transforming-growth-factor-alpha and Adenoma

Transforming growth factor alpha (TGFα) and TGFβ1 are growth-promoting and -inhibiting autocrine/paracrine growth factors, respectively, that may (1) affect risk for colorectal cancer and (2) be modifiable by anti-proliferative exposures. The effects of supplemental calcium and vitamin D3 on these two markers in the normal-appearing colorectal mucosa in humans are unknown. We conducted a pilot, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial (n = 92; 23/treatment group) of calcium 2 g and/or vitamin D3 800 IU/d versus placebo over 6 mo. TGFα and TGFβ1 expression was measured in biopsies of normal-appearing rectal mucosa using automated immunohistochemistry and quantitative image analysis at baseline and 6-mo follow-up. In the calcium, vitamin D3 , and calcium plus vitamin D3 groups relative to the placebo group (1) the mean overall expression of TGFβ1 increased by 14% (P= 0.25), 19% (P = 0.17), and 22% (P = 0.09); (2) the ratio of TGFα expression in the upper 40% (differentiation zone) to that in the lower 60 (proliferation zone) of the crypts decreased by 34% (P = 0.11), 31% (P = 0.22), and 26% (P = 0.33); and (3) the TGFα/TGFβ1 ratio in the upper 40% of the crypts decreased by 28% (P = 0.09), 14% (P = 0.41), and 22% (P = 0.24), respectively. These preliminary results, although not statistically significant, suggest that supplemental calcium and vitamin D3 may increase TGFβ1 expression and shift TGFα expression downward from the differentiation to the proliferation zone in the crypts in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, and support further investigation in a larger clinical trial.

Topics: Adenoma; Aged; Anticarcinogenic Agents; Calcium, Dietary; Cholecalciferol; Colorectal Neoplasms; Dietary Supplements; Double-Blind Method; Female; Humans; Immunohistochemistry; Intestinal Mucosa; Male; Middle Aged; Rectum; Transforming Growth Factor alpha; Transforming Growth Factor beta1; Transforming Growth Factors

Adrenocorticotrophin (ACTH)-secreting pituitary adenomas account for approximately 7% - 14% of all pituitary adenomas, but its pathogenesis is still enigmatic. This study aimed to explore mechanisms underlying the pathogenesis of ACTH-secreting pituitary adenomas.. We used fiber-optic beadarray to examine gene expression in three ACTH-secreting adenomas compared with three normal pituitaries. Four differentially expressed genes from the three ACTH-secreting adenomas and three normal pituitaries were chosen randomly for validation by reverse transcriptase-real time quantitative polymerase chain reaction (RT-qPCR). We then analyzed the differentially expressed gene profile with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway.. Fiber-optic beadarray analysis showed that the expression of 28 genes and 8 expressed sequence tags (ESTs) were significantly increased and the expression of 412 genes and 31 ESTs were significantly decreased. Bioinformatic and pathway analysis showed that the genes HIGD1B, EPS8, HPGD, DAPK2, and IGFBP3 and the transforming growth factor (TGF)-β signaling pathway and extracellular matrix (ECM)-receptor interaction pathway may play important roles in tumorigenesis and progression of ACTH-secreting pituitary adenomas.. Our data suggest that numerous aberrantly expressed genes and several pathways are involved in the pathogenesis of ACTH-secreting pituitary adenomas. Fiber-optic beadarray combined with pathway analysis of differential gene expression appears to be a valid method of investigating tumour pathogenesis.

Topics: ACTH-Secreting Pituitary Adenoma; Adenoma; Adult; Disease Progression; Expressed Sequence Tags; Extracellular Matrix Proteins; Female; Fiber Optic Technology; Gene Expression Profiling; Humans; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Transforming Growth Factor alpha

