Zsuzsa Darvas

Paracrine and autocrine interactions in melanoma: histamine is a relevant player in local regulation

Abstract Malignant melanoma is a life-threatening tumor, with a high rate of metastasis and strong malignant potential. The local immune response against melanoma is compromised by multiple escape mechanisms of the tumor, which have been uncovered partially by thorough molecular and immunological analyses. These analyses were completed recently by gene-expression profiling. In this article, we summarize data suggesting that melanoma-derived histamine should be included as an important factor involved in bi-directional interactions between the tumor tissue and infiltrating immune cells. The presence and activity of histamine seems to be relevant by both directly stimulating or suppressing growth of the melanoma (depending on the local histamine-receptor balance) and indirectly shifting the local T-cell polarization towards a predominance of T helper 2 cells.

Locally generated VGVAPG and VAPG elastin-derived peptides amplify melanoma invasion via the galectin-3 receptor.

Melanomas containing more elastin are associated with higher stages of the disease. The interaction between elastin‐derived peptides and melanoma cells appears to play an important role in the progression of melanomas. The effects of the elastin‐derived peptides VGVAPG and VAPG have been investigated on the migration, invasion, adhesion and angiogenesis of human melanoma cells of different invasive potential. Elastin, tropoelastin and VGVAPG peptide were demonstrated at the invasion site of melanoma using histochemistry and immunohistochemistry. Not only the VGVAPG elastin‐derived peptide, which exhibits the XGXXPG consensus sequence in its primary structure, but also the shorter VAPG bind directly to 3 cell surface receptors: galectin‐3, integrin αvβ3 and elastin‐binding protein. Our results suggest that the increased levels of elastin‐derived peptides facilitate the invasion of melanoma cells: (i) VGVAPG and VAPG elastin‐derived peptides are chemotactic for melanoma cells; (ii) they can increase the migration of melanoma cells and the expression of CXCR‐4 and CXCL‐12 chemokines; (iii) they enhance the expression of the elastin‐degrading MMP‐2 and MMP‐3; (iv) they increase the attachment of melanoma cells and the expression of different adhesion molecules; (v) they increase the expression of the lymphangiogenic VEGF‐C and (vi) the galectin‐3 receptor can mediate all these effects. Clinical and therapeutic aspects are also discussed.

The pathogenesis of nasal polyposis by immunoglobulin E and interleukin-5 is completed by transforming growth factor-β1

Objectives/Hypothesis Nasal polyps are benign mucosal protrusions into the nasal cavity of multifactorial origin and are characterized by chronic mucosal inflammation. The suggested multifactorial pathological mechanisms comprise several factors including cytokines and immunoglobulin E (IgE). The study was designed to examine the suggested roles of IgE, interleukin‐5 (IL‐5), and transforming growth factor‐β1 (TGF‐β1) in the pathogenesis of nasal polyposis.

Histamine and histamine-receptor antagonists modify gene expression and biosynthesis of interferon gamma in peripheral human blood mononuclear cells and in CD19-depleted cell subsets

The effect of histamine and histamine antagonists was examined on gene expression and biosynthesis of bacterial endotoxin (LPS) induced interferon gamma (IFNgamma) both in human peripheral mononuclear cells (PMBC) and in T-cell enriched fractions. We found, that histamine inhibited the LPS induced transcription of IFNgamma gene and biosynthesis of IFNgamma protein in PMBC and also in CD19-depleted cell populations. The inhibitory effect of histamine could be reversed by the H2 histamine receptor (HR2) antagonists cimetidine and ranitidine both in PMBC and in CD19-depleted cells, but not with triprolidine, an H1 receptor antagonist, suggesting that the inhibition of IFNgamma production is mediated through H2 receptors in these cell populations. In contrast to the inhibitory effect of histamine, cimetidine alone (in the absence of exogenous histamine) strongly stimulated both the IFNgamma mRNA and protein production, whereas this effect was hardly seen by and other H2 receptor blocker, ranitidine. This superinduction of IFNgamma gene by cimetidine disappeared if the CD19+ cells are removed from PMBC. These results suggest, that inhibition of IFNgamma gene expression by histamine is a direct effect of histamine on H2 receptor of T lymphocytes; however, the superinduction of IFNgamma by cimetidine requires the presence of other (probably primarily B) cell subsets.

