|
Current Molecular Medicine
ISSN: 1566-5240
Current Molecular Medicine
Volume 7, Number 8, December 2007
Contents
Receptor for Advanced Glycation Endproducts (RAGE):
Coming Full Circle in Unraveling the Pathogenesis of Chronic
Disease
Guest Editor: Ann Marie Schmidt
Editorial Pp. 697-698
Ann Marie Schmidt
Receptor for Advanced Glycation Endproducts (RAGE):
A Formidable Force in the Pathogenesis of the Cardiovascular
Complications of Diabetes & Aging Pp. 699-710
Shi Fang Yan, Vivette D’Agati, Ann Marie Schmidt
and Ravichandran Ramasamy
[Abstract]
RAGE: A Single Receptor for Several Ligands and Different
Cellular Responses: The Case of Certain S100 Proteins
Pp. 711-724
Rosario Donato
[Abstract]
RAGE as a Receptor of HMGB1 (Amphoterin): Roles in
Health and Disease Pp. 725-734
Heikki Rauvala and Ari Rouhiainen
[Abstract]
RAGE: A Potential Target for Aβ-Mediated
Cellular Perturbation in Alzheimer’s Disease
Pp. 735-742
Xi Chen, Douglas G. Walker, Ann Marie Schmidt, Ottavio
Arancio, Lih-Fen Lue and Shi Du Yan
[Abstract]
Receptor for AGE (RAGE): Weaving Tangled Webs Within
the Inflammatory Response Pp. 743-751
Raphael Clynes, Bernhard Moser, Shi Fang Yan, Ravichandran
Ramasamy, Kevan Herold and Ann Marie Schmidt
[Abstract]
RAGE in Diabetic Nephropathy Pp. 752-757
Hiroshi Yamamoto, Takuo Watanabe, Yasuhiko Yamamoto, Hideto
Yonekura, Seiichi Munesue, Ai Harashima, Kazuyo Ooe, Sharmin
Hossain, Hidehito Saito and Naho Murakami
[Abstract]
RAGE and its Ligands in Retinal Disease Pp.
758-765
Gaetano R. Barile and Ann M. Schmidt
[Abstract]
RAGE, Diabetes, and the Nervous System Pp.
766-776
Cory Toth, Jose Martinez and Douglas W. Zochodne
[Abstract]
RAGE and RAGE Ligands in Cancer Pp. 777-789
Craig D. Logsdon, Maren K. Fuentes, Emina H. Huang and
Thiruvengadam Arumugam
[Abstract]
Abstracts
[Back to top]
Editorial
Ann Marie Schmidt
In unraveling the biology of the Receptor for Advanced Glycation
Endproducts (RAGE), it has become increas-ingly apparent that
the ligands of RAGE stimulate signal transduction through
this receptor – leading to cascades of events that,
depending on the microenvironment, initiate and sustain chronic
cell stress. In certain settings, how-ever, RAGE-dependent
signaling may augur repair and resolution of stress, especially
where acute injury stimulates rapid generation and removal
of RAGE ligands. Although first described as a receptor for
the products of nonenzy-matic glycation and oxidation of proteins,
the Advanced Glycation Endproducts (AGEs) [1] the biology
of RAGE blossomed upon the discovery that at least four other
classes of molecules might bind this receptor. In addition
to AGEs, RAGE binds S100/calgranulins, High Mobility Group-1,
Mac-1, and amyloid-β
peptide and β-sheet
fibrils (Aβ)
[2-5]. Together, these ligand families bespeak unifying mechanisms
underlying the pathogenesis of chronic disease. Thus, irrespective
of the specific etiology, the intriguing upregulation and
accumulation of RAGE ligands in tissues beset by chronic disease
brings RAGE squarely to the battlefield in disorders such
as diabetes, chronic inflammation and autoimmunity, neurodegeneration,
tumors and aging. As outlined in the reviews in this series,
data in both cell culture and animal models of disease reveal
significant protection from chronic injury in RAGE-modified
mice, or in animals treated with antagonists of RAGE and its
ligands. A key question has been asked many a time; how can
this receptor be involved in such distinct settings of chronic
stress? We propose that a common thread tying RAGE and its
ligands to diverse disorders is the link to the inflammatory
response. In each case, there is a plethora of evidence suggesting
that monocytes, macrophages, T and B lymphocytes and in the
central nervous system, glial cells, all of which express
RAGE, contribute to tissue-perturbing signaling mechanisms
that upregulate matrix met-alloproteinases (MMPs), cytokines
and other factors that damage tissue and suppress repair [6].
