beta-endorphin and Carcinoma--Small-Cell

One case of breast neuroendocrine primary small cell carcinoma with light microscopic and immunohistochemical findings is reported. The patient died of unrelated disease 21 months after diagnosis and treatment by modified radical mastectomy, radiotherapy and subsequent chemotherapy. Immunohistochemical studies revealed cytokeratin and neuroendocrine markers (chromogranin, neuron-specific enolase) immunostaining on tumoral cells. Expression for neuropeptides (met-enkephalin, leu-enkephalin, beta-endorphin) and CALLA antigen was found. Based on this case report and six other previously reported cases, breast neuroendocrine primary small cell carcinoma appears to be a very aggressive tumor for which no firm conclusions regarding treatment can be drawn.

Topics: Aged; beta-Endorphin; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Small Cell; Chromogranins; Cytoplasm; Enkephalin, Leucine; Female; Humans; Immunohistochemistry; Keratins; Mammography; Mastectomy, Modified Radical; Phosphopyruvate Hydratase; Radiotherapy, Adjuvant

Topics: Adenocarcinoma; Amine Oxidase (Copper-Containing); APUD Cells; beta-Endorphin; Calcitonin; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Differentiation; Cell Division; Cell Line; Dopa Decarboxylase; Endorphins; Humans; Lung Neoplasms

The small cell lung carcinoma cell line U-1690 bound beta-endorphin via nonopioid binding sites also recognized by the C-terminal part of this opioid peptide Lys-Lys-Gly-Glu, but not by opiate alkaloids such as naloxone and morphine or other opioid peptides. The beta-endorphin binding did not affect the production of cAMP, but was enhanced by dexamethasone pretreatment. The beta-endorphin-stimulated proliferation of U-1690 cells was inhibited by Lys-Lys-Gly-Glu and increased by dexamethasone pretreatment. The cells also produce beta-endorphin, suggesting an autocrine mechanism.

Topics: Amino Acid Sequence; beta-Endorphin; Binding Sites; Carcinoma, Small Cell; Cell Division; Cyclic AMP; Humans; Lung Neoplasms; Molecular Sequence Data; Narcotics

Previous reports have demonstrated that beta-endorphin stimulates the clonal growth of human small cell lung carcinoma (SCLC) cell lines. In this study, the human SCLC lines, NCI-H69, NCI-H345, and NCI-N417, were observed to be highly-enriched in saturable, high-affinity binding sites which are labeled by [125I]beta-endorphin. In contrast to conventional opioid receptors, [125I]beta-endorphin SCLC binding was insensitive to naloxone and other mu, delta, or kappa opioid ligands. Further analysis of the NCI-H69 cells demonstrated that specific (naloxone-insensitive) binding was dependent on receptor concentration, reversible, sensitive to sodium ion, but insensitive to the GTP analogue, Gpp(NH)p. These results suggest a role for naloxone-insensitive beta-endorphin in modulating SCLC metabolism.

Topics: Animals; beta-Endorphin; Binding Sites; Binding, Competitive; Carcinoma, Small Cell; Cell Membrane; Humans; Iodine Radioisotopes; Lung Neoplasms; Naloxone; Prosencephalon; Rats; Receptors, Opioid; Sensitivity and Specificity; Tumor Cells, Cultured

The endogenous opioid beta-endorphin, a derivative of proopiomelanocortin, stimulates the growth of cloned human small cell lung carcinoma. The present hypothesis states that mutations of the retinoblastoma gene (a tumor suppressor gene) associated to the malignant transformation of bronchial cells would trigger a cascade of biomolecular events leading to 'de novo' proopiomelanocortin expression in small cell lung carcinoma.

Topics: ACTH Syndrome, Ectopic; beta-Endorphin; Carcinoma, Small Cell; Cushing Syndrome; Female; Gene Expression Regulation, Neoplastic; Genes, fos; Genes, Retinoblastoma; Hormones, Ectopic; Humans; Lung Neoplasms; Models, Biological; Neoplasm Proteins; Pro-Opiomelanocortin; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-fos; Retinoblastoma Protein