Transforming growth factor-alpha (TGF-alpha), a stimulatory growth factor and member of the epidermal growth factor family, is a mediator of oncogenesis and malignant progression in colorectal carcinogenesis. Limited evidence suggests its utility as a growth-related biomarker of risk for colorectal cancer.. We measured expression of TGF-alpha in biopsies of normal-appearing colorectal mucosa using automated immunohistochemistry and quantitative image analysis in a subsample of 29 cases and 31 controls from a colonoscopy-based case-control study (n = 203) of biomarkers of risk for incident sporadic colorectal adenoma. Diet, lifestyle, and medical history were assessed with validated questionnaires.. TGF-alpha expression in the rectum was 51% higher in cases compared with controls (P = 0.05) and statistically significantly associated with accepted risk factors for colorectal neoplasms (36% lower among nonsteroidal anti-inflammatory drug users, 49% lower among women using hormone replacement therapy, 79% higher among persons with a family history of colorectal cancer).. TGF-alpha expression in the normal-appearing rectal mucosa shows promise as an early, potentially modifiable biomarker of risk for colorectal cancer.

Topics: Adenoma; Adult; Aged; Biomarkers, Tumor; Case-Control Studies; Chi-Square Distribution; Colonoscopy; Colorectal Neoplasms; Diet; Female; Humans; Immunohistochemistry; Incidence; Intestinal Mucosa; Male; Middle Aged; Phenotype; Regression Analysis; Risk Factors; Surveys and Questionnaires; Transforming Growth Factor alpha

A role of the epidermal growth factor receptor (EGFR) family has been suggested in colon cancer etiology, progression, and/or severity. Our recently identified pan-erbB inhibitor EGFR-related protein (ERRP) targets EGFRs by attenuating their activation and subsequent signaling leading to cellular growth inhibition. In the present study, we evaluated the therapeutic effectiveness of ERRP on early and intermediate stages of colon cancer by examining regression of chemically induced aberrant crypt foci (ACF) in the colon of CF1 mice and intestinal adenomas in APC(Min+/-) (Min) mice. After formation of ACF or adenomas, the mice were injected (i.p.) with ERRP (50 microg/mouse) for 10 consecutive days. This treatment significantly reduced the number of ACF from 25.0 +/- 3.0 (controls) to 14.9 +/- 1.6 (ERRP-treated; P = 0.011) and also reduced their size (P < 0.01). In Min mice, ERRP caused the regression of adenomas throughout the small intestine (P < 0.05) and reduced their size (P < 0.001). This could partly be attributed to inhibition of proliferation and stimulation of apoptosis in the intestinal mucosa and was associated with decreased activation of several EGFR family members, suppression of downstream effector nuclear factor kappaB and down-regulation of cyclooxygenase-2. ERRP-induced attenuation of EGFR activation could be due to increased sequestration of the ligand(s) by ERRP, rendering them unavailable for binding to and activation of the receptor. In conclusion, our data show that ERRP is effective in regressing both early and intermediate intestinal lesions and could be an effective therapeutic agent for colon cancer.

Topics: 1,2-Dimethylhydrazine; Adenoma; Animals; Apoptosis; Carcinogens; Cell Growth Processes; Colonic Neoplasms; Drosophila Proteins; ErbB Receptors; Female; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; Neoplasm Staging; NF-kappa B; Precancerous Conditions; Receptors, Estrogen; Recombinant Fusion Proteins; Transforming Growth Factor alpha

We investigated the preventive effects of a synthetic acyclic retinoid, NIK-333, on the early and late events of hepatocarcinogenesis in male F344 rats treated with 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB). NIK-333 was administered once a day on consecutive days at a dose of 10, 40, or 80 mg/kg body weight along with the supplementation with 3'-MeDAB-containing diet for 16 wk. Animals from each group were sacrificed at 4 and 16 wk after the commencement of the experiment to determine the effect of NIK-333 on the early and late stages of carcinogenesis, respectively. NIK-333 suppressed the emergence of both oval-like cells expressing transforming growth factor (TGF)-alpha, putative progenitors of hepatocellular carcinoma (HCC), and activated hepatic stellate cells, major matrix-producing cells of the liver, in the early stage and inhibited the incidence of HCC in the late phase. These results suggest that NIK-333 is a promising drug for the chemoprevention of HCC by uniquely suppressing the early events of hepatocarcinogenesis, that is, development of both oval-like cells and fibrogenesis.

