transforming-growth-factor-beta and Carcinoid-Tumor

Carcinoid tumors are part of a heterogeneous group of gastrointestinal and pancreatic endocrine tumors that are characterized by their capacity to produce and secrete hormones, 5-hydroxytryptamine, tachykinins and other mediators. These substances are thought to be responsible for the collection of symptoms, which include diarrhea, flushing and wheezing, that is known as carcinoid syndrome. Fibrosis that occurs either local to or distant from the primary tumor is one of the hallmarks of carcinoid tumors that originate from the midgut. The fibrotic process can occur in the mesentery as a desmoplastic response and may lead to obstruction of the small bowel, but it can also occur in the lungs, skin or retroperitoneum. Importantly, up to one-third of patients develop cardiac valvulopathy. One or more products that are secreted by the tumor and enter into the circulation are likely to have a role in this process. This Review discusses the incidence and prevalence of fibrosis in carcinoid syndrome and explores evidence to date for causative agents, in particular the roles of 5-hydroxytryptamine and elements of the downstream signaling pathway. Improved understanding of the etiology of carcinoid-tumor-related fibrosis may lead to better treatments for this condition than those we currently have.

Topics: Carcinoid Tumor; Fibrosis; Humans; Serotonin; Transforming Growth Factor beta

Topics: Amino Acid Sequence; Animals; Carcinoid Tumor; Cell Differentiation; Cell Division; Extracellular Matrix; Extracellular Matrix Proteins; Humans; Models, Structural; Molecular Sequence Data; Protein Conformation; Transforming Growth Factor beta

TGF beta 1 commonly produced by normal and neoplastic human cells, has capacity to regulate new blood vessel formation, to establish and maintain the vessel wall integrity; was found to have some significance in the lung cancer prognosis. Tumour angiogenesis is an important factor for tumour growth and metastasis. The purpose of this study was to find, if the immunoexpression of TGF beta 1 has any significance in determination of the histologic subtypes of carcinoids?; to find, if TGF beta 1 has any role and relation to carcinoids angiogenesis?; and to explore TGF beta 1 expression and angiogenesis with respect to metastatic potential of carcinoids. The study was performed on 48 resected broncho-pulmonary carcinoids: 35 typical (TC) and 13 atypical (AC), classified according to the WHO. Semiquantitative analysis for TGF beta 1 was performed. Sections stained using monoclonal antibody against TGF beta 1 were scored in scale from 0 to 4, according to the percentage of positively stained cells (pc) plus percentage of positively stained stroma (ps). The microvessels stained with CD34 monoclonal antibody, were counted in 0.75 mm2 field (microvessel density--MD), using the computerised image analysis system SAMBA 2005 (the morphometric software). The histologic subtype of carcinoids was related to age of the pts (AC occurred in older pts than TC, p = 0.027), to the tumour size (AC were larger than TC: respectively--3.25 cm and 2.4 cm, p = 0.009). Lymph node metastases were significantly more frequent in AC than in TC (38% vs 13%, p = 0.025). 85% carcinoids showed TGF beta 1 expression with various intensity, mainly in the stroma. There was no significant correlation between TGF beta 1 expression and tumour size, the histologic subtype nor the lymph node metastases. The angiogenesis expressed as MD, was not related to histology, nor to the presence of lymph node metastases. There was no correlation between TGF beta 1 expression and angiogenesis. Shown in our study, lack of relation between TGF beta 1 expression and angiogenesis, could support some of the published data indicating indirect action of TGF beta 1 on the angiogenesis. The rich vascularity found in carcinoids morphology could result from TGF beta 1, commonly expressed by the tumoural stroma. The angiogenesis nor TGF beta 1 expression do not determinate the carcinoids histology.

Topics: Adult; Biomarkers, Tumor; Carcinoid Tumor; Female; Humans; Immunohistochemistry; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neovascularization, Pathologic; Retrospective Studies; Transforming Growth Factor beta; Transforming Growth Factor beta1

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

Studies of growth-regulation of neuroendocrine cells have been hampered by a lack of suitable in vitro models. We established and have maintained a functioning human pancreatic carcinoid cell (BON) line. BON cells synthesize and secrete several growth factors. Among those, we have found that serotonin stimulates growth of BON cells through specific receptors linked to cyclic AMP pathway. In this study, effects of other growth factors on growth and serotonin release, and the effects of serotonin and TGF-beta 1 on the polyamine biosynthetic pathway, were examined. TGF-beta 1 inhibited both growth and serotonin release in a dose-dependent fashion. Basic FGF stimulated growth, but failed to affect serotonin release. Other peptide growth factors had no effect on either growth or serotonin release. Serotonin stimulated ODC enzyme activity, but TGF-beta 1 failed to affect ODC enzyme activity. These findings suggest that growth of neuroendocrine cells can be delicately regulated by their own products in an autocrine fashion.

