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The receptor RAGE: Bridging inflammation and cancer.

Riehl A, Németh J, Angel P, Hess J - Cell Commun. Signal (2009)

Bottom Line: RAGE is a multifunctional receptor that binds a broad repertoire of ligands and mediates responses to cell damage and stress conditions.It activates programs responsible for acute and chronic inflammation, and is implicated in a number of pathological diseases, including diabetic complications, stroke, atheriosclerosis, arthritis, and neurodegenerative disorders.Here, we will summarize molecular mechanisms through which RAGE signalling contributes to the establishment of a pro-tumourigenic microenvironment.

View Article: PubMed Central - HTML - PubMed

Affiliation: German Cancer Research Center, DKFZ-ZMBH Alliance, Division of Signal Transduction and Growth Control (A100), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. p.angel@dkfz-heidelberg.de.

ABSTRACT
The receptor for advanced glycation end products (RAGE) is a single transmembrane receptor of the immunoglobulin superfamily that is mainly expressed on immune cells, neurons, activated endothelial and vascular smooth muscle cells, bone forming cells, and a variety of cancer cells. RAGE is a multifunctional receptor that binds a broad repertoire of ligands and mediates responses to cell damage and stress conditions. It activates programs responsible for acute and chronic inflammation, and is implicated in a number of pathological diseases, including diabetic complications, stroke, atheriosclerosis, arthritis, and neurodegenerative disorders. The availability of Rage knockout mice has not only advanced our knowledge on signalling pathways within these pathophysiological conditions, but also on the functional importance of the receptor in processes of cancer. Here, we will summarize molecular mechanisms through which RAGE signalling contributes to the establishment of a pro-tumourigenic microenvironment. Moreover, we will review recent findings that provide genetic evidence for an important role of RAGE in bridging inflammation and cancer.

No MeSH data available.


Related in: MedlinePlus

RAGE function in inflammation-associated carcinogenesis. RAGE is expressed in all cell types implicated in tumour formation, including tumour cells, endothelial cells, myeloid cells, MDSCs, and lymphocytes. Signalling pathways downstream of RAGE that are activated by the accumulation of its ligands (AGE, HMGB1, S100 proteins) regulate cellular interactions during neoplastic transformation and malignant progression: (1) A pro-tumourigenic microenvironment is established by the secretion of pro-inflammatory cytokines such as TNFα, IL-1, and IL-6, and the production of RAGE ligands. (2, 3) RAGE and RAGE ligands activate endothelial and myeloid cells resulting in the recruitment and accumulation of further myeloid cells, including MDSCs. (4) MDSCs inhibit T and natural killer cells leading to T cell tolerance and impaired anti-tumour immunity. (5) RAGE ligands and subsequent signalling also fuel tumour cell proliferation and survival by autocrine and paracrine feed-back loops. MDSC, myeloid derived suppressor cell; AGE, advanced glycation end products; HMGB1, high mobility group box-1; TNFα, tumour necrosis factor α, IL-1, interleukin-1; IL-6, interleukin-6.
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Figure 1: RAGE function in inflammation-associated carcinogenesis. RAGE is expressed in all cell types implicated in tumour formation, including tumour cells, endothelial cells, myeloid cells, MDSCs, and lymphocytes. Signalling pathways downstream of RAGE that are activated by the accumulation of its ligands (AGE, HMGB1, S100 proteins) regulate cellular interactions during neoplastic transformation and malignant progression: (1) A pro-tumourigenic microenvironment is established by the secretion of pro-inflammatory cytokines such as TNFα, IL-1, and IL-6, and the production of RAGE ligands. (2, 3) RAGE and RAGE ligands activate endothelial and myeloid cells resulting in the recruitment and accumulation of further myeloid cells, including MDSCs. (4) MDSCs inhibit T and natural killer cells leading to T cell tolerance and impaired anti-tumour immunity. (5) RAGE ligands and subsequent signalling also fuel tumour cell proliferation and survival by autocrine and paracrine feed-back loops. MDSC, myeloid derived suppressor cell; AGE, advanced glycation end products; HMGB1, high mobility group box-1; TNFα, tumour necrosis factor α, IL-1, interleukin-1; IL-6, interleukin-6.

Mentions: Numerous findings, ranging from epidemiological studies to molecular analyses of mouse models, have highlighted a strong contribution of chronic inflammation to tumour development [1,2]. Irrespective of the cause of cancer-related inflammation, either driven by genetic alterations, tissue damage or arising from preceding infection, the generation of an inflammatory microenvironment supports tumourigenesis by promoting cancer cell survival, proliferation, migration, and invasion [3,4]. The generation of the pro-tumourigenic microenvironment strongly depends on the activation of several transcription factors, mainly nuclear factor-κB (NF-κB), signal transducer and activator of transcription 3 (Stat3) and hypoxia-inducible factor-1α (HIF-1α) [4]. These transcription factors regulate the expression of important cytokines, such as tumour necrosis factor α (TNFα), interleukin-1 and -6 (IL-1, IL-6) that are critically involved in the crosstalk between cancer cells and cells of the tumour stroma [5-7]. Importantly, these soluble factors and their respective receptors recruit and activate immune cells of lymphoid and myeloid origin and trigger signalling pathways resulting in the production of a large number of pro-inflammatory mediators in a positive feed forward loop [4,8] (Figure 1). Yet, the exact molecular mechanisms by which a pro-tumourigenic microenvironment is established and maintained, and subsequently promotes carcinogenesis remain largely elusive.