Topics: Actins; Adenoma; Animals; Antineoplastic Agents; Carcinoma; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Fibrosis; Liver; Liver Neoplasms, Experimental; Male; Methyldimethylaminoazobenzene; Rats; Rats, Inbred F344; Retinoids; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Transforming Growth Factor alpha; Tretinoin

The activin-follistatin system is a potent growth regulatory system of liver tissue homeostasis. Activin A inhibits hepatocellular DNA synthesis and induces cell death. Follistatin binds activin and sequesters it from the signaling pathway. Consistently, follistatin has been reported to act as an inducer of DNA synthesis in the liver. Using RNase protection analysis, we studied the expression of follistatin in rat and mouse liver tumors as a possible mechanism to overcome activin growth control. Approximately 40% of the tumors (nine of 24 each), most of them hepatocellular carcinomas, displayed increased levels of follistatin mRNA when compared to tumor-surrounding liver tissue. The degree of overexpression was highly variable but independent of the carcinogen treatment that animals had received. It was also independent from the histological stage of malignancy and further found in rat liver adenomas. Follistatin expression was also observed in cell lines derived from human hepatocellular carcinomas. Overexpression of follistatin may represent a unique strategy of hepatic tumors to overcome the inhibitory action of a growth factor, activin, by decreasing its local bioavailability.

Topics: Activins; Adenoma; Alternative Splicing; Animals; Blotting, Western; Carcinoma, Hepatocellular; Cell Division; Diethylnitrosamine; Follistatin; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Male; Mice; Mice, Inbred Strains; Nafenopin; Phenobarbital; Rats; Reference Values; RNA, Messenger; Transforming Growth Factor alpha; Tumor Cells, Cultured

LT97, a permanent cell line consisting of epithelial cells with an early premalignant genotype was established from small colorectal polyps. LT97 cells have lost both alleles of the APC tumour suppressor gene. In addition, they carry a mutated Ki-ras oncogene, while TP53 is normal. LT97 growth characteristics are thus representative of early adenomas. They had to be passaged as multicellular aggregates indicating a dependency of survival on cell-cell contact and in accordance with their premalignant genotype were not capable of growth in soft agar. LT97 cells did express both the EGF-receptor and small amounts of TGF(alpha) establishing an autocrine growth or survival pathway. However, in spite of autocrine TGF(alpha) production, growth was strongly dependent on exogenous growth factors--mainly EGF, insulin and HGF. Inhibition of the EGF-receptor kinase induced apoptosis at an IC(50) concentration of 4 micromolar indicating that TGF(alpha) activated survival pathways in the early adenoma cell.

Topics: Adenoma; Apoptosis; Cell Division; Colonic Neoplasms; Flow Cytometry; Genes, ras; Humans; Mutation; Precancerous Conditions; Transforming Growth Factor alpha; Tumor Cells, Cultured