Further, earlier observations that many of RAGE’s ligands,
particularly the S100/calgranulins, were “biomarkers”
of inflammation, ischemia/reperfusion stress and malignancy
may now hold a mechanism-based context – we predict
that autocrine and/or paracrine interactions of released RAGE
ligands with RAGE-expressing cells amplify tissue stress and,
if left unchecked, lead to chronic disease.
Articles in this Review Series
In this review series, we have gathered a compendium of reports
that illustrate the evolving tale of RAGE. The first four
articles focus on the discovery and implications of the ligand
families of RAGE. Yan, Ramasamy and colleagues share insights
on AGEs and RAGE, as well as other ligands, and how this interaction
contributes importantly to diabetic complications in the cardiovascular
system [7]. Donato provides a timely review on the key question
– do all S100/calgranulins bind RAGE? In presenting
the argument that the answer is probably “no”,
Donato elucidates the effects of RAGE signaling stimulated
by at least certain members of this family and their implications
in inflammatory and neuronal stress [8]. Rauvala and Rouhaianen
critically review what is currently known about HMGB1 and
RAGE. In detailing the data indicating that RAGE is a signal
transduction receptor for HMGB1, they present evidence on
distinct receptors that may also engage this molecule [9].
Chen, Yan and colleagues reflect on the discovery that RAGE
binds amyloid-β
peptide and β-sheet
fibrils. The implications of these species in neurode-generation
disorders such as Alzheimer’s disease may reflect the
tip of the iceberg in settings wherein such “tangled
webs” may form, aggregate and emerge as new oligomeric
structures highly capable of stimulating and signaling via
RAGE [10].
Following these papers is a review on RAGE and its roles in
the inflammatory response. Clynes, Schmidt and colleagues
present the evidence – from delayed type hypersensitivity
studies in non-diabetic mice – to T cell priming experiments
in unique T cell receptor-modified mice and lymphocytes, that
RAGE is essential for effective T cell priming in vivo
[11]. These data provide definitive evidence linking RAGE
to the adaptive immune response.
The next articles focus on four specific areas in which RAGE
and its ligands have been implicated using both cell culture
and in vivo models. Yamamoto, Murakami and colleagues
review key studies linking RAGE to diabetic nephropathy wherein
experiments using RAGE-modified mice clearly reveal that RAGE
is essential for the development and progression of this disorder
[12]. Barile and Schmidt review the state of RAGE in diabetic
and aging-linked reti-nopathies [13], and Toth, Martinez and
Zochodne review the state of RAGE in diabetic neuropathy [14].
In retinopathy and neuropathy, animal models of diabetes revealed
striking upregulation of RAGE in these affected tissues, and
that pharmacological and/or genetic deletion of RAGE provided
protection against the functional and pathological indices
of these two disorders.
Lastly, Logsdon, Arumugam and colleagues review the biology
of RAGE and its ligands in cancer. Far from being “innocent
bystanders” and biomarkers in cancer, evidence is mounting
that RAGE may be important in mechanisms linked to tumor growth
and metastases [15]. Fascinating questions arise in cancer
in the context of tumor and/or host roles for this receptor
as detailed by these authors.
RAGE & Human Biology
RAGE blockade is the subject of ongoing clinical trials, thus,
there are no data at this time revealing “efficacy”
of targeting this approach in human subjects with chronic
diseases. It is too soon. Yet, studies in cells and animals
continue to deeply probe the questions of “natural”
roles for RAGE. Indeed, we speculate that analogous mechanisms
linking RAGE to injury may be evolutionarily conserved pathways
that in simpler systems, evoked repair.
Is there evidence, though, suggesting links between RAGE and
human disease? The answer is an emphatic “yes!”
