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Critical role of RAGE in lung physiology and tumorigenesis: a potential target of therapeutic intervention?

Significance Statement

This review aims to identify and highlight important – yet not clearly illustrated aspects of lung physiology and cancer and discuss potential therapeutic suggestions. Particular emphasis has been given to the role of the receptor for advanced glycation endproducts (RAGE) in normal lung function and lung cancer development.

Lung cancer is one of the most common malignancies and a leading cause of death from cancer for both males and females. Understanding normal lung physiology and cancer biology is fundamental in order to design new therapeutic tools. In this context, RAGE intrigues as a receptor with certain exceptional characteristics. RAGE expression is low in most type of cells under normal circumstances. However, RAGE expression is upregulated in chronic inflammation and in most types of malignancies. The opposite is true for normal alveolar epithelial cells where RAGE expression is increased; on the contrary RAGE downregulation has been related to lung tumor development. In order to address this phenomenal paradox we first have to answer certain basic questions. First, how RAGE recognizes and binds to a myriad of structurally different ligands still remains a mystery. Currently, the most popular explanation that has been formulated is the assumption of a three-dimensional model of molecular recognition between RAGE and its diverse ligands. Second, what is the exact role of RAGE in normal lung physiology and functioning? And third, why RAGE is downregulated during lung tumor development?

In this work, strong evidence related to the electrostatic nature of RAGE-ligand interaction has been presented and connected to normal lung functioning. Moreover, it’s been suggested that RAGE downregulation in lung epithelial cells is related to cell de-differentiation, regression back to embryonic phenotypes and malignant transformation. Finally, potential therapeutic interventions targeting RAGE expression are discussed in detail.

Critical role of RAGE in lung physiology and tumorigenesis a potential target of therapeutic intervention

Journal Reference

Marinakis E, Bagkos G, Piperi C, Roussou P, Diamanti-Kandarakis E.

Clin Chem Lab Med. 2014;52(2):189-200.


Lung cancer is one of the most common malignancies in the world and one of the leading causes of death from cancer. In the search for molecules that may be involved in lung tumor induction and progression, the receptor of advanced glycation end products (RAGE) comes across as a critical regulator of lung physiology. RAGE is a multiligand receptor that presents a differential expression pattern in lungepithelial cells compared to other cell types being gradually increased from fetal to birth and adult life. Under stress conditions, RAGEexpression and activation are rapidly elevated resulting in chronic inflammation, which, in turn, in many instances, promotes epithelial cell malignant transformation. RAGE overexpression in normal lung alveolar type I epithelial cells is followed by rapid downregulation upon malignant transformation, being associated with increased aggressiveness. This is a striking paradox, since in every other cell type the pattern of RAGE expression follows the opposite direction, suggesting the involvement of RAGE in the well-functioning of lung cells. Additionally, RAGE has been attributed with the role of adhesion molecule, since it can stabilize mature alveolar epithelial cells to their substrate (basal lamina) by interacting electrostatically with other molecules. However, the reduction of RAGE observed in lungtumorigenesis interrupts cell-to-cell and cell-to-substrate communication, which is a critical step for cancer cell induction, progression and migration. This review addresses the differential properties of RAGE in lung physiology and carcinogenesis, providing evidence oftherapeutic possibilities.

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