Topics: Adult; Carcinoid Tumor; Cell Division; Humans; Male; Ornithine Decarboxylase; Pancreatic Neoplasms; Serotonin; Stimulation, Chemical; Transforming Growth Factor beta; Tumor Cells, Cultured

We have shown recently that 5-HT is an autocrine growth stimulatory factor for a cell line (BON) that is derived from a human pancreatic carcinoid tumor. This action is mediated by a 5-HT receptor-linked decrease of cyclic adenosine monophosphate (AMP) production, but not mediated by a 5-HT receptor-linked stimulation of phosphatidylinositol hydrolysis. The BON cells also express transforming growth factor betas (TGF beta s) (1, 2, and 3) and release TGF beta into their medium. In this study, we examined the effects of TGF beta on the secretion of 5-HT, on signal transduction pathways involved in 5-HT secretion, and on growth of BON cells. TGF beta 1 inhibited basal and acetylcholine-stimulated release of 5-HT, but did not inhibit isobutylmethylxanthine-stimulated release of 5-HT. TGF beta 1 inhibited both basal and acetylcholine-stimulated hydrolysis of phosphatidylinositol in a dose dependent manner, but did not affect cyclic AMP production. TGF-beta 1 inhibited growth of BON cells in culture; this effect was reversed by exogenously administered 5-HT. Three different specific and saturable TGF beta 1 binding sites were identified; binding assays performed after mild acid wash (0.1% acetic acid, pH 2.5) conditions uncovered TGF beta receptors that were apparently occupied by endogenously produced TGF beta species. Affinity cross-linking assay showed that BON cells had three different TGF beta binding proteins. These results suggest that TGF beta 1 can inhibit growth of BON cells by altering secretory responses of 5-HT by means of receptor-mediated inhibition of phosphatidylinositol hydrolysis. We conclude that growth of BON cells is regulated, at least in part, by the opposing receptor-mediated autocrine actions of 5-HT and TGF beta.

Topics: Affinity Labels; Carcinoid Tumor; Cell Division; Cyclic AMP; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Male; Pancreatic Neoplasms; Phosphatidylinositols; Receptors, Cell Surface; Receptors, Transforming Growth Factor beta; Serotonin; Signal Transduction; Transforming Growth Factor beta; Tumor Cells, Cultured

Neuroendocrine tumors of the digestive system are slow growing neoplasms which often present with pronounced fibrosis around tumor cells and in the peritoneal cavity. In this report 30 midgut carcinoids and endocrine pancreatic tumors were examined for the expression of peptide growth factors and their receptors, both by immunohistochemistry and in situ hybridization. Our data indicate that multiple peptide growth factors, PDGF, TGF-beta, and bFGF are expressed by these tumors. PDGF was expressed on tumor cells and stroma in 70% of tissues examined. PDGF alpha-receptor was seen on clusters of tumor cells and occasionally on adjacent stroma, whereas PDGF beta-receptor was seen only in the stroma. Our data suggest that PDGF may be involved in the autocrine stimulation of tumor cells and stimulation of stromal cell growth through paracrine and possibly autocrine mechanism. In addition, tumor tissues express all three isoforms of TGF-beta in more than half of the tissues examined. Tumor cells produce small latent complexes causing an escape from potent inhibitory effect of TGF-beta and stimulation of stromal cell growth and matrix deposition through paracrine mechanism. bFGF, a potent stimulant of endothelial cell growth, was expressed by all tumor tissues examined. Our data suggest that multiple peptide growth factors may have an important role in tumor progression and desmoplastic reaction accompanying these tumors.

Topics: Adenoma, Islet Cell; Adolescent; Adult; Aged; Aged, 80 and over; Animals; Carcinoid Tumor; Digestive System Neoplasms; Fibroblast Growth Factor 2; Growth Substances; Humans; Immunohistochemistry; Mice; Middle Aged; Neoplasm Proteins; Pancreatic Neoplasms; Peptide Biosynthesis; Peptides; Platelet-Derived Growth Factor; Rabbits; Receptors, Platelet-Derived Growth Factor; Receptors, Somatotropin; Transforming Growth Factor beta

Advanced gastrointestinal endocrine tumors respond poorly to conventional chemotherapy. In this study we examined the effects of two agents that promote cellular differentiation, sodium butyrate and hexamethylene bisacetamide, on the in vitro growth and secretory responses of a human pancreatic carcinoid (BON) and human gastrinoma (PT-2 and PT-SM) cell lines that have been established in our laboratory. We found that both sodium butyrate and hexamethylene bisacetamide strongly inhibited growth of BON, PT-2, and PT-SM cells. With continuous exposure of BON cells to sodium butyrate (2 mmol/L), the doubling time was prolonged, from 60 hours in controls to 156 hours, and saturation density was reduced to 28% that of controls. Hexamethylene bisacetamide (4 mmol/L) reduced saturation density to 37% that of controls in BON cells and prolonged the doubling time, from 60 hours to 103 hours. Antiproliferative effects of similar magnitudes were observed in the gastrinoma cell lines. In contrast, differential effects were produced on amine biosynthesis in BON cells; sodium butyrate stimulated levels of 5-hydroxytryptamine in the cells, whereas hexamethylene bisacetamide caused a profound dose-dependent inhibition of amine biosynthesis. The significant antiproliferative activity of sodium butyrate and hexamethylene bisacetamide and the inhibitory effects of hexamethylene bisacetamide on amine biosynthesis warrant evaluation of these agents or analogues for treatment of metastatic carcinoid and gastrinoma.

Topics: 5-Hydroxytryptophan; Acetamides; Analysis of Variance; Butyrates; Butyric Acid; Carcinoid Tumor; Cell Division; Gastrinoma; Humans; Hydroxyindoleacetic Acid; Pancreatic Neoplasms; Serotonin; Transforming Growth Factor beta; 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