transforming-growth-factor-alpha and Carcinoid-Tumor

Tissue growth depends on both cell proliferation and cell death. This study was designed to examine the growth characteristics of rectal carcinoid tumors.. Fifty rectal carcinoid tumors were studied clinicopathologically and experimentally. Expression of Ki-67, TGF-alpha, p53, and bcl-2 was examined immunohistochemically, and apoptotic cells were identified by the in situ DNA nick end labeling method. EGF receptor expression was examined by a colorimetric in situ mRNA hybridization technique.. The median Ki-67 labeling index (LI) in all lesions was 0.62 +/- 0.59%. Ki-67 LI was significantly (p < 0.01) higher in lesions larger than 5 mm than in lesions smaller than 5 mm. TGF-alpha was expressed more frequently (p < 0.01) in lesions larger than 5 mm (100%) than in lesions smaller than 5 mm (65.2%). Ki-67 LI was significantly (p < 0. 05) higher in lesions with TGF-alpha expression than in lesions without TGF-alpha expression. The in situ hybridization revealed EGF receptor expression in all 46 lesions with intact mRNA (100%), and coexpression of TGF-alpha and EGF receptor was found in 39 of the 46 (84.8%) lesions. The median apoptotic index (AI) in all lesions was 0.15 +/- 0.12%. AI has increased with tumor size and was significantly (p < 0.05) higher in lesions with a higher Ki-67 LI than in lesions with a lower Ki-67 LI. p53 protein was detected in only 1 patient who had liver metastases, and the gene mutation was confirmed by polymerase chain reaction and single-strand conformation polymorphism analysis. bcl-2 expression was absent in all lesions.. The Ki-67 LI indicated a low cellular proliferative activity in rectal carcinoid tumors. AI was very low, and was significantly correlated with proliferative rate. Inhibition of apoptosis by mutated p53 or bcl-2 may not have occurred in most of these tumors. TGF-alpha/EGF receptor autocrine mechanisms may play a possible role in tumor growth, and the cellular proliferative activity may increase as tumors grow larger.

Topics: Apoptosis; Carcinoid Tumor; Cell Division; ErbB Receptors; Genes, p53; Humans; In Situ Hybridization; Ki-67 Antigen; Neoplasm Metastasis; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Prognosis; Proto-Oncogene Proteins c-bcl-2; Rectal Neoplasms; Transforming Growth Factor alpha; Tumor Suppressor Protein p53

Ovarian metastatic carcinoids are rare neoplasms that show prominent fibrosis of tumor stroma and are often associated with peritoneal carcinomatosis. We studied formalin-fixed and paraffin-embedded tumor specimens of 2 cases of ovarian metastases from ileal enterochromaffin cell carcinoids immunohistochemically to evaluate whether acidic fibroblast growth factor (aFGF), transforming growth factor-alpha (TGFalpha), and their respective receptors (fibroblast growth factor receptor-4 [FGFR4] and epidermal growth factor receptor [EGFR]) may play a role in the pathogenesis of stromal fibroblast reaction and in the mechanism of tumor dissemination.. In both cases, the majority of tumor cells expressed immunoreactivity for aFGF, FGFR4, and TGFalpha. Immunoreactivity for FGFR4 was detected in stromal cells of both cases, while EGFR-positive stromal cells were found in only 1 case. Immunoreactivity for FGFR4 was also found in peritoneal mesothelial cells.. The coexpression of aFGF and FGFR4 in neoplastic enterochromaffin cells suggests that aFGF may act as an autocrine factor stimulating tumor cell growth. In addition, aFGF and TGFalpha may stimulate, in a paracrine fashion, the proliferation of FGFR4- and EGFR-immunoreactive stromal fibroblasts. Finally, interaction of aFGF-immunoreactive enterochromaffin cells with FGFR4-bearing mesothelial cells may play a role in the mechanism of serosal implant and spread of tumor cells.