Two major areas of research are ongoing probing these exact
concepts. First, “soluble” forms of RAGE have
been detected in the plasma of human subjects. Apparently
produced by alternative splicing programs yielding “endogenous
secretory” or esRAGE, these circulating levels of RAGE
appear to be associated with disease states, and perhaps may
be mutable in response to therapeutic interventions (recently
reviewed in [16]).
Second, polymorphisms of RAGE have been uncovered that may,
especially upon study in large scale observational trials,
shed light on vulnerability to development of chronic
diseases such as diabetic complications, neurode-generation
or to autoimmune disorders, and/or to the severity of
chronic disease states [17]. Published information on RAGE
polymorphisms and cardiovascular disease is presented in the
review by Yan and Ramasamy [7].
Perspective
Taken together, evidence presented herein links RAGE to the
pathogenesis of an array of chronic disease states characterized
by upregulation and accumulation of RAGE ligands. Far from
reflecting “one ligand – one disease,” emerging
evidence points to the family of RAGE ligands as key players
in the steps launching and perpetuating chronic disease and
tissue damage. Drawing the fine line between injury and repair
in the biology of RAGE is an important challenge but one well
worth the effort of in-depth and hypothesis-driven experimentation.
We predict that solving this puzzle may lead to effective
therapies for chronic diseases such as inflammation and autoimmunity,
neuronal degeneration, unchecked cellular proliferation and
metastasis, and AGEing.
ACKNOWLEDGEMENTS
Thank you to all the authors and peer reviewers who contributed
to the development and refinement of this review series on
RAGE. Together, we thank the editors of Current Molecular
Medicine for the gracious invitation to prepare this series
on RAGE, the molecule to which our lives are dedicated!
REFERENCES
[1] Schmidt, A.M., Vianna, M., Gerlach, M., Brett, J., Ryan,
J., Kao, J., Esposito, C., Hegarty, H., Hurley, W., Clauss,
M., Wang, F., Pan, Y.C., Tsang, T.C., and Stern, D. (1992).
J. Biol. Chem., 267, 14987-14997.
[2] Hofmann, M.A., Drury, S., Fu, C., Qu, W., Taguchi, A.,
Lu, Y., Avila, C., Kambham, N., Bierhaus, A., Nawroth, P.,
Neurath, M.F., Slattery, T., Beach, D., McClary, J., Nagashima,
M., Morser, J., Stern, D., and Schmidt, A.M. (1999). Cell,
97, 889-901.
[3] Taguchi, A., Blood, D.C., del Toro, G., Canet, A., Lee,
D.C., Qu, W., Tanji, N., Lu, Y, Lalla, E., Fu, C., Hofmann,
M.A., Kislinger, T., In-gram, M., Lu, A., Tanaka, H., Hori,
O., Ogawa, S., Stern, D.M., and Schmidt, A.M. (2000). Nature,
405, 354-360.
[4] Yan, S.D., Chen, X., Fu, J., Chen, M., Zhu, H., Roher,
A., Slattery, T., Nagashima, M., Morser, J., Migheli, A.,
Nawroth, P., Godman, G., Stern, D., and Schmidt, A.M. (1996).
Nature, 382, 685-691.
[5] Chavakis, T., Bierhaus, A., Al-Fakhri, N., Schneider,
D., Witte, S., Linn, T., Nagashima, M., Morser, J., Arnold,
B., Preissner, K.T., Naw-roth, P.P. (2003). J. Exp. Med.,
198, 1507-1515.
[6] Herold, K., Moser, B., Chen, Y., Zeng, S., Yan, S.F.,
Ramasamy, R., Emond, J., Clynes, R., and Schmidt, A.M. J.
Leukoc. Biol., 82, 204-212.
[7] Yan, S.F., D’Agati, V.D., Schmidt, A.M., and Ramasamy,
R. (2007). Curr. Mol. Med., In press.
[8] Rauvala, H., and Rouhiainen, A. (2007) Curr. Mol.
Med., In press.
[9] Donato, R. (2007) Curr. Mol. Med., In press.
[10] Chen, J.X., Walker, D.G., Schmidt, A.M., Arancio, O.,
Lue, L.F., and Yan, S.D. (2007). Curr. Mol. Med.,
In press.
