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  • br Role of FPRs in Cancer br Concluding Remarks

    2021-09-03


    Role of FPRs in Cancer
    Concluding Remarks Activation of FPRs by formylated bacterial peptides or by host-derived mitochondrial peptides is required for local control of infection and wound healing. Nevertheless, various detrimental effects can result from the release of formylated peptides into the bloodstream, either through conditions such as sepsis or through severe trauma. Thus, inhibitory strategies to prevent FPR activation might be considered as a novel candidate approach for treating sepsis or perhaps SIRS, although evidently, extensive work is necessary to determine this. From another angle, targeting FPRs to treat certain cancer types seems to be more complex, since at least two aspects must be considered. Specifically, since the activation of human leukocytes may require FPR1 expression, functional FPR1 seems to be necessary in humans to achieve effective chemotherapy or radiotherapy [27]. However, increased FPR expression on tumor JSH-23 can also enhance proliferation and metastasis, and the mechanisms for these processes remain elusive 24, 67 (see Outstanding Questions). To assess potential therapeutic strategies, it is important to understand in which context the activation or inhibition of FPRs is advantageous or detrimental to ameliorating disease processes. Furthermore, as FPRs are expressed on diverse cell types, it will be necessary to elucidate and fully dissect the consequences of FPR activation in different cell types and for different types of diseases including as discussed, infections, cancers, and inflammatory conditions such as SIRS or ARDS [e.g., epithelial cells vs. leukocytes (see Outstanding Questions)]. However, the investigation of such molecules is JSH-23 often difficult, since mouse and human Fprs/FPRs vary significantly in terms of ligand recognition and their activation by specific ligands (Box 4). An important limitation to acknowledge is the extent to which many of the findings described in this review can be generalized to human populations. Indeed, only very few FPR-modulatory peptides have recently progressed into clinical trials. For instance, two Phase I clinical studies showed that the FPR2 agonist ACT-389949 was safe, but was not a viable drug due to rapid receptor desensitization (ClinicalTrials.gov NCT02099071 and NCT02099201) [74]. Moreover, the proteolytic instability of natural peptide ligands has also provided challenges in the development of FPR ligands. Thus, the design of synthetic peptide mimetics that are partially composed of unnatural amino acid-like residues [75] might be considered as a strategy aiming to enhance proteolytic stability and increase bioavailability of these agents in preclinical experiments (see Outstanding Questions). Although FPRs represent long known ancient receptors, not much is known about the consequences of receptor activation and induction of receptor expression, especially in epithelial and endothelial cells. In the light of treatment failures in inflammatory and infectious diseases as well as in cancer, a big challenge in the future will be to increase our understanding of FPR mechanisms of action in the context of these diseases.
    Acknowledgments We thank Andreas Peschel for helpful discussion. This work was supported by Grants (TRR34) of the German Research Council to D.K. and E.W.
    Introduction The formyl peptide receptors (FPRs) belong to the family of classic chemoattractant G protein-coupled receptors and function as pattern recognition receptors in host defense and inflammation (Migeotte et al., 2006, Ye et al., 2009, Dahlgren et al., 2016). FPRs were originally discovered as receptors that bind highly conserved N-formyl methionine-containing protein and peptide sequences of bacterial and mitochondrial origin (Schiffmann et al., 1975). However, it has become evident that FPRs recognize a variety of structurally diverse ligands and that their biologic function extends beyond mediating leukocyte trafficking. Indeed, FPRs were found to exert important regulatory effects under a broad range of pathological conditions, including atherosclerosis, inflammation, neo-angiogenesis, chronic obstructive pulmonary diseases and cancer. This review will focus on recent advances in FPRs pertinent to orchestration of the inflammatory response. We will discuss checkpoints governed by FPRs in acute host defense, which could be exploited for the development of novel therapeutic strategies. The readers are recommended to refer to other comprehensive reviews on general overview and FPR nomenclature (Ye et al., 2009) and ligand recognition mechanisms (Dahlgren et al., 2016, He and Ye, 2017).