Topics: Aged; Carcinoid Tumor; Female; Fibroblast Growth Factor 1; Fibroblast Growth Factors; Growth Substances; Humans; Ileal Neoplasms; Immunohistochemistry; Ovarian Neoplasms; Receptor, Fibroblast Growth Factor, Type 4; Receptors, Fibroblast Growth Factor; Receptors, Growth Factor; Transforming Growth Factor alpha

Transforming growth factor-alpha (TGF-alpha), a potent growth factor belonging to the epidermal growth factor family, exerts its role in the proliferation and differentiation of normal and neoplastic cells by binding to epidermal growth factor receptor (EGFR). Coexpression of TGF-alpha and EGFR in carcinomas is believed to confer growth advantage to tumor cells. To evaluate their role in such indolent tumors as gastrointestinal (GI) carcinoids, we investigated the immunohistochemical expression of TGF-alpha and EGFR in 25 GI carcinoids (nine foregut, 13 midgut, and three hindgut) and studied the correlation of their expression with the secretory and clinicopathologic profiles of these tumors. TGF-alpha was expressed in 18 (72%) of these tumors, and whereas 16 of 17 tumors showed immunopositivity for the extracellular domain of EGFR, none expressed its intracellular domain. Ten TGF-alpha-positive tumors were positive for serotonin, seven for somatostatin, three for calcitonin, and one tumor each for gastrin, glucagon, pancreatic polypeptide, vasoactive intestinal peptide, and growth hormone-releasing factor, respectively. Seven TGF-alpha-positive tumors were multihormonal, eight were monohormonal, and three were completely nonreactive for the regulatory substances studied. Except for its correlation with 5-hydroxytryptamine (serotonin) expression by the tumor cells, expression of TGF-alpha showed no significant association with other pathologic attributes, for example, the site of origin, size, depth of intramural penetration, metastases, and the secretory profiles of the tumors. These findings indicate that although TGF-alpha is expressed by a high proportion of GI carcinoids, the absence of its intact receptor molecule (EGFR) on the tumor cells renders it functionally ineffective as a growth factor. Thus, unlike in carcinomas of the GI tract, TGF-alpha appears to play no role in the growth and progression of GI carcinoids, which perhaps explains the indolent behavior and slow biological progression of GI carcinoids.

Topics: Amino Acid Sequence; Carcinoid Tumor; ErbB Receptors; Gastrointestinal Neoplasms; Humans; Immunohistochemistry; Molecular Sequence Data; Retrospective Studies; Transforming Growth Factor alpha

Carcinoid tumors of the gastrointestinal tract are known to be associated with fibrosis and vascular elastosis, either within the tumor or at distant sites. The current report describes prominent vascular proliferation in the villi extending 38 cm proximal and 15 cm distal to an ileal carcinoid tumor. These villi were expanded by vessels, producing a segmental carpet of multiple small polypoid protrusions around the tumor. Immunohistochemical analysis suggested that the major stromal components were of endothelial and myofibroblastic cell origin. The stroma of the tumor itself had minimal fibrosis and vascularity. To our knowledge, this is the first description of vascular proliferation in the vicinity but distinct from a carcinoid tumor. The demonstration of transforming growth factor-alpha (TGF-alpha) synthesis by tumor cells supports the possibility of a field effect by angiogenic factor(s) secreted by the tumor.

Topics: Actins; Aged; Biomarkers; Carcinoid Tumor; Factor VIII; Female; Humans; Ileal Neoplasms; Immunohistochemistry; Intestinal Mucosa; Neovascularization, Pathologic; Transforming Growth Factor alpha

The genesis of human gastric carcinoma is ill understood but is invariably related to achlorhydria. Gastrin secretion is negatively regulated by luminal acid and hypergastrinaemia is thus associated with low acid states which may be natural (atrophic gastritis) or owing to acid inhibitory therapy. Apart from its acid secretory activity, gastrin is trophic to the mucosa, via stimulation of the fundic enterochromaffin-like (ECL) cells to secrete histamine. In conditions of elevated gastrin levels, ECL cell hyperplasia and even neoplasia have been noted. The relationship between low acid, hypergastrinaemia, ECL cell hyperplasia, and neoplasia may be of relevance since ECL cells secrete histamine and TGF alpha which are both recognised mitogens. We studied the rodent mastomys, which spontaneously develop gastric carcinoid tumours, which can be generated in 4 months under conditions of drug-induced acid inhibition and inhibited by octreotide administration. A pure (90-95%) cell preparation was used to evaluate ECL cell physiology and trophic regulation. A gastrin/CCKB receptor responsible for histamine secretion and DNA synthesis was identified, cloned and sequenced. Octreotide lowers plasma gastrin levels, decreases ECL cell neoplasia and, in vitro, inhibits ECL cell DNA synthesis. H1 receptor antagonists inhibited DNA synthesis in vitro and ECL neoplasia in vivo without altering gastrin levels. Hypergastrinaemia increased TGF alpha/EGF receptor and TGF alpha production and TGF alpha massively stimulated ECL cell DNA synthesis. Since ECL cells produce both histamine and TGF alpha and regulate parietal cells which produce TGF alpha, it is possible that achlorhydria-generated ECL cell dysfunction may play an initiative role in the pathobiology of gastric adenocarcinoma. The long-term clinical consequences of drug-induced sustained acid inhibition are worthy of further consideration.

