Immunogenic cell death markers HMGB1 and sRAGE as new predictive and prognostic serum biomarkers in cancer disease

Immunogenic cell death markers are an inhomogeneous group of molecules which are released from apoptotic, necrotic or otherwise dying cells. Once in the extracellular milieu, these danger associated molecular patterns (DAMPs) such as the high mobility group box 1 protein (HMGB1) are able to exert activating and suppressive effects on the immunity system. On the one hand, continuously released HMGB1 - via interaction with its cellular binding partner receptor of advanced glycation end products (RAGE) - can promote tumor growth, whereas, on the other hand, pulsatile release of HMGB1 during cytotoxic therapies may activate the immunity system against tumor cells. Soluble RAGE (sRAGE), however, can act as a decoy receptor, balancing the extracellular effects of HMGB1. Here, we review the structural and functional characteristics of these immunogenic cell death markers and their role in the pathophysiology of diverse benign and malignant diseases. Further, we report on their relevance as serum biomarkers for the diagnosis, estimation of prognosis, as well as the prediction and monitoring of response to cytotoxic therapy in cancer patients. Elevated levels of HMGB1 and lower levels of sRAGE were found to be present in blood of patients suffering from various tumor entities as compared with healthy controls. Furthermore, high HMGB1 and low sRAGE serum levels of cancer patients before or during cytotoxic therapy were associated with poor treatment response and shortened overall survival. These results indicate that immunogenic cell death markers such as HMGB1 and sRAGE are promising new biomarkers for prognosis, patients' stratification and therapy monitoring in cancer patients.