Immunomodulatory role of histamine H4 receptor in breast cancer

Sterle, Helena Andrea; Nicoud, Melisa Beatriz; Massari, N; Delgado, Mònica; Ducloux, María Verónica Herrero; Cremaschi, Graciela; Medina, Vanina Araceli

doi:10.1038/s41416-018-0173-z

Cited by 32 publications

(43 citation statements)

References 68 publications

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“…Both macroscopic and microscopic evaluations reveal that the absence of H 4 R reduced inflammation, leading to the reduced number and diameter of tumors. This observation is highly similar to findings observed in an experimental model of breast cancer [35].…”

Section: Discussionsupporting

confidence: 91%

Genetic Deficiency of the Histamine H4-Receptor Reduces Experimental Colorectal Carcinogenesis in Mice

Schirmer

Rother

Bruesch

et al. 2020

Cancers

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Colorectal cancer (CRC), a severe complication of inflammatory bowel diseases, is a common type of cancer and accounts for high mortality. CRC can be modeled in mice by application of the tumor promoter, azoxymethane (AOM), in combination with dextran sodium sulfate (DSS), which are able to induce colitis-like manifestations. Active colitis correlates with high mucosal concentrations of histamine, which, together with the histamine receptor subtype 4 (H4R), provide a pro-inflammatory function in a mouse colitis model. Here, we analyzed whether H4R is involved in the pathogenesis of AOM/DSS-induced CRC in mice. As compared to wild type (WT) mice, AOM/DSS-treated mice lacking H4R expression (TM) demonstrate ameliorated signs of CRC, i.e., significantly reduced loss of body weight, stiffer stool consistency, and less severe perianal bleeding. Importantly, numbers and diameters of tumors and the degree of colonic inflammation are dramatically reduced in TM mice as compared to WT mice. This is concomitant with a reduced colonic inflammatory response involving expression of cyclooxygenase 2 and the production of C-X-C motif chemokine ligand 1 (CXCL1) and CXCL2. We conclude that H4R is involved in the tumorigenesis of chemically-induced CRC in mice via cyclooxygenase 2 expression and, probably, CXCL1 and CXCL2 as effector molecules.

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Section: Discussionsupporting

confidence: 91%

Genetic Deficiency of the Histamine H4-Receptor Reduces Experimental Colorectal Carcinogenesis in Mice

Schirmer

Rother

Bruesch

et al. 2020

Cancers

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“…A plethora of studies have related the heterogenic and complex pharmacology of histamine receptors to various diseases: H 1 R to the allergic inflammation, anaphylaxis, and motion sickness [28,29], H 2 R to the stimulation of gastric acid secretion leading to peptic ulcer, GERD and aspiration pneumonitis [30,31], H 3 R to the neurotransmission controlling sleep, cognitive processes, schizophrenia, epilepsy, and pain [32][33][34][35][36][37], and H 4 R to the immune responses (cancers, myocarditis) and inflammation [38][39][40][41][42] (Figure 2). The H 3 and H 4 receptors have relatively high affinity for histamine (5-10 nM) compared to the low affinity of H 1 R and H 2 R which is in the µM range [6,43].…”

Section: The Histamine Receptors-localization and Functionmentioning

confidence: 99%

Enigmatic Histamine Receptor H4 for Potential Treatment of Multiple Inflammatory, Autoimmune, and Related Diseases

Mehta

Miszta

Rzodkiewicz

et al. 2020

Life

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The histamine H4 receptor, belonging to the family of G-protein coupled receptors, is an increasingly attractive drug target. It plays an indispensable role in many cellular pathways, and numerous H4R ligands are being studied for the treatment of several inflammatory, allergic, and autoimmune disorders, including pulmonary fibrosis. Activation of H4R is involved in cytokine production and mediates mast cell activation and eosinophil chemotaxis. The importance of this receptor has also been shown in inflammatory models: peritonitis, respiratory tract inflammation, colitis, osteoarthritis, and rheumatoid arthritis. Recent studies suggest that H4R acts as a modulator in cancer, neuropathic pain, vestibular disorders, and type-2 diabetes, however, its role is still not fully understood.

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“…Considering the pleiotropic nature of histamine actions and its numerous immunomodulatory roles, recently it was demonstrated a novel role of H4R in the antitumor immunity of breast cancer (Sterle et al, 2019). The study was performed in a model of TNBC developed orthotopically with 4T1 cells in H4R KO compared with wild type mice and no treatments were used.…”

Section: H4r Expression In Gynecological and Breast Cancermentioning

confidence: 99%

Pathophysiological Role of Histamine H4 Receptor in Cancer: Therapeutic Implications

2019

Self Cite

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Cancer is a leading cause of death in both developed and developing countries. Although advances in cancer research lead to improved anti-neoplastic therapies, they continue to have unfavorable outcomes, including poor response and severe toxicity. Thus, the challenge for the new therapeutic approaches is to increase anti-tumor efficacy by targeting different molecules encompassed in the tumor and its microenvironment, as well as their specific interactions. The histamine H4 receptor (H4R) is the last discovered histamine receptor subtype and it modulates important immune functions in innate and in adaptive immune responses. Several ligands have been developed and some of them are being used in clinical trials for immune disorders with promising results. When searched in The Cancer Genome Atlas (TCGA) database, human H4R gene was found to be expressed in bladder cancer, kidney cancer, breast cancer, gastrointestinal cancers, lung cancer, endometrial cancer, and skin cancer. In the present work, we aimed to briefly summarize current knowledge in H4R’s pharmacology and in the clinical use of H4R ligands before focusing on recent data reporting the expression of H4R and its pathophysiological role in cancer, representing a potential molecular target for cancer therapeutics. H4R gene and protein expression in different types of cancers compared with normal tissue as well as its relationship with patient prognosis in terms of survival will be described.

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Immunomodulatory role of histamine H4 receptor in breast cancer

Abstract: This is the first report that demonstrates the participation of H4R in antitumour immunity, suggesting that H4R could be a target for cancer treatment.

Cited by 32 publications

References 68 publications

Genetic Deficiency of the Histamine H4-Receptor Reduces Experimental Colorectal Carcinogenesis in Mice

Genetic Deficiency of the Histamine H4-Receptor Reduces Experimental Colorectal Carcinogenesis in Mice

Enigmatic Histamine Receptor H4 for Potential Treatment of Multiple Inflammatory, Autoimmune, and Related Diseases

Pathophysiological Role of Histamine H4 Receptor in Cancer: Therapeutic Implications

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