Topics: Animals; Base Sequence; Carcinoid Tumor; Cell Transformation, Neoplastic; DNA; DNA, Neoplasm; Enterochromaffin Cells; Gastrins; Histamine Release; Molecular Sequence Data; Polymerase Chain Reaction; Rats; Receptors, Cholecystokinin; Stomach Neoplasms; Transforming Growth Factor alpha; Tumor Cells, Cultured

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

Transforming growth-factor-alpha (TGF-alpha) is a 50-amino-acid polypeptide that binds to the epidermal growth factor (EGF) receptor and stimulates cell growth. It has been suggested that enhanced production of TGF-alpha and EGF receptors by tumour cells promote tumour-cell growth by autocrine mechanisms. In the present study we have investigated the expression of TGF-alpha and EGF receptors in human neuroendocrine tumours, including midgut carcinoid tumours, phaeochromocytomas and medullary thyroid carcinomas. TGF-alpha expression was demonstrated in biopsies of all tumours examined (n = 30) and EGF receptors in a majority of tumours by Northern analysis and/or immunocytochemistry. Expression of TGF-alpha and EGF receptors was also demonstrated in primary cultures of tumour cells. Carcinoid tumours and phaeochromocytomas in culture secreted detectable amounts of TGF-alpha into the culture medium (400-700 pM). The amount of secreted TGF-alpha could be suppressed by octreotide treatment in individual tumours. Administration of exogenous TGF-alpha stimulated carcinoid tumour growth in vitro as determined by the DNA contents of cell cultures. The growth-stimulatory effect of TGF-alpha could be partially blocked by the use of neutralizing anti-EGF receptor monoclonal antibodies (MAbs). In conclusion, several human neuroendocrine tumours express both TGF-alpha and EGF receptors in in vivo and in vitro, suggesting that TGF-alpha may regulate tumour-cell growth by autocrine mechanisms.

Topics: Adrenal Gland Neoplasms; Aged; Antibodies, Monoclonal; Autoreceptors; Carcinoid Tumor; Carcinoma, Medullary; Cell Division; DNA, Neoplasm; ErbB Receptors; Female; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Proteins; Neuroendocrine Tumors; Paraganglioma; Pheochromocytoma; Retroperitoneal Neoplasms; RNA, Messenger; RNA, Neoplasm; Thyroid Neoplasms; Transforming Growth Factor alpha; Tumor Cells, Cultured

A serotonin-secreting human pancreatic carcinoid cell line (BON) is demonstrated to express transcripts for all three mammalian types of transforming growth factor beta (TGF beta 1, 2, and 3). Similarly, freshly excised carcinoid tumors from six patients were also found to express mRNA for all three of the type-beta TGFs. Medium conditioned by BON cells had detectable TGF beta activity, although most of the activity was latent as determined by radioreceptor assay with and without prior acid treatment. However, nonactivated BON-conditioned medium stimulated DNA synthesis, soft agar growth, and an increase in TGF beta 1 and fibronectin mRNA expression in AKR-2B fibroblasts. In addition, BON-conditioned medium had a potent endothelial cell growth-stimulatory activity. Since the TGF beta s inhibit growth of endothelial cells, the presence of other growth factors was suspected. TGF alpha, c-sis, and basic fibroblast growth factor transcripts were also found to be expressed by the BON carcinoid cells. These data indicate that multiple peptide growth factors may have a paracrine role in the desmoplastic reaction accompanying carcinoid tumors.

Topics: Amino Acid Isomerases; Blotting, Northern; Carcinoid Tumor; Carrier Proteins; Cell Division; DNA; Dose-Response Relationship, Drug; Endothelium; Fibroblasts; Fibronectins; Growth Substances; Humans; Insulin; Pancreatic Neoplasms; Peptidylprolyl Isomerase; Procollagen; RNA, Messenger; Time Factors; Transcription, Genetic; Transforming Growth Factor alpha; Transforming Growth Factor beta