[11] Clynes, R., Moser, B., Yan, S.F., Ramasamy, R., Herold,
K., and Schmidt, A.M. (2007). Curr. Mol. Med., In
press.
[12] Yamamoto, H., Watanabe, T., Yamamoto, Y., Yonekura, H.,
Munesue, S., Harashima, A., Ooe, K., Hossain, S., Saito, H.,
and Murakami, N. (2007). Curr. Mol. Med., In press.
[13] Barile, G.R., and Schmidt, A.M. (2007). Curr. Mol. Med.,
In press.
[14] Toth, C., Martinez, J., and Zochodne, D.W. (2007). Curr.
Mol. Med., In press.
[15] Logsdon, C., Fuentes, K., Huang, E.H., and Arumugam,
T. (2007). Curr. Mol. Med., In press.
[16] Geroldi, D., Falcone, C., and Emanuele, E. (2006). Curr.
Med. Chem., 13, 1971-1978.
[17] Hudson, B.I., Stickland, M.H., and Grant, P.J. (1998).
Diabetes, 47, 1155-1157.
Ann Marie Schmidt
Division of Surgical Science
Department of Surgery
Columbia University Medical Center
630 West 168th Street
P&S 17-501
New York, NY 10032
USA
Tel: 212 305 6406
Fax: 212 305 5337
E-mail: ams11@columbia.edu
[Back to top]
Receptor for Advanced Glycation Endproducts (RAGE):
A Formidable Force in the Pathogenesis of the Cardiovascular
Complications of Diabetes & Aging
Shi Fang Yan, Vivette D’Agati, Ann Marie Schmidt
and Ravichandran Ramasamy
Unifying mechanisms for the consequences of aging and chronic
diabetes are coming to light with the identification that
common to both settings is the production and accumulation
of the largely irreversible Advanced Glycation Endproducts
(AGEs). AGEs impart multiple consequences in the tissues;
a key means by which they exert maladaptive effects is via
their interaction with and activation of their chief cell
surface receptor, Receptor for AGE or RAGE. Although the time
course, rate and extent of AGE generation and accumulation
in diabetes and aging may be distinct, unifying outcomes of
the ligand-RAGE interaction in the vasculature and heart are
linked to upregulation of inflammatory and tissue-destructive
mechanisms. Consistent with these concepts, administration
of the ligand-binding decoy of RAGE, soluble or sRAGE, suppresses
early initiation and progression of atherosclerosis in diabetic
mice; suppresses exaggerated neointimal expansion consequent
to arterial injury; and mitigates the adverse impact of ischemia/reperfusion
injury in the heart. Importantly, the RAGE ligand repertoire
upregulated in these settings is not limited to AGEs. The
key finding that RAGE was a multi-ligand receptor unified
the concept that in diabetes and aging, innate and adaptive
inflammatory mechanisms contribute to the pathogenesis of
tissue injury. We conclude that antagonism of RAGE may reflect
a novel and therapeutically logical and safe target in cardiovascular
stress induced by aging and chronic diabetes.
[Back to top]
RAGE: A Single Receptor for Several Ligands and Different
Cellular Responses: The Case of Certain S100 Proteins
Rosario Donato
The S100 protein family comprises at least 25 members which,
with the exception of S100G, act as Ca2+-sensor
proteins that participate in Ca2+
signal transduction by interacting with target proteins thereby
modifying their activities. S100 proteins are expressed in
vertebrates exclusively, display a cell-specific distribution,
and regulate a large variety of intracellular activities.
Some S100 proteins are released by a non-classical pathway
and exert regulatory effects on several cell types. The receptor
for advanced glycation end products (RAGE) has been shown
to transduce extracellular effects of S100B, S100A4, S100A6,
S100A11, S100A12, S100A13 and S100P. However, some S100 proteins
can signal by engaging RAGE as well as non-RAGE receptors.
