Pathophysiological Role of Histamine H4 Receptor in Cancer: Therapeutic Implications

Abstract

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.

Study of the antitumour effects and the modulation of immune response by histamine in breast cancer

“…immune system in the response to anticancer treatments could not be evaluated, the treatment with H4R agonists showed very promising outcomes. [18][19][20][21]40,53,54 In line with this, the results indicate that elevated HRH4 gene expression was associated with improved relapse-free survival outcomes in all breast cancer patients.…”

“…therapeutic benefit globally, by considering the role of immune response in the outcome. 40 Given the relationship between the histamine-forming enzyme and the patient's prognosis, the effect of histamine systemic treatment on tumour growth and in the immune tumour microenvironment as a whole was explored in a TNBC syngeneic model developed in immunocompetent mice. The 4T1 tumour model resembles human TNBC as it leads to metastasis formation.…”

<p>Histamine H3 Receptor Promotes Cell Survival via Regulating PKA/CREB/CDKN1A Signal Pathway in Hepatocellular Carcinoma</p>

“…8 Histamine and histamine receptors have been identified as critical molecules during inflammation and carcinogenesis, which might be potential molecular target for cancer therapeutics. 6,17 Abnormal expression of HRH3 has been reported in different types of cancer, including HCC, cholangiocarcinoma, melanoma, pancreatic, and breast cancer. 7,10 Yu et al reported that HRH3 was upregulated in HCC tissues.…”

Commentary: Pathophysiological Role of Histamine H4 Receptor in Cancer: Therapeutic Implications

“…Besides its distribution on immune cells, H4R was also differentially expressed in a wide variety of cancers, cancer models, and tumor cell lines. In this regard, we read with great interest the elegant work of Nicoud et al, which comprehensively reviewed the recent research on the pathophysiological role of H4R in cancer (Nicoud et al, 2019). The authors summarized the current knowledge on H4R pharmacology, clinical applications, and differential expression in many in vitro and in vivo experimental models of cancer as well as in cancer patient cohorts.…”

“…Finally, we perfectly agree with the authors that several challenges remain to be addressed in H4R-based translational research. Such limitations include, but are not limited to, ligand selectivity, experimental models' heterogeneity, and the undetermined specificity of many commercially available antibodies (Nicoud et al, 2019). Nevertheless, the ongoing extensive investment in…”