vasoactive-intestinal-peptide and Skin-Neoplasms

Nitric oxide (NO) and the NO generating agent nitroprusside (SNP), inhibit the binding of [125I] vasoactive intestinal peptide (VIP) to its receptor at the surface of IGR39 human melanoma cells. Cysteine (10 mM) increases the sensitivity of the system to SNP while N-acetylcysteine (10 mM) decreases it. The NO gas as well as SNP inhibits the [125I]VIP binding capacity. These observations sustain an effect of SNP-generated NO rather than an effect of the SNP molecule per se or the cyanoferrate portion of the molecule. The inhibitory effect of NO is time and concentration dependent and is fully reversible. Affinity constants of high and low affinity VIP receptors of SNP-treated IGR39 cells are not modified while maximal binding capacity (Bmax) of both receptor types are decreased to the same extent. Production of cGMP by SNP-treated cells is time and concentration dependent and the maximum amount of cGMP obtained reaches 13 times the basal level. The cAMP production is not affected by SNP. However, the SNP effects on the [125I]VIP binding are not mimicked by the membrane permeant cGMP analogs dibutyryl cGMP and 8-bromo cGMP even at concentrations as high as 0.5 mM. Taken altogether, these data demonstrate a regulatory action of NO on VIP binding capacity of IGR39 melanoma cells which is not cGMP mediated. They also evidence a new step which could be involved in the NO-VIP interaction.

Topics: Cyclic AMP; Cyclic GMP; Dibutyryl Cyclic GMP; Humans; Melanoma; Neoplasm Proteins; Nitric Oxide; Nitroprusside; Protein Binding; Receptors, Vasoactive Intestinal Peptide; Skin Neoplasms; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

We studied the production of parathyroid-hormone-related protein, chromogranin A, calcitonin and calcitonin-gene-related peptide in the neuroendocrine skin cell line, MKL1, and a subsequently derived cell line designated MKL2. Both cell lines had cytological, histological and electron-microscopic features typical of neuroendocrine differentiation. Immunohistology and radioimmunoassay studies demonstrated the presence of parathyroid-hormone-related protein, chromogranin A, calcitonin-gene-related peptide, and calcitonin in the MKL2 cell line and the last three substances in both cell lines. The secretion of each of the first three substances was regulated by phorbol in the MKL2 cells. Additional immunohistochemical studies demonstrated the variable expression of bombesin, substance P, and vasoactive intestinal polypeptide in MKL2 cells, and the expression of synaptophysin in both MKL1 and MKL2 cells. These studies demonstrate the neuroendocrine characteristics of the MKL cell lines and provide a novel model for studies of the production and interactions of several neuroendocrine proteins and peptides by human skin cells.

Topics: Bombesin; Calcitonin; Calcitonin Gene-Related Peptide; Chromogranin A; Chromogranins; Humans; Microscopy, Electron; Neurosecretory Systems; Parathyroid Hormone-Related Protein; Proteins; Skin Neoplasms; Substance P; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

The occurrence of neuropeptides was studied in neurofibromas of von Recklinghausen's disease by indirect immunofluorescence. All non-plexiform cutaneous neurofibromas contained abundant vasoactive intestinal polypeptide, peptide histidine-isoleucine and calcitonin gene-related peptide immunoreactive nerves. The nerves were small and unmyelinated. Neuropeptides might be responsible for itch that occurs especially in small cutaneous neurofibromas. Neuropeptides are also suggested to act as modulators and/or trophic factors for neurofibroma growth.

