Role of innate host defense proteins in oral cancerogenesis

Abstract

It is nowadays well accepted that chronic inflammation plays a pivotal role in tumor initiation and progression. Under this aspect, the oral cavity is predestined to examine this connection because periodontitis is a highly prevalent chronic inflammatory disease and oral squamous cell carcinomas are the most common oral malignant lesions. In this review, we describe how particular molecules of the human innate host defense system may participate as molecular links between these two important chronic noncommunicable diseases (NCDs). Specific focus is directed toward antimicrobial polypeptides, such as the cathelicidin LL-37 and human defensins, as well as S100 proteins and alarmins. We report in which way these peptides and proteins are able to initiate and support oral tumorigenesis, showing direct mechanisms by binding to growth-stimulating cell surface receptors and/or indirect effects, for example, inducing tumor-promoting genes. Finally, bacterial challenges with impact on oral cancerogenesis are briefly addressed.

Keywords: S100 proteins; alarmins; chronic inflammation; defensins; innate host defense; oral tumorigenesis.

FIGURE 1

Risk factors, effects, and molecular participants in the axis of chronic infection–inflammation (CP)–oral tumorigenesis. Persisting bacterial challenges in form of dental plaque or biofilm lead to a manifestation of CP and permanent activation of the innate host defense system, which affects malignant transformation and hence oral tumorigenesis. Thereby, antimicrobial peptides and alarmins serve as molecular links between these cellular processes. Furthermore, pathogens also have a direct impact on oral cancer.

FIGURE 2

From bacterial challenge to tumor development. Schematic description of how the innate host defense system affects tumorigenesis. PAMPs bind and activate PRRs, such as TLRs. Subsequently, NF‐κB is translocated into the nucleus enhancing gene activation of cytokines, AMPs, and alarmins. These molecules are secreted and exert their work, partly as DAMPs, outside of the cell by acting as ligands for TLRs or RAGE. Hence, these molecules function as signal amplifiers. Moreover, cell proliferation can be promoted by AMPs serving as ligands for EGFR. AMP, antimicrobial peptide; DAMP, damage‐associated molecular pattern; EMT, epithelial–mesenchymal transition; EGFR, epidermal growth factor receptor; HMGB1, high mobility group protein B1; LPS, lipopolysaccharides; LTAs, lipoteichoic acids; NF‐κB, nuclear factor‐κB; PAMPs, pathogen‐associated molecular patterns; RAGE, receptor for advanced glycation end products; TLR, toll‐like receptor.

FIGURE 3

Schematic molecular structures of AMPs. HBD1 representing the group of defensins with the typical β‐sheet motifs, S100A7 with multiple α‐helices, characteristic for S100 proteins, and the cathelicidin LL‐37 consisting of one single α‐helix. Rod‐like shapes represent α‐helical structures, and arrows stand for β‐sheet strands.

FIGURE 4

Impact of molecules of the innate host defense system on “hallmarks of cancer”., The effects of LL‐37, α‐ and β‐defensins, S100 proteins (metastasin, psoriasin, and calgranulin A, B, and C), and HMGB1 on the different hallmarks of cancer are described. hBD, human β‐defensin; HMGB1, high mobility group protein B1; HNP, human neutrophil peptide.

FIGURE 5

Overview of effects initiated by hBDs after TLR activation. Middle part: Bacterial PAMPs are binding to TLR leading to activation, NF‐κB translocation, and induction of genes encoding inflammatory cytokines and hBDs. These proteins are secreted to the extracellular matrix. HBDs attack as AMPs the present bacteria. Left: Cytokines (IL‐1β and IL‐6) induce a tumor‐promoting microenvironment. Additionally, pro‐inflammatory cytokines also induce the hBD expression and thus function as amplifiers. Right: HBD1 re‐enters the cells and can function as tumor suppressor. HBD2 chemoattracts granulocytes. HBD1, hBD2, and hBD3 can bind to EGFR and promote proliferation via cyclin D induction. Degranulation of granulocytes leads to release of HNPs, which can bind to EGFR and RAGE. Also, LL‐37 and calprotectin (S100A8/A9) are liberated and work as RAGE ligands. Consequentially, RAGE activation affects inflammation, migration, angiogenesis, and proliferation. EGFR, epidermal growth factor receptor; hBD, human β‐defensin; IL‐1‐R, IL‐1 receptor; IL‐6‐R, IL‐6 receptor; NF‐κB, nuclear factor‐κB; PAMPs, pathogen‐associated molecular patterns; RAGE, receptor for advanced glycation end products; TLR, toll‐like receptor.