Z. Darvas

Decreased expression of histamine H1 and H4 receptors suggests disturbance of local regulation in human colorectal tumours by histamine

Production of histamine in colon tumours has been described earlier. Histamine-mediated signals have been shown to be implicated in tumour growth, and the effects of histamine are largely determined locally by the histamine receptor expression pattern. We analysed histamine receptor expression in human colorectal cancer, adenoma and normal mucosa by quantitative reverse transcription-polymerase chain reaction (RT-PCR), Western blot analysis and immunostaining. Real-time RT-PCR results revealed significantly decreased (p<0.001) H1R and H4R mRNA levels in tumours compared to normal colonic mucosa, without any significant change in H2R mRNA expression. H3R was absent in most samples; it was detected at low levels in 7.9% of the cases. Protein analysis showed a similar decrease in histamine receptor expression in carcinoma and adenoma compared to normal mucosa controls. Based on these results, we performed further Western blot analysis on Dukes-classified and -selected tumour samples. We found significantly decreased H4R levels in neoplastic samples compared to normal colonic tissue, but there was no significant correlation between histamine receptor expression profile and the Dukes stage of tumours. Immunohistochemical staining revealed expression patterns of H1R, H2R and H4R similar to those suggested by the mRNA and Western blot results. In the present study, we demonstrate that H1R, H2R and H4R are expressed in colon carcinoma and the adjacent normal mucosa. The results suggest a dramatic alteration in the distribution of histamine receptors in colon cancer. These findings raise the perspective of targeted pharmacological studies with selective histamine receptor antagonists or agonists in the therapy of colorectal tumours.

Histamine Suppresses Fibulin-5 and Insulin-like Growth Factor-II Receptor Expression in Melanoma

We previously showed that transgenic enhancement of histamine production in B16-F10 melanomas strongly supports tumor growth in C57BL/6 mice. In the present study, gene expression profiles of transgenic mouse melanomas, secreting different amounts of histamine, were compared by whole genome microarrays. Array results were validated by real-time PCR, and genes showing histamine-affected behavior were further analyzed by immunohistochemistry. Regulation of histamine-coupled genes was investigated by checking the presence and functional integrity of all four known histamine receptors in experimental melanomas and by administering histamine H1 receptor (H1R) and H2 receptor (H2R) antagonists to tumor-bearing mice. Finally, an attempt was made to integrate histamine-affected genes in known gene regulatory circuits by in silico pathway analysis. Our results show that histamine enhances melanoma growth via H1R rather than through H2R. We show that H1R activation suppresses RNA-level expression of the tumor suppressor insulin-like growth factor II receptor (IGF-IIR) and the antiangiogenic matrix protein fibulin-5 (FBLN5), decreases their intracellular protein levels, and also reduces their availability in the plasma membrane and extracellular matrix, respectively. Pathway analysis suggests that because plasma membrane-bound IGF-IIR is required to activate matrix-bound, latent transforming growth factor-beta1, a factor suggested to sustain FBLN5 expression, the data can be integrated in a known antineoplastic regulatory pathway that is suppressed by H1R. On the other hand, we show that engagement of H2R also reduces intracellular protein pools of IGF-IIR and FBLN5, but being a downstream acting posttranslational effect with minimal consequences on exported IGF-IIR and FBLN5 protein levels, H2R is rather irrelevant compared with H1R in melanoma.

Histamine in Normal and Malignant Cell Proliferation

Histamine is a biogenic amine widely distributed throughout the body. Given the observations that histamine can be induced and made available in an unstored diffusible form in tissues undergoing rapid growth (such as tumors and regenerating liver), it could have a role beyond inflammatory and allergic responses.

Hormone evolution studies: multiplication promoting and imprinting ("memory") effects of various amino acids on Tetrahymena.

Aromatic, heterocyclic, polar and non-polar amino acids were examined for imprinting potential in a unicellular (Tetrahymena) model system. Serine gave rise to positive, glycine to negative imprinting, whereas valine, tryptophan, tyrosine and phenylalanine had no imprinting effect whatever. However, tyrosine and phenylalanine stimulated the division of Tetrahymena already at primary interaction, the former even for a relatively long time. It follows that amino acids, too, can give rise to imprinting, although their imprinting potentials are dissimilar. These phenomena have attracted attention to possible interrelationships between the supposed amino acid receptors of Tetrahymena and the evolution of amino acids to hormones.