Angiogenesis, the formation of a new blood supply, is an essential step in tumorigenesis. Although vascular endothelial growth factor (VEGF) is known to be a very potent angiogenic factor in most solid tumors, little is known about its production and regulation in pituitary adenomas. We have investigated basal and stimulated VEGF production by rodent pituitary tumor cells (mouse corticotrope AtT20, rat lactosomatotrope GH3, mouse gonadotrope alpha T3-1 and mouse folliculostellate TtT/GF cells), and by hormone-inactive (27), corticotrope (9), lactotrope (3) and somatotrope (21) human pituitary adenoma cell cultures. All 4 pituitary cell lines secreted VEGF, which in the case of AtT20, GH3 and TtT/GF cells was inhibited by approximately 50% by dexamethasone. TtT/GF cells were the most responsive to the different stimuli used since basal values were augmented by pituitary adenylate cyclase activating polypeptide-38 (PACAP-38), interleukin-6 (IL-6), transforming growth factor-alpha (TGF-alpha), IGF-I and the somatostatin analogue ocreotide. However, in GH3, AtT20 and alpha T3-1 cells, basal VEGF levels where not enhanced with any of the stimuli tested. The majority of the human adenomas tested (92%) basally secreted measurable VEGF which was inhibited by dexamethasone in most cases (84%). VEGF levels were increased in hormone inactive adenomas, somatotrope tumors and prolactinomas by TGF-alpha, PACAP-38, and 17 beta-estradiol, respectively. In conclusion, pituitary tumor cells are capable of producing VEGF which may be involved in tumoral angiogenesis. Our results concerning the suppression of VEGF by dexamethasone suggest that glucocorticoids may have anti-angiogenic properties and therefore therapeutic relevance for the treatment of pituitary adenomas.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Animals; Dexamethasone; Endothelial Growth Factors; Estradiol; Female; Humans; Lymphokines; Male; Mice; Middle Aged; Neovascularization, Pathologic; Neuropeptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Pituitary Neoplasms; Rats; Rodentia; Somatostatin; Transforming Growth Factor alpha; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Twenty-seven plurihormonal and 21 growth hormone- prolactin- (GH- PRL-) mixed cell adenomas obtained from patients with acromegaly undergoing transnasal-transsphenoidal surgery were investigated immunohistochemically for expression of Epidermal Growth Factor (EGF), Transforming Growth Factor alpha (TGF alpha), Insulin-like Growth Factor-1 (IGF-1), Estrogen Receptor-Related Protein (ERRP), Multidrug Resistance Marker (MDRM), Protein Kinase C (PKC), Gs alpha,. Cathepsin D and p53. Five plurihormonal adenomas grew invasively. The panel of markers used in this study represents a selection of functional and proliferative markers thought to be associated with the function and development of pituitary adenomas. Our results imply that the growth factors (EGF, TGF alpha, IGF-1), the cell signalling protein Gs alpha and the MDRM are expressed by both types of pituitary adenomas in a similar pattern. Non-invasive GH-PRL-mixed cell adenomas showed an increased expression of IGF-1, TGF alpha and MDRM compared to non-invasive plurihormonal adenomas. No factor was found which would reliably distinguish between invasive and non-invasive adenomas. We failed to confirm the findings of others that p53 and cathepsin D might be indicators of tumor aggressiveness. A participation of ERRP and PKC in the development of bi- and plurihormonal adenomas with acromegaly appears unlikely, as the immunostains were all negative.

Topics: Acromegaly; Adenoma; Adult; Aged; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biomarkers, Tumor; Cathepsins; Cell Count; Epidermal Growth Factor; Female; Growth Hormone; GTP-Binding Protein alpha Subunits, Gs; Humans; Immunoenzyme Techniques; Insulin-Like Growth Factor I; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Transforming Growth Factor alpha

Transforming growth factor alpha (TGF-alpha), a protein structurally similar to epidermal growth factor (EGF), is implicated in the development of many human tumours. This study examines the expression of TGF-alpha in gallbladder and extrahepatic biliary tract tumours in which EGFR expression has been previously shown to be important.. A monoclonal antibody to the TGF-alpha protein was used to investigate the immunohistochemical expression of TGF-alpha in carcinoma of the gallbladder (n = 13), common bile duct (CBD) (n = 6) and ampulla of Vater (n = 8). Tissues from cases of chronic cholecystitis (n = 11), gallbladder dysplasia (n = 3) and adenoma (n = 1), and ampullary carcinoma in situ (CIS) (n = 3) were used as non-malignant controls. These cases were previously studied for EGFR expression.. TGF-alpha overexpression, defined as intense immunoreactivity in more than two-thirds of cells immunostained for TGF-alpha, was present in most gallbladder carcinomas (n = 10; 77%) but with no significant differences in expression between different tumour grades. None of the cases of gallbladder dysplasia or chronic cholecystitis had strong TGF-alpha expression and this was significantly different from the carcinomas (P = 0.013 and P = 0.0001, respectively; chi 2 test), although a few cases of chronic cholecystitis showed weak (n = 4), moderate (n = 6) or no (n = 1) immunoreactivity. A few ampullary carcinomas (n = 2; 25%) and CIS (n = 1; 33%), and half of the CBD carcinomas (50%) had strong TGF-alpha immunoreactivity. There was correlation between TGF-alpha and EGFR immunoreactivity in the tumour cases (r = 0.70, r2 = 0.49, P = 0.0001; simple regression analysis), although the rate of EGFR immunoreactivity in CBD and ampullary carcinomas was somewhat higher than that of TGF-alpha. However, no statistically significant correlation between TGF-alpha expression with patient survival or tumour recurrence (r = 0.11, r2 = 0.012, P = 0.65; simple regression analysis) was found.. Increased TGF-alpha expression occurs more frequently in gallbladder carcinoma than in gallbladder dysplasia, chronic cholecystitis, CBD or ampullary tumour, with no specific relationship to tumour grade, suggesting that TGF-alpha overexpression occurs early in the development of gallbladder cancers, and that biliary tract cancers have a different molecular origin. Correlation was found between TGF-alpha and EFGR expression in gallbladder and biliary tract tumours.

