Triggers in the pathway from lung cell damage to malignancy: The glycans.

Abstract

e22189 Background: It has been reported that carbon nanoparticles (CN) produce mesothelioma as readily as do asbestos fibers. We have studied early CN damage in experimental animals, quantifying toxicity by release from cells of the nuclear chaperone HMGB1. Damage-released HMGB1 binds to receptors (RAGE, CD24) to upregulate cytokines and produce regulatory signals that control cell homeostasis. Further, HMGB1 has recently been shown to form a complex with P53, one of the most commonly mutated genes in human cancers, and HMGB1 is the controlling factor in autophagy, an important new field in translational cancer research. Methods: One HMGB1 receptor, CD24, is the source of a whole-receptor antibody used to determine extent of malignancy during surgery. CD24 is highly glycosylated. We hypothesized that carbohydrate vs protein specificity would show differences in tumor character. Would antibodies to the CD24 carbohydrate moiety reflect a tumor glycan character, and how would this relate to the tumor profile such as metastasis? With cooperation of TMC pathology Dept, blocks (N=15 each) of lung squamous cell, adenocarcinoma, and small cell cancer were sectioned and stained with mouse monoclonals to CD24, IgM –glycan, IgG-protein fraction. Results: Small cell and adenocarcinoma lung tumors showed mostly similar staining by CD24 protein vs CD24 glycan antibodies. Squamous cell CA showed elevated carbohydrate CD24 staining with negative or low protein stain in over half of the cases, and examination of patient records are being studied to determine metastatic character, lung- damage history and tumor chemotherapy response. Conclusions: Squamous cell tumors demonstrate significantly more staining by antibody to the glycan moiety of CD24, p=0.02. There was no relationship between numbers of positive nodes and staining, although other chart information awaits analysis. Research continues into the significance of this glycan CD24 receptor for HMGB1, our marker for nanoparticle lung damage, and its relationship to malignant transformation. [Table: see text]