Presence of digoxin detectable by radioimmunoassay inTetrahymena

Digoxin was demonstrated inTetrahymena pyriformis by radioimmunoassay, at a concentration of 4.3 ng/100,000 cells. Pretreatment of the cells with digoxin or ouabain did not significantly alter the digoxin concentration of the progeny generations.

Long-lasting effect of single ecdysone injections in newborn rats

Single injections of ecdysone to newborn rats were followed by increases in the weights of the adrenals and decreases in the weights of the thymuses in the adults. No change was registered in body weights and in the weights of the gonads. The plasma androsterone levels seemed to decrease; however, the interindividual differences proved to be too great to draw definite conclusions.

Myeloma multiplex kórlefolyása során megjelenő plazmasejtes bőrinfiltráció@@@Plasmacytic skin infiltration in multiple myeloma

UNLABELLED Authors present a case of a therapy-resistant multiple myeloma who developed plasmacytic skin infiltration in the course of the disease. AIM To define characteristics of skin infiltrating plasma cells, which differentiate them from those cells residing in the bone marrow in order to contribute to a better understanding of the epidermoinvasion process. METHODS Histidine decarboxylase is the only enzyme capable for histamine synthesis having significance in cell proliferation. Histidine decarboxylase was determined in skin samples and bone marrow slides by immunohistochemical procedures and in bone marrow cells using flow cytometry analysis. RESULTS The histidine decarboxylase expression of plasma cells participating in skin invasion disappeared, while that of bone marrow plasma cells remained. CONCLUSIONS Authors conclude that the histidine decarboxylase loss would serve as an evidence for the dedifferentiation of epidermoinvasive cells as being the result of fundamental changes in histamine metabolism. As extramedullary myeloma cells differ from those residing in the bone marrow, their therapeutical response might also be different.

Plasmacytic skin infiltration in multiple myeloma

UNLABELLED Authors present a case of a therapy-resistant multiple myeloma who developed plasmacytic skin infiltration in the course of the disease. AIM To define characteristics of skin infiltrating plasma cells, which differentiate them from those cells residing in the bone marrow in order to contribute to a better understanding of the epidermoinvasion process. METHODS Histidine decarboxylase is the only enzyme capable for histamine synthesis having significance in cell proliferation. Histidine decarboxylase was determined in skin samples and bone marrow slides by immunohistochemical procedures and in bone marrow cells using flow cytometry analysis. RESULTS The histidine decarboxylase expression of plasma cells participating in skin invasion disappeared, while that of bone marrow plasma cells remained. CONCLUSIONS Authors conclude that the histidine decarboxylase loss would serve as an evidence for the dedifferentiation of epidermoinvasive cells as being the result of fundamental changes in histamine metabolism. As extramedullary myeloma cells differ from those residing in the bone marrow, their therapeutical response might also be different.

Loss of histidine decarboxylase as a marker of malignant transformation and dedifferentiation of B-cells infiltrating the skin. A case report of a therapy-resistant multiple myeloma complicated by skin infiltration

Multiple myeloma (MM) is a B-cell lymphoma of matured plasmacytic origin. There is a well described spectrum of cutaneous diseases in MM including cell infiltration and amyloid deposition [1]. Little is known about the basic processes involved that allow malignant plasma cells or lymphomas to grow outside the bone marrow environment. Several experimental models have been used to study this issue [2]. Hedvat et al. found altered gene expression profile pattern in plasma cells growing in extramedullary sites mostly involved in angiogenesis and adhesion [3]. Identification of other tumour-specific alterations required for extramedullary growth would confer better understanding of tumour metastasis. In an earlier study authors found that histidine decarboxylase (HDC)that is the only enzyme capable of histamine synthesisis absent from B-lymphocytes infiltrating the skin in a B-cell chronic lymphocytic leukemia patient who developed cutaneous infiltrations in the course of the disease. In contrast to this, those cells that remained in the bone marrow had their HDC activity been preserved [4]. There is evidence that besides histamine being a well known mediator of allergic reactions, may also be involved in certain types of cell proliferations like wound healing, embryonic development and tumor growth [5,6]. There are data confirming that a functioning HDC gene is important in maintaining immune homeostasis [7]. The relation of histamine metabolism and metastatising human plasma cell malignancies has not been examined so far. The case reported here served an appropriate occasion for that.