RAGE signaling sustains inflammation and promotes tumor development
Christoffer Gebhardt1, Astrid Riehl, Moritz Durchdewald
1Division of Signal Transduction and Growth Control, German Cancer Research Center, 69120 Heidelberg, Germany.
The Journal of Experimental Medicine
|January 23, 2008
Summary
Mice lacking the receptor for advanced glycation end-products (RAGE) resist skin cancer. RAGE is crucial for sustaining inflammation, a key factor in tumor promotion and development.
Area of Science:
- Oncology
- Immunology
- Dermatology
Background:
- Chronic inflammation is linked to tumor development.
- Molecular mechanisms connecting inflammation and cancer promotion are not fully understood.
Purpose of the Study:
- To investigate the role of the receptor for advanced glycation end-products (RAGE) in skin carcinogenesis.
- To elucidate the molecular mechanisms by which RAGE influences inflammation during tumor promotion.
Main Methods:
- Utilized a DMBA/TPA-induced skin carcinogenesis model in mice.
- Assessed the impact of RAGE deficiency on inflammatory mediators, immune cell infiltration, and epidermal hyperplasia.
- Employed bone marrow chimera experiments to determine cell-specific roles of RAGE.
Main Results:
- RAGE-deficient mice showed resistance to skin carcinogenesis.
- RAGE deficiency impaired sustained inflammation, proinflammatory mediator upregulation, immune cell infiltration, and epidermal hyperplasia.
- An S100/RAGE feed-forward loop was implicated in chronic inflammation and tumor promotion.
- RAGE expression on immune cells, not keratinocytes or endothelial cells, was essential for TPA-induced effects.
Conclusions:
- RAGE signaling is critical for maintaining inflammatory responses during tumor promotion.
- RAGE plays a novel, essential role in linking chronic inflammation to cancer development.
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