angio-
genesis and influence the invasiveness of cancer by
stimulating extracellular matrix breakdown and remod-
eling as well as by increasing tumor cell motility and the
egress of tumor cells in the blood vessels . The
specific signals that determine the differences between
normal macrophages and TAMs are currently un-
known. In some cases, activation of RAGE has been
suggested to lead to the destruction of macrophages
. On the other hand, RAGE activity has been re-
ported to increase the conversion of monocytes to
macrophages and to stimulate macrophage function
associated with inflammation and diabetes . An-
RAGE and RAGE Ligands in Cancer Current Molecular Medicine, 2007, Vol. 7, No. 8 785
other way in which RAGE may influence macrophage
function is through its ability to influence leukocyte ad-
hesion and monocyte transendothelial migration .
In fact, RAGE itself can act as a counter receptor for
the leukocyte integrin Mac-1 . Clearly, the effects
of RAGE activity on the function of macrophages under
different circumstances remain to be fully elucidated,
but this may be another context in which RAGE influ-
RAGE IS A POTENTIAL TARGET FOR IN-
TERVENTION IN CANCER
Despite the fact that RAGE seems to be primarily
involved in pathological responses and RAGE null ani-
mals are largely normal, it is likely that RAGE has
physiologic functions involved in homeostasis. There-
fore, some caution is prudent when it comes to inhibit-
ing RAGE function. On the other hand, in the case of
serious diseases, including cancer, the potential nega-
tive effects of inhibiting RAGE in normal tissues are
likely superseded by the advantages of its inhibition in
diseased tissues. Thus, the development of means to
interfere with RAGE activity would seem highly desir-
able. Currently, small molecule inhibitors that target
RAGE are under development but have not been clini-
cally evaluated. However, RAGE has been inhibited
experimentally in a variety of ways, including  ex-
pression of a dominant-negative truncated receptor ;
 treatment with sRAGE ;  treatment with a
blocking RAGE antibody ;  treatment with an an-
tagonistic peptide derived from HMGB1 ;  treat-
ment with cromolyn ; and  gene silencing with
anti-sense oligonucleotides . Several of these ap-
proaches would probably not be clinically applicable.
However, some warrant further consideration.
Fig. (3). Targeting of RAGE for therapy can occur at multiple
levels. Several molecules have been found that can bind or
sequester RAGE ligands. Receptor antagonists exist in sev-
eral forms. The cellular signaling pathways important for the
actions of RAGE are not completely worked out but there is a
positive feedback system known to bring about increased
expression of RAGE that might be a good target for therapy.
The most widely used approach for investigating the
role of RAGE is with sRAGE, a synthetic version of the
naturally occurring secreted form of the receptor that
can act to sequester RAGE ligands. sRAGE treatment
also has been reported to be useful as an experimental
cancer treatment in animal models. Application of
sRAGE was shown to drastically suppress the growth
of tumor cells in vitro and in vivo . This suggests that
blocking RAGE activation may be useful as a treatment
in cancer. Furthermore, the use of sRAGE has contrib-
uted greatly to our understanding of the role of RAGE
ligands in experimental settings. However, several
questions have arisen with regard to the specificity of
this approach. One important issue was raised when it
was observed that sRAGE could still influence disease
processes, including diabetic nephropathy, neuropathy,
and arterial restenosis, in RAGE-deficient animals .
One explanation for this observation is that RAGE
ligands likely also interact with other receptors. There-
fore, administration of sRAGE may inhibit a variety of
cellular pathways in addition to its effect on RAGE. A
more recent issue is that sRAGE could directly affect
cell function by interacting with cells expressing Mac-1,
triggering a cellular response . In this study,
sRAGE was found to be chemotactic for leukocytes
and to lead to their activation. This observation perhaps
should not be totally surprising, as it has long been
known that RAGE could interact with Mac-1 during cell-
to-cell interactions . However, this observation
may necessitate a reevaluation of some of the previous
studies using sRAGE to determine the roles of RAGE
in disease processes. sRAGE is also a large molecule
that is relatively difficult to produce and may provoke
an immune response. Therefore, for several reasons
sRAGE is likely to remain an experimental tool rather
than become a therapeutic treatment in the clinical set-
Another potential approach is to find drugs that in-
terfere with specific RAGE ligands. Recently, it was
demonstrated that the small molecule cromolyn, which
is widely used to treat allergic symptoms, can bind the
RAGE ligand S100P and prevent its activation of
RAGE . Cromolyn also binds to other S100 mole-
cules , but it is unknown whether it will inhibit
RAGE activation by these or other RAGE ligands.
Cromolyn was found to inhibit pancreatic cancer cell
function and pancreatic tumor formation in animal
models, likely through its ability to block an autocrine
loop involving S100P and RAGE . Cromolyn has
the advantage of having been used in humans for
many years. However, cromolyn has other targets and
it has some pharmacokinetic properties, including low
oral bioavailability, that are not desirable . Other
anti-allergy drugs have also been reported to bind to
members of the S100 family of RAGE ligands .
Potentially, these or other drugs could be developed to
act on specific RAGE ligands.
A peptide antagonist for RAGE was developed from
a COOH-terminal motif in amphoterin that was found to
be responsible for RAGE binding . Treatment with
this peptide was found to efficiently inhibit process ex-
786 Current Molecular Medicine, 2007, Vol. 7, No. 8 Logsdon et al.
tension and transendothelial migration of tumor cells.
Furthermore, in an in vivo model of melanoma, the
peptide significantly suppressed the formation of lung
metastases. This peptide has also been found to inhibit
the interaction between S100P and RAGE , sug-
gesting that peptides with broad antagonistic properties
against RAGE may be possible. Peptides are increas-
ingly being developed as cancer therapeutics .
Therefore, an approach based on peptide antagonists
of RAGE may be an alternative to small molecules.
RAGE is a receptor with a wide array of ligands that
seem to dictate its involvement in disease. These
RAGE ligands are widely overexpressed in cancer. The
roles of RAGE and RAGE ligands in cancer are likely to
be multidimensional. The broad range of ligands with
which RAGE interacts and the multiple alternative
mechanisms of action of these ligands make it difficult
to determine the specific mechanisms involved in par-
ticular functions. Furthermore, RAGE can influence not
only cancer cells but also cells within the tumor micro-
environment that are important for tumor progression
and metastasis. From what is currently known, it seems
that interference with RAGE ligands will be of therapeu-
tic benefit in cancer. However, further studies are nec-
essary to determine whether the promising results ob-
served with the inhibition of RAGE and RAGE ligands
in animal models of cancer will be translated into sig-
nificant clinical benefit.
This work was supported by funds from the Lockton
Endowment at M. D. Anderson Cancer Center and NCI
K08 91975 (to EH).
RAGE = Receptor for advanced glycation end-
sRAGE = Soluble RAGE
esRAGE = Expressed secretory RAGE
NtRAGE = N-truncated RAGE
DAMPs = Damage-associated molecular pattern
TAMs = Tumor-associated macrophages
HMGB1 = High-mobility group box 1
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Received: July 10, 2007
Revised: September 28, 2007 Accepted: October 16, 2007