Topics: Adenocarcinoma; Adenoma; Bile Duct Neoplasms; Carcinoma; Cholecystitis; Chronic Disease; Gallbladder Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; Transforming Growth Factor alpha

We have previously demonstrated in short-term experiments that altered hepatocytes in liver acini draining the blood from intraportally transplanted pancreatic islets in streptozotocin-induced diabetic rats with mild persisting diabetes resemble those in preneoplastic foci of altered hepatocytes. We now present the results of long-term studies (up to 22 months) in this animal model. Glycogen-storing foci (which were the first parenchymal alteration observed some days after transplantation) persisted at least for 6 months, when the first mixed-cell foci and the first hepatocellular adenoma emerged. After 15 to 22 months, 86% of the animals exhibited at least one hepatocellular adenoma and four animals (19%) showed a hepatocellular carcinoma. The transplants were found in a close spatial relationship with the preneoplastic foci and the hepatocellular neoplasms. The mitotic indices, the 5-bromo-2'-desoxyuridine labeling indices and the apoptotic indices showed significant differences between the unaltered liver parenchyma, different types of preneoplastic foci, and hepatocellular neoplasms. The immunohistochemical expression of transforming growth factor-alpha increased during the stepwise development from glycogen-storing liver acini to hepatocellular carcinomas. Hepatocarcinogenesis in this new animal model is probably due to the hormonal and growth-stimulating effects of insulin secreted by the intraportally transplanted islets of Langerhans in diabetic rats.

Topics: Adenoma; Animals; Blood Glucose; Body Weight; Carcinoma, Hepatocellular; Case-Control Studies; Cause of Death; Cytoplasm; Diabetes Mellitus, Type 2; Endoplasmic Reticulum; Immunohistochemistry; Islets of Langerhans Transplantation; Liver Neoplasms, Experimental; Male; Microscopy, Electron; Neoplasm Staging; Precancerous Conditions; Rats; Rats, Inbred Lew; Streptozocin; Transforming Growth Factor alpha

Detection of apoptotic cells and of immunoreactivity to transforming growth factor alpha (TGF-alpha) and to its ligand, epidermal growth factor receptor (EGFR), was studied in 20 cases of parathyroid adenoma. The DNA nick-end labelling method revealed that 85% of these adenomas contained apoptotic cells. Detection rates of TGF-alpha and EGFR were very high, but neither TGF-alpha nor EGFR was correlated to apoptosis. As TGF-alpha exerts its effect via EGFR, the concomitant demonstration of the two factors occurring in both the adenomatous tissue and the surrounding rim of normal tissue may reflect a significant mutual association. The markers were located mainly within the cytoplasm, indicating their important role in growth regulation, cell differentiation and cell function. The synchronous expression of TGF-alpha and EGFR in both parathyroid adenomas and normal glandular parenchyma suggests that these functions may be mediated by an autocrine mechanism.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Apoptosis; Data Interpretation, Statistical; ErbB Receptors; Female; Growth Substances; Humans; Immunohistochemistry; Male; Middle Aged; Parathyroid Neoplasms; Transforming Growth Factor alpha