Topics: Calcitonin Gene-Related Peptide; Female; Humans; Immunohistochemistry; Male; Neurofibromatosis 1; Neuropeptide Y; Neuropeptides; Peptide PHI; Skin Neoplasms; Somatostatin; Vasoactive Intestinal Peptide

Twenty-one examples of neuroendocrine carcinoma of the skin were examined by the unlabeled antibody enzyme method for several neural hormones and peptides, carcinoembryonic antigen, S-100 protein, neuron-specific enolase, and three intermediate filaments: neurofilament, glial fibrillary acidic protein, and cytokeratin. Vasoactive intestinal polypeptide from two sources reacted with the neoplastic cells of four (18%) and seven (32%) of the cases, and pancreatic polypeptide reacted with scattered cells of one case. Neuron-specific enolase reactivity occurred in 50% of the cases. Neurofilament (70, 150, 200 kilodaltons) was strongly positive in 40% of the tumors whereas neurofilament (200 kilodaltons) was negative. Two monoclonal anticytokeratin antibodies of 54 kilodaltons and 44-54 kilodaltons reacted in 77% and 64% of the cases, respectively, in a distribution similar to the neurofilament. Sections reacted with antisera against cytokeratins of higher molecular weight were negative. The demonstration of vasoactive intestinal polypeptide, pancreatic polypeptide, neurofilament, and neuron-specific enolase is evidence of the neuroendocrine nature of this neoplasm.

Topics: Carcinoma; Epidermal Cells; Epidermis; Humans; Immunoenzyme Techniques; Intermediate Filament Proteins; Keratins; Neurofilament Proteins; Pancreatic Polypeptide; Phosphopyruvate Hydratase; Skin Neoplasms; Vasoactive Intestinal Peptide

An unusual tumor of the skin was removed from the thigh of a 52-year-old white male. By light microscopy, the tumor was composed of intermediate and small cells in sheets and clusters. Ultrastructural study of the tumor cells showed numerous dense core granules and dendritic cell processes as well as intermediate filaments and cell junctions frequently within the same cells. Most of the tumor cells were stained intensely by antibodies to neurone-specific enolase (NSE), a marker of cells of the central and peripheral nervous system. The neuropeptides met-enkephalin and vasoactive intestinal peptide (VIP) were also found in tumor cells. Immunohistochemistry furthermore demonstrated cytokeratin. Both the ultrastructural appearance and keratin content of this tumor set it apart from conventional Merkel cell (or trabecular) carcinoma of the skin in a manner analogous to bipartite (i.e., epidermoid and small cell) carcinoma of lung. The production of neuropeptides simultaneously with the production of keratin establishes this as a bipartite skin tumor (i.e., ectodermal and neuroectodermal phenotype). We suggest that at least some primary neuroendocrine tumors of the skin arise from multipotential ectodermal cells not of neural crest origin, as has been proposed for small cell carcinoma of lung.

Topics: Apudoma; Cytoplasmic Granules; Enkephalin, Methionine; Humans; Keratins; Male; Microscopy, Electron; Middle Aged; Phosphopyruvate Hydratase; Skin; Skin Neoplasms; Vasoactive Intestinal Peptide

An 8-mo-old male child presented with generalized flushing and apnea which followed irritation of a 1.5 x 0.5 cm cutaneous mastocytoma on the left upper arm. Peripheral venous blood samples were drawn before and after manipulation of the tumor, immediately after excision, and again 30 days later. The plasma vasoactive intestinal polypeptide level before excision was high (345 pg/ml) and was accompanied by low acid secretion (15.4 mEq/L) and hypergastrinemia (209 pg/ml), all of which returned to normal after excision of the tumor (50 pg/ml, 35.7 mEq/L, and 131 pg/ml, respectively). Serum histamine levels were undetectable. Histology of the tumor showed only mast cells and no enterochromaffin tissue. The immunoreactive vasoactive intestinal polypeptide content of the tumor was 28 ng/g wet wt and the extracted vasoactive intestinal polypeptide was immunologically indistinguishable from natural porcine vasoactive intestinal polypeptide. The child has remained asymptomatic postoperatively. We conclude that the symptoms associated with this mastocytoma may have been produced by oversecretion of vasoactive intestinal polypeptide and not histamine.

Topics: Apnea; Gastrointestinal Hormones; Histamine Release; Humans; Hyperemia; Infant; Male; Mast-Cell Sarcoma; Skin Neoplasms; Syndrome; Vasoactive Intestinal Peptide