Autonomous histamine metabolism in human melanoma cells

Melanoma cells constitutively produce various cytokines as well as growth factors and express their corresponding receptors. Exogenous histamine is known to be a growth factor for some tumours while in other cases histamine inhibits tumour growth, and acts on G protein-coupled H1 and H2 histamine receptors. In previous studies we have detected the expression of the l-histidine decarboxylase (HDC) gene and the presence of HDC protein in human melanoma cell lines. In the present study, the activities of the histamine-forming enzyme HDC and of the degrading enzymes diamine oxidase (DAO) and histamine N-methyltransferase (HNMT) were measured in primary (WM35 and WM983) and metastatic (M1 and HT168) human melanoma cell lines. HDC activity was found in WM35 and WM983 cell lines, while detectable HNMT activity was measured in WM983, M1 and HT168 lines. In contrast, DAO showed very low activity in melanoma cell lines. Melanoma cells release a detectable amount of histamine into the medium without external stimuli. These findings support the possibility of autonomous histamine metabolism in melanoma cells. Our results suggest that not only exogenous histamine but also histamine produced and released by the melanoma cells and acting as an autocrine and paracrine factor may influence cell proliferation and modulate the in situ immune response of the host.

Histamine as a potential autocrine regulator of melanoma.

Malignant tumor cells express autocrine and paracrine growth factors that can block immune effectiveness and facilitate the acquisition of partial or complete growth autonomy. Recently histamine (Hi) was proved to have an important role as a mediator in normal and malignant cell proliferation. We have reported that Hi behaves as an autocrine growth factor in an experimental mammary carcinoma and in pancreatic carcinoma cells [1, 2]. Human melanoma cells contain high HDC activity and mRNA expression [3, 4]. In this work, we thus investigated the possible role of Hi in the regulation of melanoma growth.

Receptor-level interrelationships of amino acids and the adequate amino acid type hormones in Tetrahymena: A receptor evolution model

Histidine stimulates the phagocytosis of Tetrahymena to the same extent as histamine, and also stimulates its division, which histamine does not. Tyrosine and diiodotyrosine equally stimulate the growth of the Tetrahymena. Both amino acids inhibit the characteristic influence of the adequate amino acid hormone when added to Tetrahymena culture 72 h in advance of it. Primary interaction with diiodotyrosine and tyrosine notably increases the cellular growth rate. Histamine has a similar, although less notable effect than histidine. In the light of these experimental observations there is reason to postulate that the receptors of the amino acid hormones have developed from amino acid receptors.

Histamine inhibits proliferation of a pancreatic carcinoma cell line without inducing apoptosis significantly

Previously we demonstrated that human pancreatic carcinoma cell line PANC-1 overexpresses histamine (Hi) H1 and H2 receptors. Both H1 and H2 agonists stimulate phosphoinositide turnover while only H2 agonists increase intracellular cAMP production [1]. Also these cells can synthesize and release Hi and the treatment with Hi, H2 agonists or forskolin produces a significant inhibition on cell proliferation [1]. In this work we used cAMP analogues to confirm the association between inhibition of cell growth and cAMP levels. We also evaluated induction of apoptosis and expression of differentiation markers to investigate the mechanism by which Hi inhibits cell proliferation.

Histidine decarboxylase and intracellular histamine in melanoma cells and in a T cell line

Action of exogeneous histamine is mediated by binding to its specific cell-surface receptor(s) resulting in converting the extracellular signal to intracellular events. Recently numerous studies suggest basic role for histamine as one of the intracellular messenger moieties [1, 2]. Both the cellular expression of histidine decarboxylase [3] (HDC) in proliferating cells and a putative receptor activity for intracellular histamine (HRIC), confirm general effectiveness of histamine in embryonic development, hematopoiesis and wound healing [4, 5]. In our studies the expression of HDC has been studied in human melanoma tissue, cell lines and in a human T lymphocyte cell line, Jurkat.

Dissimilar effects of L and D amino acids on the growth of Tetrahymena

Of the L and D configurations of four amino acids (phenylalanine, valine, tryptophan, tyrosine) tested for influence on the growth rate of Tetrahymena, only L-tyrosine was able to induce imprinting in Tetrahymena pyriformis Zeuthen. D-valine stimulated the division of T.pyriformis NT-1, but failed to induce imprinting. The experiments have substantiated the selectivity of the amino acid receptors of Y.pyriformis, and the extraordinary imprinting potential of tyrosine as well, as judged by its influence on the growth rate.