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

Abstract

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 lung epithelial cells compared to other cell types being gradually increased from fetal to birth and adult life. Under stress conditions, RAGE expression 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 lung tumorigenesis 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 of therapeutic possibilities.

The diagnostic utility and tendency of the soluble receptor for advanced glycation end products (sRAGE) in exudative pleural effusion

“…Second, the serum and pleural samples used in our study had been stored for several days or months at −70 °C. As reported in previous studies of serum sRAGE (11,12,18), it remains unknown as to whether this extended storage has any effect on the serum and pleural sRAGE levels.…”

“…Whereas upregulation of the RAGE expression was observed in most of the primary human tumors examined (17), the RAGE and sRAGE levels were decreased in lung cancer, suggesting their use as markers of diagnosis or prognosis in lung cancer (11,18). Because RAGE plays a role in cell adhesion, migration, and proliferation of lung tissue, the downregulation of RAGE and sRAGE results in differentiation, proliferation, and migration of cancer cells in the lung (11,18). In our study, the sRAGE levels for lung cancer were lower than those for tuberculosis, and this tendency was explained by the carcinogenetic effect of the lower sRAGE state.…”

Defining a Research Agenda to Address the Converging Epidemics of Tuberculosis and Diabetes

“…The receptor for AGEs, RAGE, is expressed on a variety of cell types including those highly relevant in the context of TB and DM (e.g., monocytes and macrophages, dendritic cells, T-cells and vascular cells). Interestingly, the highest expression of RAGE occurs in the lungs 25 , the primary site of M. tuberculosis infection. Activation of RAGE up-regulates inflammation through the production of reactive oxigen species (ROS) and inflammatory cytokines, and alters phagocytosis and cellular lipid metabolism.…”

Role of receptor for advanced glycation end products in the complication and progression of various types of cancers

“…This dual action-mechanism (either cancer cell proliferations in most of the cancer cells or attenuation of cancer cell proliferation in lung cancer cells) of RAGE seems to emanate on account of the differences in genetic control governing three important factors including (a) vicinity dependent functioning, (b) spliced variants and (c) tissue-specific abundance of particular ligands. Previously we [5] and recently Marinakis et al [25] discussed the specialized role of RAGE in pulmonary physiology and pathophysiology and Marinakis et al advocated the use of anti-RAGE therapy as a potential treatment strategy for lung cancer. The present review article focused on the mechanism of RAGE dependent cancer formation and complication in various types of cancers, other than in lung cancer cells.…”