Phenotypic Profiling of Engineered Mouse Melanomas with Manipulated Histamine Production Identifies Histamine H2 Receptor and Rho-C as Histamine-Regulated Melanoma Progression Markers

Abstract

In the present study, the impact of acquired neoplastic L-histidine decarboxylase (HDC) expression, and its direct consequence, the release of histamine in the tumor environment, was assessed on melanoma tumor progression. B16-F10 mouse melanoma cells were manipulated via stable transfection, and nine novel transgenic variants were generated in triplicates, constitutively expressing the full-length sense mouse HDC mRNA, a mock control, and an antisense HDC RNA segment, respectively. Establishing both primary skin tumors and lung metastases in C57BL/6 mice, the nine variants with different histamine-releasing capacities were subjected to a comprehensive comparative progression profiling in vivo. Our analyses showed trends of markedly accelerated tumor growth (P < 0.001), and moderately increased metastatic colony-forming potential (P = 0.010) along with rising levels of local histamine production. Using RNase protection assay for screening of the melanoma progression profile, and Western blotting for subsequent result validation, we looked for molecular progression markers affected by melanoma histamine secretion. Investigation of 21 functionally clustered markers associated with tumor proliferation, angiogenesis, invasivity, metastasis formation, local or systemic immunomodulation, and histamine signaling revealed positive correlations between histamine production, tumor histamine H2 receptor and rho-C expression (P < 0.001, P = 0.002, respectively). These observations confirm the involvement of histamine in the molecular machinery of melanoma progression. (Cancer Res 2005; 65(10): 4458-66)

1H NMR metabolomics study of metastatic melanoma in C57BL/6J mouse spleen

“…A recent research conducted by Noelia and coworkers has concluded the exhibition of antitumor effect of histamine in vitro and in vivo on human melanoma, suggesting histamine as a potential therapeutic compound for the treatment of malignant melanoma (Massari et al 2013). Significant elevation of histamine in melanoma group observed in this study may be a result of up-regulation of histidine decarboxylase expression caused by metastatic melanoma in spleen, which is consistent with previous reports where B16F10 mouse melanoma cells show a rising level of histamine compared with normal melanocytes (Pos et al 2005; Davis et al 2011; Gruetter et al 2009; Gruetter et al 2008). Alanine is most commonly produced from pyruvate via alanine transaminase.…”

Histamine in brain development

“…HA may promote the proliferation of NSCs and cancer stem cells (Pós et al 2005;Molina-Hernandez and Velasco 2008). In contrast, Medina et al (2009) showed that HA impairs the proliferation of human malignant melanoma cells, probably by increasing hydrogen peroxide levels.…”

“…HA may promote the proliferation of NSCs and cancer stem cells (Pós et al. 2005; Molina‐Hernandez and Velasco 2008).…”

Histamine therapeutic efficacy in metastatic melanoma: Role of histamine H4 receptor agonists and opportunity for combination with radiation

“…On one side, the use of specific anti-sense oligonucleotides against histidine decarboxylase (HDC) decreased the proliferation rate of human melanoma cells [11], while over-expression of HDC markedly accelerates tumor growth and increases metastatic colony-forming potential in mouse melanoma [12, 13]. On the other side, it was demonstrated by using histamine agonists, antagonists and genetic tools, that histamine treatment produced an inhibitory effect on proliferation mediated in part through the stimulation of the H 4 R in WM35 and M1/15 human melanoma cells.…”

“…Histamine dihydrochloride inhibits the formation of reactive oxygen species from monocytes/macrophages by suppressing the activity of NADPH oxidase, and thus preventing the inactivation of T cells and NK cells [15]. In addition, it is not possible to discard a direct action of histamine on melanoma cells, considering that the expression of H 1 R, H 2 R, H 3 R and H 4 R in human melanoma cell lines was shown [8, 12, 16]. In addition, literature suggests that those with allergy have a reduced risk of developing cancer versus the general population [17] and that a history of asthma may be a protective factor in cutaneous melanoma [18].…”