Transforming growth factor-alpha (TGF alpha) is a positive growth regulator in epithelial cells, including hepatocytes. Overexpression of TGF alpha has been associated with increased growth and malignancy of end-stage cancers in humans and rodents. The overall aim of this study was to characterize TGF alpha staining in diethylnitrosamine-induced hepatic foci from male F344 rats with the hematoxylin and eosin (H and E) histological phenotype. The association between the individual focal DNA synthesis labeling index and the presence of TGF alpha was also examined. Hepatic foci were identified as eosinophilic, basophilic, clear cell, or mixed cell. Of these foci, 37.5% labeled positive for TGF alpha. There were distinct differences in the pattern of TGF alpha labeling between the different H and E histological phenotypes. Intense, uniform TGF alpha labeling was observed in eosinophilic foci. Basophilic foci labeled for TGF alpha diffusely uniform throughout the cytoplasm. In clear-cell foci, TGF alpha labeling occurred primarily along the periphery of the cell membrane. In mixed-cell foci, labeling occurred both along the periphery and diffusely throughout the cytoplasm. On those slides stained, glutathione-S-transferase (placental; GSTP) was detected in almost all eosinophilic and mixed-cell foci, whereas approximately half of the basophilic and clear-cell foci stained for GSTP. The presence of GSTP in a focus was not always associated with the presence of increased TGF alpha protein. All rat hepatic adenomas and the one carcinoma labeled positive for TGF alpha. Increased levels of TGF alpha protein were associated with increased DNA synthesis labeling index. The number of TGF alpha-positive foci with the highest DNA synthesis labeling indices were statistically higher than those with lower levels of DNA synthesis labeling. Although characteristic staining patterns for TGF alpha were associated with specific histological subtype, the role that TGF alpha plays in the progression of focal lesions to neoplasia requires further definition. High levels of TGF alpha protein appear to be acquired sometime during the hepatocarcinogenic process. It may be that early lesions that acquire high levels of TGF alpha are the ones to develop into hepatocellular carcinoma (e.g., hepatocellular carcinoma is determined very early in the carcinogenic process). It is apparent that further work is needed to delineate the role of TGF alpha in both rodent and human hepatocarcinoge

Topics: Adenoma; Animals; Carcinoma; Coloring Agents; Diethylnitrosamine; DNA; Glutathione Transferase; Immunohistochemistry; Liver; Liver Neoplasms, Experimental; Male; Phenotype; Rats; Rats, Inbred F344; Time Factors; Transforming Growth Factor alpha

Transforming growth factor (TGF)-alpha stimulates the growth and development of mammary epithelial cells and is implicated in the pathogenesis of human breast cancer. In this report we evaluate the consequences of overexpressing TGF-alpha in the mammary gland of transgenic mice and examine associated cellular mechanisms. When operating on a FVB/N genetic background (line MT100), TGF-alpha induced the stochastic development of mammary adenomas and adenocarcinomas f secretory epithelial origin in 64% of multiparous females. In contrast, tumors were exceedingly rare in virgin MT100 females, MT100 males, and multiparous FVB/N females. In MT100 females multiple foci of hyperplastic secretory lesions preceded the development of frank tumors; these initial lesions appeared during the involution period after the first lactation. Serial transplantation of these hyperplasias indicated an absence of proliferative immortality. Nevertheless, they gave rise to tumors at a low frequency and after a prolonged latency in virgin hosts; in multiparous hosts, tumors developed earlier and at a high incidence. The TGF-alpha transgene was highly expressed in hyperplasias and tumors but not in virgin and nonlesion-bearing tissue, suggesting that TGF-alpha overexpression provides a selective growth advantage. TGF-alpha also induced at lactation a 6.4-fold increase in DNA synthesis in MT100 epithelial cells, many of which were binucleated. MT100 mammary tissue experienced an obvious delay in involution, resulting in the postlactational survival of a significant population of unregressed secretory epithelial cells. In contrast, another line of transgenic mice on a CD-1 genetic background (MT42), in which TGF-alpha overexpression induced liver but not mammary tumors, failed to demonstrate postlactational epithelial cell survival. These data show that TGF-alpha promotes mammary tumorigenesis in multiparous MT100 mice by stimulating secretory epithelial cell proliferation during lactation and prolonging survival during involution. These points support the notion that TGF-alpha can act as a mitogen and also as a differentiation factor in mammary epithelium.

