epidermal-growth-factor and Carcinoid-Tumor

Capillaries expressing the laminin alpha2 chain in basement membranes may be considered early developing vessels in normal and neoplastic human tissues. Therefore, we investigated whether up-regulation of this extracellular matrix protein favors transendothelial migration of neoplastic cells and then metastasis. In lung small and large cell neuroendocrine carcinomas, which exhibit a stronger metastatic tendency among carcinomas, laminin alpha2 chain-positive vessels were more numerous than in carcinoid tumors and supraglottis, breast, and lung non-small cell carcinomas, suggesting a direct relationship between these vessels and metastasis. In vitro studies showed that epidermal growth factor (EGF) induced a more efficient migration of the AE-2 lung neuroendocrine carcinoma cell line through the purified laminin alpha2 chain rather than through the laminin beta1 chain and fibronectin. AE-2 cells constitutively expressed all EGF receptors and the alpha6beta1 integrin, which is one of the laminin alpha2 chain receptors. EGF up-regulated alpha6beta1 expression in several tumors. In this regard, we show that EGF increased the chemo-kinetic migration of AE-2 cells through EAHY endothelial monolayers, which was inhibited by the anti-alpha6 integrin chain monoclonal antibody. These data indicate that laminin alpha2 chain and alpha6beta1 may be mutually involved in EGF-dependent migration of AE-2 cells and that laminin alpha2 chain-positive vessels may favor metastasis of EGF-dependent tumors.

Topics: Antibodies, Monoclonal; Capillaries; Carcinoid Tumor; Carcinoma, Neuroendocrine; Cell Line, Tumor; Cell Movement; Epidermal Growth Factor; Gene Expression; Humans; Laminin; Lung Neoplasms; Models, Biological; Neoplasm Invasiveness; Neoplasm Metastasis; Up-Regulation

Gastric carcinoids evolved from enterochromaffin-like (ECL) cell hyperplasia are usually associated with high pH and hypergastrinemia. The Mastomys species exhibits a genetic propensity to gastric carcinoid formation that can be accelerated by acid inhibition-induced hypergastrinemia. Although gastrin is critical in the initiation of the ECL cell transformation, the role of other growth factors involved in the evolution of the tumor autonomy has not been established. The aim of this study was to evaluate the role of transforming growth factor (TGF) alpha in the regulation of ECL cell transformation.. Mastomys were orally administered an irreversible H2-receptor antagonist loxtidine for 0, 8, and 16 weeks, and ECL cell transformation was monitored by assessing gastrin levels, mucosal histamine content, and chromogranin immunoreactivity. The ECL cells were purified, and cell proliferation at each stage in response to gastrin and TGF alpha was measured by bromodeoxyuridine uptake. TGF-alpha expression was evaluated by radioimmunoassay and Northern blot, and epidermal growth factor (EGF) receptor expression was determined by Western blot, immunoprecipitation, and immunocytochemistry.. Although the response to gastrin decreased during hypergastrinemia, the proliferative effect of TGF-alpha on ECL cells was specifically amplified during the development of hyperplasia. TGF-alpha and EGF receptor expression increased steadily in the transformed cells.. During low acid-induced hypergastrinemia, the expression of TGF-alpha and EGF receptor may constitute an autocrine regulatory mechanism in ECL cell tumor transformation.

Topics: Animals; Carcinoid Tumor; Cell Division; Cell Transformation, Neoplastic; Cells, Cultured; Enterochromaffin Cells; Epidermal Growth Factor; ErbB Receptors; Gastrins; Histamine; Muridae; Stomach Neoplasms; Transforming Growth Factor alpha

The present paper describes the primary structure, glycosylation and tissue localization of fetal antigen 1 (FA1) isolated from second-trimester human amniotic fluid. FA1 is a single-chained, heterogeneous glycoprotein of 225-262 amino acid residues. FA1 has six well conserved epidermal-growth-factor motifs and contains up to ten O-glycosylation and N-glycosylation sites, six of which are differentially glycosylated. Alignment to the translated sequences of Mus. musculus dlk and human dlk revealed 86% and 99% identity, respectively, to a 259-amino-acid residue overlap, and this high similarity extends with minor corrections to the human adrenal-specific mRNA, pG2 as well. Immunohistochemical analysis demonstrated the presence of FA1 in 10 out of 14 lung tumors containing neuroendocrine elements, and in the placental villi where FA1 was exclusively seen in stromal cells in close contact to the vascular structure. In the pancreas, FA1 co-localized with insulin in the insulin secretory granules of the beta cells within the islets of Langerhans. Our findings suggest that FA1 is synthesized as a membrane anchored protein and released into the circulation after enzymic cleavage, and that circulating FA1 represents the post-translationally modified gene product of human dlk which, in turn, is identical to human adrenal-specific mRNA pG2.

Topics: Amino Acid Sequence; Amniotic Fluid; Animals; Carcinoid Tumor; Epidermal Growth Factor; Female; Glycoproteins; Glycosylation; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Mice; Molecular Sequence Data; Neoplasm Proteins; Neuroendocrine Tumors; Pancreas; Placenta; Pregnancy; Pregnancy Trimester, Second; RNA, Messenger; Sequence Homology, Amino Acid

The regulation of parathyroid hormone-related protein (PTH-rP) mRNA levels and immunoreactive (ir)PTH-rP formation by peptide growth factors, particularly transforming growth factor-beta (TGF-beta) and epidermal growth factor (EGF), in squamous cell carcinomas of gynecologic origin is largely unknown.. PTH-rP mRNA levels were evaluated by Northern analysis in A431 cells (derived from a human vulvar epidermoid carcinoma) and ME-180 cells (derived from a human papillomavirus-infected squamous cell carcinoma of the cervix). PTH-rP protein levels in cell culture media were evaluated using both radioimmunoassay and immunoradiometric assay techniques. These results were compared with those from a lung carcinoid cell line known to produce PTH-rP, namely, NCI-H727 cells.. TGF-beta 1 or EGF treatment caused an increase in the levels of PTH-rP mRNA in A431 cells; these increases in PTH-rP mRNA were detectable after 60 minutes of treatment, were maximal at approximately 4-8 hours, and were approximately additive. Immunoreactive PTH-rP was not detectable (using two different PTH-rP immunoassays) in the culture medium or cell sonicates of A431 cells before or after treatment with TGF-beta 1, EGF, or TGF-beta 1 plus EGF. ME-180 cells responded to EGF (but not to TGF-beta 1) with an increase in the level of PTH-rP mRNA as early as 2 hours; irPTH-rP was present (by use of either immunoassay) in the medium of these cells at 8 and 24 hours. In NCI-H727 (human lung carcinoid) cells, TGF-beta 1 and EGF acted alone and synergistically to effect increases in PTH-rP mRNA and the accumulation of irPTH-rP.. TGF-beta 1 and EGF regulation of PTH-rP gene expression in squamous cell carcinomas of gynecologic origin is unique for each cell line studied and different from that in human lung carcinoid cells.

Topics: Base Sequence; Carcinoid Tumor; Carcinoma, Squamous Cell; Epidermal Growth Factor; Female; Gene Expression Regulation, Neoplastic; Genital Neoplasms, Female; Humans; Lung Neoplasms; Molecular Sequence Data; Neoplasm Proteins; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Proteins; RNA, Messenger; Transforming Growth Factor beta; Tumor Cells, Cultured; Uterine Cervical Neoplasms; Vulvar Neoplasms