Immune cells (i.e., monocytes/macrophages/microglia, neutrophils
and lymphocytes), activated endothelial and vascular smooth
muscle cells, neurons, astrocytes, chondrocytes and pancreatic
tumor cells are the cell types reported to respond to certain
S100 proteins via RAGE engagement. In general, relatively
high concentrations of S100 proteins are required for activation
of RAGE in responsive cells. S100B is unique in that it can
engage RAGE in neurons at low and high concentrations with
trophic and toxic effects, respectively, and S100A4 stimulates
matrix metalloproteinase 13 release from chondrocytes at nanomolar
doses in a RAGE-mediated manner. Oligomerization of S100 proteins
under the non-reducing, high-Ca2+
conditions found extracellularly appears to play a relevant
role in RAGE activation, and binding of at least S100A12 and
S100B results in RAGE oligomerization. Thus, S100/RAGE interactions
might have important consequences during development and in
tissue homeostasis as well as in inflammatory, degenerative
and tumor processes.
[Back to top]
RAGE as a Receptor of HMGB1 (Amphoterin): Roles in
Health and Disease
Heikki Rauvala and Ari Rouhiainen
HMGB1/Amphoterin is a ubiquitous, highly conserved DNA-binding
protein that can be also released to the extracellular space
by various cell types. Extracellular HMGB1 regulates migratory
responses of several cell types through binding to RAGE that
communicates with the cytoskeleton to regulate cell motility.
HMGB1-induced cell signalling has been associated with mechanisms
of several diseases, including cancer, sepsis, rheumatoid
arthritis, stroke and atherosclerosis. This article reviews
the evidence linking the functional roles of HMGB1 to RAGE
signalling. Furthermore, we discuss the molecular and cellular
mechanisms that may explain the roles of HMGB1/RAGE in diverse
disease processes.
[Back to top]
RAGE: A Potential Target for Aβ-Mediated
Cellular Perturbation in Alzheimer’s Disease
Xi Chen, Douglas G. Walker, Ann Marie Schmidt, Ottavio
Arancio, Lih-Fen Lue and Shi Du Yan
This review focuses on the current findings regarding interaction
between amyloid β
peptide (Aβ)
and receptor for advanced glycation endproducts (RAGE) and
its roles in the pathogenesis of Alzheimer’s disease
(AD). As a ubiquitously expressed cell surface receptor, RAGE
mediates the effects of Aβ
on microglia, blood-brain barrier (BBB) and neurons through
activating different signaling pathways. Data from autopsy
brain tissues, in vitro cell cultures and transgenic
mouse models suggest that Aβ-RAGE
interaction exaggerates neuronal stress, accumulation of Aβ,
impaired learning memory, and neuroinflammation. Blockade
of RAGE protects against Aβ-mediated
cellular perturbation. These findings may have an important
therapeutic implication for neurodegenerative disorders relevant
to AD.
[Back to top]
Receptor for AGE (RAGE): Weaving Tangled Webs Within
the Inflammatory Response
Raphael Clynes, Bernhard Moser, Shi Fang Yan, Ravichandran
Ramasamy, Kevan Herold and Ann Marie Schmidt
The family of RAGE ligands, including Advanced Glycation Endproducts
(AGEs), S100/calgranulins, High Mobility Group Box-1 (HMGB1)
and amyloid β
peptide (Aβ)
and β-sheet
fibrils are highly enriched in immune and inflammatory foci.
In parallel, upregulation of Receptor for AGE (RAGE) is noted
in diverse forms of inflammation and autoimmunity, based on
experiments examining human tissues as well as animal models.
Indeed, prior to the demonstration that S100/calgranulins
were signal transduction ligands of RAGE, these molecules
were considered “biomarkers” of disease and disease
activity in disorders such as colitis and arthritis. Premiere
roles for RAGE in advancing cellular migration implicate this
receptor in targeting immune cells to vulnerable foci. Once
engaged, ligand-RAGE interaction in inflammatory and vascular
cells amplifies upregulation of inflammatory cytokines, adhesion
molecules and matrix metalloproteinases (MMPs). Discerning
the primal versus chronic injury-provoking roles for this
ligand-receptor interaction is a challenge in delineating
the functions of the ligand/RAGE axis. As RAGE is expressed
by many of the key cell types linked integrally to the immune
response, we propose that the sites and time course of ligand-RAGE
stimulation determine the pheno-type produced by this axis.
Ultimately, drawing the fine line between antagonism versus
stimulation of the receptor in health and disease will depend
on the full characterization of RAGE in repair versus injury.
[Back to top]
RAGE in Diabetic Nephropathy
Hiroshi Yamamoto, Takuo Watanabe, Yasuhiko Yamamoto, Hideto
Yonekura, Seiichi Munesue, Ai Harashima, Kazuyo Ooe, Sharmin
Hossain, Hidehito Saito and Naho Murakami
As is diabetes itself, diabetic angiopathy is a multi-factorial
disease. Advanced glycation endproducts (AGE) cause vascular
cell derangement characteristic of diabetes, and this is mainly
mediated by their interaction with receptor for AGE (RAGE).
When made diabetic, RAGE-overexpressing transgenic mice exhibited
exacerbation of the indices of nephropathy, and this was prevented
by the inhibition of AGE formation. On the other hand, RAGE-deficient
animals showed amelioration of diabetic nephropathy. Accordingly,
AGE and RAGE should be regarded as environmental and cellular
accounts and as a potential therapeutic target for diabetic
nephropathy. In effect, substances that inhibit the formation
of AGE, break preformed AGE, change metabolic flows away from
glycation, antagonize RAGE, and capture RAGE ligands have
been proven as effective remedies against this life-threatening
disease.
[Back to top]
RAGE and its Ligands in Retinal Disease
Gaetano R. Barile and Ann M. Schmidt
RAGE, the receptor for advanced glycation endproducts (AGEs),
is a multiligand signal transduction receptor of the immunoglobulin
superfamily of cell surface molecules that has been implicated
in the pathogenesis of diabetic complications, neurodegenerative
diseases, inflammatory disorders, and cancer. These diverse
biologic disorders reflect the multiplicity of ligands capable
of cellular interaction via RAGE that include, in
addition to AGEs, amyloid-beta (Aβ)
peptide, the S100/calgranulin family of proinflammatory cytokines,
and amphoterin, a member of the High Mobility Group Box (HMGB)
DNA-binding proteins. In the retina, RAGE expression is present
in neural cells, the vasculature, and RPE cells, and it has
also been detected in pathologic cellular retinal responses
including epiretinal and neovascular membrane formation. Ligands
for RAGE, in particular AGEs, have emerged as relevant to
the pathogenesis of diabetic retinopathy and age-related macular
disease. While the understanding of RAGE and its role in retinal
dysfunction with aging, diabetes mellitus, and/or activation
of pro-inflammatory pathways is less complete compared to
other organ systems, increasing evidence indicates that RAGE
can initiate and sustain significant cellular perturbations
in the inner and outer retina. For these reasons, antagonism
of RAGE interactions with its ligands may be a worthwhile
therapeutic target in such seemingly disparate, visually threatening
retinal diseases as diabetic retinopathy, age-related macular
degeneration, and proliferative vitreoretinopathy.
[Back to top]
RAGE, Diabetes, and the Nervous System
Cory Toth, Jose Martinez and Douglas W. Zochodne
Longstanding diabetes mellitus targets kidney, retina, and
blood vessels, but its impact upon the nervous system is another
important source of disability. Diabetic peripheral neuropathy
is a serious complication of inadequately treated diabetes
leading to sensory loss, intractable neuropathic pain, loss
of distal leg muscles, and impairment of balance and gait.
Diabetes has been implicated as a cause of brain atrophy,
white matter abnormalities, and cognitive impairment and a
risk factor for dementia. Recent studies have incriminated
advanced glycation end products (AGEs) and their receptor
(RAGE) in the pathogenesis of diabetic nervous system complications.
The availability of RAGE knockout mice and a competitive decoy
for AGEs, soluble RAGE (sRAGE), has advanced our knowledge
of the RAGE-mediated signalling pathways within the nervous
system. They also provide hope for a future novel intervention
for the prevention of diabetes-associated neurological complications.
This review will discuss current knowledge of diabetes- and
RAGE-mediated neurodegeneration, involving the distal-most
level of epidermal nerve fibers in skin, major peripheral
nerve trunks, dorsal root ganglia, spinal cord, and brain.
[Back to top]
RAGE and RAGE Ligands in Cancer
Craig D. Logsdon, Maren K. Fuentes, Emina H. Huang and
Thiruvengadam Arumugam
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 disease. 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 variety 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 microenvironment
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.
|
