Pattern Recognition Receptors in Cancer Progression and Metastasis

Abstract

The innate immune system is an integral component of the inflammatory response to pathophysiological stimuli. Toll-like receptors (TLRs) and inflammasomes are the major sensors and pattern recognition receptors (PRRs) of the innate immune system that activate stimulus (signal)-specific pro-inflammatory responses. Chronic activation of PRRs has been found to be associated with the aggressiveness of various cancers and poor prognosis. Involvement of PRRs was earlier considered to be limited to infection- and injury-driven carcinogenesis, where they are activated by pathogenic ligands. With the recognition of damage-associated molecular patterns (DAMPs) as ligands of PRRs, the role of PRRs in carcinogenesis has also been implicated in other non-pathogen-driven neoplasms. Dying (apoptotic or necrotic) cells shed a plethora of DAMPs causing persistent activation of PRRs, leading to chronic inflammation and carcinogenesis. Such chronic activation of TLRs promotes tumor cell proliferation and enhances tumor cell invasion and metastasis by regulating pro-inflammatory cytokines, metalloproteinases, and integrins. Due to the decisive role of PRRs in carcinogenesis, targeting PRRs appears to be an effective cancer-preventive strategy. This review provides a brief account on the association of PRRs with various cancers and their role in carcinogenesis.

Keywords: HMGB1; damage-associated molecular patterns (DAMPs); inflammasome; pattern recognition receptors (PRRs); toll-like receptors (TLRs).

Figure 1

TLR diversity, ligands, and signaling. TLRs are expressed on the epithelial and immune cells on the plasma membrane (TLR1, TLR2, TLR4, and TLR5) and endosomal membrane (TLR3, TLR7, and TLR9). Pathogenic PAMPS are the natural ligands of TLRs: eg, bacterial lipid-derived macromolecules are ligands for TLR1, TLR2, TLR4, and TLR6, while nucleic acid derivatives like dsDNA (TLR3) nucleotide complexes with other macromolecules (TLR7) and the CpG nucleotide sequence (TLR9). TLR signaling in an MyD88-dependent and TRIF-mediated (MyD88-independent) pathway leads to the translocation of AP-1, NF-κB, and IRF-3, respectively, to the nucleus, which induces the transcriptional activation of pro-inflammatory genes.

Figure 2

Coordinated action of TLRs and NLRP3 inflammasomes in tumor progression, angiogenesis, and metastasis.

Figure 3

Activation of TLRs and inflammasomes by DAMPs released by apoptotic and necrotic cells. DAMPs from nucleus (HSPs, histones, HMGB1), cytosol (uric acid, ATP), and mtDNA activate PRR signaling in tumor and myeloid cells, which leads to the secretion of pro-inflammatory mediators such as TNF-α, IL-1-β, and IL-6. TLR signaling eventually promotes the transcriptional activation of pro-inflammatory cytokines via localization of NF-κB, while inflammasome activation guides caspases-1 to cleave pro IL-1-β to mature IL-1β, altering integrin and chemokine expression leading to the tumor growth and metastasis by promoting angiogenesis and tumor cell migration.