Neuroendocrine tumours of the lung may be associated with the ectopic adrenocorticotrophin (ACTH) syndrome and may synthesize and secrete ACTH-related peptides in the absence of the syndrome. However, immunocytochemical analysis may not confirm these biochemical findings, particularly in small cell carcinoma, which is poorly granulated. To investigate further the morphological evidence for expression of the pro-opiomelanocortin (POMC) gene in neuroendocrine lung tumours, we have examined a series of 46 small cell carcinomas and 13 carcinoid tumours of the lung by in situ hybridization for POMC mRNA using a digoxigenin-labelled oligoprobe. We have compared the findings with the immunocytochemical detection of ACTH and beta-endorphin. In situ hybridization was positive in 15 of 46 small cell carcinomas (33 per cent) and in 8 of 13 carcinoid tumours (62 per cent). Immunocytochemical staining was positive in only one carcinoid tumour. These in situ hybridization studies have corroborated biochemical data indicating POMC gene expression in a high proportion of lung neuroendocrine tumours. This suggests that the low levels of expression detected by immunocytochemistry may be due to low levels of hormone storage. Multivariate analysis showed a weak negative association between POMC expression and survival in small cell carcinomas, although this did not reach statistical significance.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Aged, 80 and over; beta-Endorphin; Carcinoid Tumor; Carcinoma, Small Cell; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; In Situ Hybridization; Lung Neoplasms; Male; Middle Aged; Pro-Opiomelanocortin; RNA, Messenger

Interleukin-2 has been shown to stimulate cortisol secretion in man. Owing to its immunosuppressive properties, an increase in cortisol levels during interleukin-2 cancer immunotherapy could potentially counteract induced activation of the antitumor immune response. Few data are available about cortisol secretion secondary to prolonged interleukin-2 administration. To investigate the problem, we evaluated cortisol circadian rhythms in 7 consecutive metastatic small cell lung cancer patients who received interleukin-2 subcutaneously for 4 weeks (daily dose: 6 x 10(6) x IU/m2). Venous blood samples were drawn at 8.00 a.m., 4.00 p.m. and 12.00 p.m., before interleukin-2, and after each week until the end of the cycle. Beta-endorphin levels were also measured on the same samples. Four patients were evaluated during a second interleukin-2 cycle. Mean cortisol levels increased during interleukin-2 therapy, but were significantly higher than those seen in basal conditions after the first week of treatment. Moreover, cortisol peaks observed during the second cycle of therapy were not significantly different from those seen during the first cycle. Mean beta-endorphin levels increased in response to interleukin-2 administration, but the increase did not reach statistical significance. The early cortisol rise progressively decreased as treatment continued. This suggests that the interleukin-2-induced cortisol rise has no relevant clinical importance in antagonizing the activation of an effective antitumor immune response during cancer immunotherapy with interleukin-2.

Topics: beta-Endorphin; Carcinoma, Small Cell; Circadian Rhythm; Female; Humans; Hydrocortisone; Injections, Subcutaneous; Interleukin-2; Lung Neoplasms; Male; Middle Aged

Topics: beta-Endorphin; Bombesin; Carcinoma, Small Cell; Cell Line; Clone Cells; Humans; Lung Neoplasms; Neurotensin

The tumor stem cell clonogenic assay was utilized to investigate the autocrine growth response of small cell lung cancer (SCLC) to bombesin (BN) and beta-endorphin (beta-E). Mycoplasma contamination was detected in the human SCLC cell line NCl-H345 by a nucleic acid hybridization assay which detects mycoplasma ribosomal RNA. Clonogenic assays of mycoplasma (+) cells were compared to assays of the same cell line following treatment for mycoplasma. Concentrations of beta-E ranging from 0.1nM to 25nM or BN (0.1nM-100nM) were added to cells, media and agarose and applied to prepared base layers. Following incubation for 12-14 days at 37 degrees C, the degree of clonal growth stimulation was determined by colony counts greater than or equal to 42 mu. The non-infected cell population grew in the presence of 25nM BN up to 69% over control growth. The infected cells, however, did not grow more than 27% above control. In the presence of 10nM beta-E, colony counts of non-infected cells exceeded the control values by up to 187% whereas the mycoplasma (+) colonies did not grow more than 20% over the control values. These results indicate a marked reduction in the response of SCLC cell lines to the peptides BN and beta-E when infected with mycoplasma. Since infecting mycoplasma typically adhere to cellular membranes, these adherent mycoplasma may interfere with membrane receptors or alter signal transduction, thus, inhibiting the development of the autocrine response.

Topics: beta-Endorphin; Bombesin; Carcinoma, Small Cell; Dose-Response Relationship, Drug; Humans; Lung Neoplasms; Mycoplasma; Tumor Cells, Cultured; Tumor Stem Cell Assay

The xenograft line, UCRU-PR-2, has been characterized further. Established from a primary human undifferentiated small cell carcinoma of the prostate, it has been maintained as a stable xenograft line in nude mice and is currently in passage 9. The tumor has maintained the features of small cell undifferentiated carcinoma but shows epithelial as well as neuroendocrine characteristics. In this paper, we describe synthesis and secretion of peptide hormones, ACTH, beta-endorphin and somatostatin in vivo and ACTH and beta-endorphin in vitro by the tumor, UCRU-PR-2. This suggests that the gene for proopiomelanocortin is expressed and that processing of the molecule occurs. This line may yield insights into the histogenesis of the subtypes of prostate cancer, and also aid studies of regulation of ectopic hormone production.