The receptor RAGE: Bridging inflammation and cancer.

Riehl A, Németh J, Angel P, Hess J - Cell Commun. Signal (2009)

RAGE function in inflammation-associated carcinogenesis. RAGE is expressed in all cell types implicated in tumour formation, including tumour cells, endothelial cells, myeloid cells, MDSCs, and lymphocytes. Signalling pathways downstream of RAGE that are activated by the accumulation of its ligands (AGE, HMGB1, S100 proteins) regulate cellular interactions during neoplastic transformation and malignant progression: (1) A pro-tumourigenic microenvironment is established by the secretion of pro-inflammatory cytokines such as TNFα, IL-1, and IL-6, and the production of RAGE ligands. (2, 3) RAGE and RAGE ligands activate endothelial and myeloid cells resulting in the recruitment and accumulation of further myeloid cells, including MDSCs. (4) MDSCs inhibit T and natural killer cells leading to T cell tolerance and impaired anti-tumour immunity. (5) RAGE ligands and subsequent signalling also fuel tumour cell proliferation and survival by autocrine and paracrine feed-back loops. MDSC, myeloid derived suppressor cell; AGE, advanced glycation end products; HMGB1, high mobility group box-1; TNFα, tumour necrosis factor α, IL-1, interleukin-1; IL-6, interleukin-6.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2690588&req=5

Figure 1: RAGE function in inflammation-associated carcinogenesis. RAGE is expressed in all cell types implicated in tumour formation, including tumour cells, endothelial cells, myeloid cells, MDSCs, and lymphocytes. Signalling pathways downstream of RAGE that are activated by the accumulation of its ligands (AGE, HMGB1, S100 proteins) regulate cellular interactions during neoplastic transformation and malignant progression: (1) A pro-tumourigenic microenvironment is established by the secretion of pro-inflammatory cytokines such as TNFα, IL-1, and IL-6, and the production of RAGE ligands. (2, 3) RAGE and RAGE ligands activate endothelial and myeloid cells resulting in the recruitment and accumulation of further myeloid cells, including MDSCs. (4) MDSCs inhibit T and natural killer cells leading to T cell tolerance and impaired anti-tumour immunity. (5) RAGE ligands and subsequent signalling also fuel tumour cell proliferation and survival by autocrine and paracrine feed-back loops. MDSC, myeloid derived suppressor cell; AGE, advanced glycation end products; HMGB1, high mobility group box-1; TNFα, tumour necrosis factor α, IL-1, interleukin-1; IL-6, interleukin-6.
Mentions: Numerous findings, ranging from epidemiological studies to molecular analyses of mouse models, have highlighted a strong contribution of chronic inflammation to tumour development [1,2]. Irrespective of the cause of cancer-related inflammation, either driven by genetic alterations, tissue damage or arising from preceding infection, the generation of an inflammatory microenvironment supports tumourigenesis by promoting cancer cell survival, proliferation, migration, and invasion [3,4]. The generation of the pro-tumourigenic microenvironment strongly depends on the activation of several transcription factors, mainly nuclear factor-κB (NF-κB), signal transducer and activator of transcription 3 (Stat3) and hypoxia-inducible factor-1α (HIF-1α) [4]. These transcription factors regulate the expression of important cytokines, such as tumour necrosis factor α (TNFα), interleukin-1 and -6 (IL-1, IL-6) that are critically involved in the crosstalk between cancer cells and cells of the tumour stroma [5-7]. Importantly, these soluble factors and their respective receptors recruit and activate immune cells of lymphoid and myeloid origin and trigger signalling pathways resulting in the production of a large number of pro-inflammatory mediators in a positive feed forward loop [4,8] (Figure 1). Yet, the exact molecular mechanisms by which a pro-tumourigenic microenvironment is established and maintained, and subsequently promotes carcinogenesis remain largely elusive.

Bottom Line: RAGE is a multifunctional receptor that binds a broad repertoire of ligands and mediates responses to cell damage and stress conditions.It activates programs responsible for acute and chronic inflammation, and is implicated in a number of pathological diseases, including diabetic complications, stroke, atheriosclerosis, arthritis, and neurodegenerative disorders.Here, we will summarize molecular mechanisms through which RAGE signalling contributes to the establishment of a pro-tumourigenic microenvironment.

View Article: PubMed Central - HTML - PubMed

Affiliation: German Cancer Research Center, DKFZ-ZMBH Alliance, Division of Signal Transduction and Growth Control (A100), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. p.angel@dkfz-heidelberg.de.

ABSTRACT
The receptor for advanced glycation end products (RAGE) is a single transmembrane receptor of the immunoglobulin superfamily that is mainly expressed on immune cells, neurons, activated endothelial and vascular smooth muscle cells, bone forming cells, and a variety of cancer cells. RAGE is a multifunctional receptor that binds a broad repertoire of ligands and mediates responses to cell damage and stress conditions. It activates programs responsible for acute and chronic inflammation, and is implicated in a number of pathological diseases, including diabetic complications, stroke, atheriosclerosis, arthritis, and neurodegenerative disorders. The availability of Rage knockout mice has not only advanced our knowledge on signalling pathways within these pathophysiological conditions, but also on the functional importance of the receptor in processes of cancer. Here, we will summarize molecular mechanisms through which RAGE signalling contributes to the establishment of a pro-tumourigenic microenvironment. Moreover, we will review recent findings that provide genetic evidence for an important role of RAGE in bridging inflammation and cancer.

No MeSH data available.


Related in: MedlinePlus