adrenomedullin and Carcinoma--Small-Cell

Several peptide hormones have been identified which alter the proliferation of lung cancer. Small cell lung cancer (SCLC), which is a neuroendocrine cancer, produces and secretes gastrin releasing peptide (GRP), neurotensin (NT) and adrenomedullin (AM) as autocrine growth factors. GRP, NT and AM bind to G-protein coupled receptors causing phosphatidylinositol turnover or elevated cAMP in SCLC cells. Addition of GRP, NT or AM to SCLC cells causes altered expression of nuclear oncogenes, such as c-fos, and stimulation of growth. Antagonists have been developed for GRP, NT and AM receptors which function as cytostatic agents and inhibit SCLC growth. Growth factor antagonists, such as the NT1 receptor antagonist SR48692, facilitate the ability of chemotherapeutic drugs to kill lung cancer cells. It remains to be determined if GRP, NT and AM receptors will served as molecular targets, for development of new therapies for the treatment of SCLC patients. Non-small cell lung cancer (NSCLC) cells also have a high density of GRP, NT, AM and epidermal growth factor (EGF) receptors. Several NSCLC patients with EGF receptor mutations respond to gefitinib, a tyrosine kinase inhibitor. Gefitinib relieves NSCLC symptoms, maintaining stable disease in patients who are not eligible for systemic chemotherapy. It is important to develop new therapeutic approaches using translational research techniques for the treatment of lung cancer patients.

Topics: Adrenomedullin; Amino Acid Sequence; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Gastrin-Releasing Peptide; Humans; Lung Neoplasms; Molecular Sequence Data; Neurotensin; Peptide Hormones; Peptides

It is suggested that adrenomedullin (AM) plays a role in lung carcinogenesis although, to confirm this suggestion, further clinical studies are needed to determine its relationship with prognosis in lung cancer. Archived 50 paraffin-embedded tumor samples of the lung were retrospectively evaluated for AM expression by immunohistochemistry and analyzed for a possible correlation with patient characteristics and survival. Quantitation of immunoreactivity was accomplished using an immunohistochemical scoring system. The pulmonary resection specimens contained 22 squamous cell carcinomas, 15 adenocarcinomas, and 13 small cell carcinomas. Non-small cell carcinomas of the lung were more likely to express AM than small cell carcinomas of the lung. Ninety-one percent of squamous cell carcinomas and 87% of adenocarcinomas expressed AM at a moderate to strong level and grade2-4 (30-100%), which were significantly higher from the non-neo-plastic lung tissue. Twenty-three percent of small cell carcinomas of lung expressed AM. Interestingly, AM immunoreactivity was essentially weak and grade 1 (<%30) in this group. AM expression is upregulated in non-small cell carcinomas of the lung, whereas it is downregulated in small cell carcinomas and non-neo-plastic lung tissues. AM expression did not show any correlation with the differentiation of the tumor, the stage of cancer, and the overall survival of patients. These results did not support the role of adrenomedullin as an independent survival factor for lung cancer. However, AM inhibition in conjunction with other anti-angiogenic agents may be useful in the prevention and treatment of malignancies.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Carcinoma; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Female; Humans; Immunohistochemistry; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Prognosis; Retrospective Studies; Survival Analysis

Adrenomedullin (AM) is a potent hypotensive peptide recently discovered in extracts of human pheochromocytoma. In this report we present evidence, using reverse transcriptase-polymerase chain reaction, immunocytochemistry, and in situ reverse transcriptase-polymerase chain reaction, that AM is synthesized by several cell populations of the normal lung, tumor cell lines of pulmonary origin, and tumor specimens. Among the normal cell populations of the lung, we found AM expression in the columnar epithelium, some glands, neurons of the pulmonary parasympathetic nervous system, endothelial cells, chondrocytes, alveolar macrophages, and smooth muscle cells. In tumors, AM expression was located in most of the nonsmall cell lung carcinomas and in half of the small cell lung carcinomas studied. These findings suggest that AM may play a broad role in respiratory homeostasis and lung carcinogenesis.

Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Adrenomedullin; Amino Acid Sequence; Base Sequence; Blotting, Southern; Blotting, Western; Carcinoid Tumor; Carcinoma, Small Cell; DNA, Antisense; Epithelial Cells; Epithelium; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Lung; Lung Neoplasms; Macrophages; Molecular Sequence Data; Muscle, Smooth; Oligonucleotides; Peptides; Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured