HMGB1: a two-headed signal regulating tumor progression and immunity

Cells of the innate immune system sense tissue damage recognizing in the extracellular environment bona fide intracellular moieties, like high mobility group box 1 (HMGB1). In the case of tumors, HMGB1 recognition has a paradoxical dual effect: it promotes tumor neoangiogenesis and triggers protective anti-neoplastic T-cell responses. Recent advances in the study of HMGB1 have identified candidate molecular mechanisms underlying these apparently contrasting outcomes. A surprising role for innate receptors, including toll like receptor 4 (TLR4), in the response to conventional cancer radio and chemotherapy has also recently emerged, providing new insight into the mechanisms by which these treatments actually work.

Introduction

All eukaryotic cells express High Mobility Group Box 1 (HMGB1), a non-histone abundant nuclear protein, highly conserved through evolution (99% identity in mammals). Several excellent reviews have focused on the molecular structure of HMGB1, and we refer to them the reader for a thorough description of this issue [1, 2]. HMGB1 endorses key functions within the nucleus: it binds without sequence specificity to the minor groove of DNA and enables physical interactions between DNA and a variety of molecules, including p53, NF-κB and steroid hormone receptors. Interestingly, some cells express HMGB1, also referred to as amphoterin, on the plasma membrane as well. Membrane-associated HMGB1 controls neurite outgrowth, smooth muscle cell chemotaxis, and tumor cell metastasis [1, 3].

HMGB1 is a molecule with a double life [4]: cells dying by necrosis release it massively in the extracellular environment [5]. Outside, after the great escape from the nucleus, HMGB1 ‘alarms’ cells belonging to the innate immune system, inciting them to initiate homeostatic responses [1]. Besides the passive release from cells undergoing necrosis, cells of the innate immune system, including monocytes, macrophages, and dendritic cells (DCs), developed a non-conventional specialized pathway to actively secrete HMGB1 [6]. The homeostatic response to hypoxia also results in HMGB1 transfer to the extracellular milieu: for example, hepatocytes and liver-associated innate immune cells (including DCs) actively release HMGB1 in vivo when the organ is under hypoxic conditions. This release involves the toll like receptor 4 (TLR4)-dependent production of reactive oxygen species and HMGB1 blockade ameliorates liver injury [7].

Extracellular HMGB1 acts as a chemoattractant for inflammatory leukocytes and stem cells [8, 9] and behaves as an immune adjuvant for soluble and particulate antigens [10, 11]: it triggers the functional maturation of DCs and supports the clonal expansion of γ-interferon (γ-INF) producing Th1 cells [12, 13], while it plays a crucial role in the ability of maturing DCs to migrate toward secondary lymphoid organs [14, 15].