Topics: Adrenocorticotropic Hormone; Animals; beta-Endorphin; Carcinoma, Small Cell; Cell Line; Hormones; Humans; Male; Mice; Mice, Nude; Neoplasm Transplantation; Peptide Biosynthesis; Peptides; Prostatic Neoplasms; Transplantation, Heterologous

Two human small cell carcinoma cell lines were assayed for total opioid and beta-endorphin-like immunoreactivity. Small cell carcinoma cell line NCI-H146 contained approximately 1.1 pmol/mg protein of total opioid immunoreactivity. This material was similar in size and immunoreactive determinants to C-terminally modified beta-endorphin. Small cell carcinoma cell line NCI-H187 contained approximately 0.2 pmol/mg protein total opioid immunoreactivity, which was of low molecular weight. NCI-H187 also contained approximately 1.2 pmol/mg protein of material similar in size and immunoreactive determinants to beta-lipotropin. The two small cell carcinoma cell lines were also examined for opioid receptors with the use of [3H]-etorphine as ligand. Both cell lines contained between 50 and 100 fmol/mg protein of specific, saturable, high-affinity opioid receptor binding sites. Together, these findings suggest a possible autocrine role for opioids in small cell carcinoma of the lung.

Topics: beta-Endorphin; Carcinoma, Small Cell; Cell Line; Endorphins; Etorphine; Humans; Lung Neoplasms; Receptors, Opioid

ACTH responses to corticotropin-releasing hormone (CRH) were studied in three patients with the ectopic ACTH syndrome caused by lung cancer. Plasma ACTH responded to synthetic CRH in two of three patients. Tumor tissues obtained from these two patients contained CRH and ACTH. In one patient, tumor ACTH secretion was stimulated by CRH in vitro. Tumor CRH was immunologically, chromatographically, and biologically similar to hypothalamic CRH. In addition, multiple forms of immunoreactive beta-endorphin were present in plasma and the tumor extracts. From these results, we conclude that some patients with the ectopic ACTH syndrome have tumors that produce both ACTH and CRH and that CRH can stimulate ACTH secretion by such tumors. Other patients with the ectopic ACTH syndrome do not have ACTH responses to CRH. Therefore, procedures other than CRH testing are needed to differentiate patients with Cushing's syndrome due to ectopic ACTH/CRH production from those with Cushing's disease, since the latter also usually have ACTH responses to CRH.

Topics: ACTH Syndrome, Ectopic; Aged; beta-Endorphin; Carcinoma, Small Cell; Corticotropin-Releasing Hormone; Endorphins; Humans; In Vitro Techniques; Lung Neoplasms; Male; Middle Aged; Paraneoplastic Endocrine Syndromes; Radioimmunoassay

The association of hormonal syndrome and APUD (amine precursor uptake, decarboxylase) features with small cell carcinoma of the lung (SCC) has suggested that SCC has a separate cell origin from other major forms of lung cancer. Recently, however, both SCC and non-SCC lung cancers have been found to contain small polypeptide hormones and APUD enzymes. The present study quantitates, in 50 samples of human lung cancer tissue, relationships among the 4 major types of lung cancer and endocrine-related properties. Among 4 parameters measured (dopa decarboxylase, histaminase, beta-endorphin, and calcitonin), no single marker clearly separated SCC from non-SCC lung cancer. The high activity of dopa decarboxylase (the "D" in "APUD") best separated SCC from non-SCC, but significant overlap existed even for this critical APUD property. In fact, 2 adenocarcinomas had among the highest concentrations of dopa decarboxylase, histaminase, and calcitonin of any tumor tissue studied. The simultaneous appearance of high levels of 2 or more markers favored SCC. This was quantitated by deriving an index unit based upon the product of the values for the 4 markers in each lesion. This index separated all SCC from all non-SCC lung carcinomas, with the exception of the above 2 adenocarcinomas. Endocrine-related properties thus occur throughout the spectrum of human lung cancer. Biochemical differences between the major histopathological types are quantitative rather than qualitative and probably reflect the fact that the major forms of lung cancer represent a continuum of differentiation within a common cell lineage which includes both SCC and non-SCC lung tumors.

Topics: Adenocarcinoma; Amine Oxidase (Copper-Containing); APUD Cells; Aromatic-L-Amino-Acid Decarboxylases; beta-Endorphin; Calcitonin; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Dopa Decarboxylase; Endorphins; Humans; Lung Neoplasms