Topics: Adenocarcinoma; Adenoma; Animals; Cell Division; Cell Line; Cell Survival; Epithelium; Female; Gene Expression; Humans; Hyperplasia; Mammary Glands, Animal; Mammary Neoplasms, Animal; Mice; Mice, Transgenic; Precancerous Conditions; Tissue Transplantation; Transforming Growth Factor alpha

Growth factors induce cell proliferation and are implicated in the multistep process of tumorigenesis. Transforming growth factor-alpha (TGF alpha), a peptide that binds to the epidermal growth factor receptor, is expressed by carcinomas and normal tissues. To investigate the possible role of TGF alpha in adenohypophysial tumorigenesis, we studied its expression in nontumorous human pituitary and different clinically and morphologically characterized human pituitary adenomas. Ribonucleic acid was reverse transcribed and amplified by polymerase chain reaction; transcript signals were identified with marked variation in 14 of 15 adenomas, and a weak signal was detected in nontumorous pituitary. Immunohistochemical positivity was found with variable intensity in all adenoma types, but not all tumors. Ultrastructural immunogold localized TGF alpha in endoplasmic reticulum, in Golgi apparatus, and on cell membranes; surface localization was confirmed by immunofluorescence. To assess possible secretion, the reverse hemolytic plaque assay was performed; small plaques were identified using an antibody that recognizes the extracellular domain of pro-TGF alpha; however, the plaques did not increase in size with time, suggesting that they detected membrane-anchored TGF alpha. Moreover, TGF alpha was undetectable by enzyme-linked immunosorbent assay in pituitary tumor-conditioned culture media. The marked variable expression of TGF alpha, the absence of secretion in measurable quantities, and the preferential membrane localization suggest a specific juxtacrine mechanism for TGF alpha in pituitary tumorigenesis.

Topics: Adenoma; Base Sequence; Gene Expression; Hemolytic Plaque Technique; Humans; Immunohistochemistry; Membranes; Molecular Sequence Data; Oligonucleotide Probes; Pituitary Gland; Pituitary Neoplasms; Polymerase Chain Reaction; Transforming Growth Factor alpha; Tumor Cells, Cultured

To determine the role of a specific member of the metalloproteinase family, stromelysin-1, in mammary carcinogenesis and tumor progression, transgenic mice expressing activated rat stromelysin-1 under the control of the mouse mammary tumor virus promoter/enhancer were treated with the carcinogen 7,12-dimethylbenzanthracene (DMBA) to induce mammary tumors. Surprisingly, the expression of stromelysin-1 during the time of DMBA treatment reduced the number of mice developing mammary tumors, in particular adenoacanthomas, from 65 to 32% (P = 0.02). In contrast, when transgenic mice expressing both transforming growth factor alpha and stromelysin-1 under the control of the mouse mammary tumor virus long terminal repeat were treated with DMBA, there was no significant difference in the number of mice that developed tumors compared to transforming growth factor alpha controls. A 4-fold increase in the number of apoptotic cells was detected in stromelysin-1 transgenic mice compared to littermate controls at the time of DMBA administration, suggesting that the reduction in DMBA-induced tumorigenicity is likely to be due, at least in part, to an increased rate of cell turnover in stromelysin-1 transgenic mice. When malignant adenocarcinomas developed in the stromelysin-expressing mice, there was no detectable alteration in the extent of invasion or in the metastatic potential of these tumors compared to tumors from control mice. These results suggest that the expression of a single metalloproteinase, stromelysin-1, is insufficient for the progression of mammary adenocarcinomas to an invasive and metastatic phenotype, but that matrix degradation by metalloproteinases can alter basic processes of cell proliferation and apoptosis.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Adenocarcinoma; Adenoma; Animals; Animals, Suckling; Apoptosis; Cell Division; Female; Lung Neoplasms; Lymphoma; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Matrix Metalloproteinase 3; Metalloendopeptidases; Metaplasia; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Neoplasm Invasiveness; Neoplasm Proteins; Time Factors; Transforming Growth Factor alpha

Patients with familial adenomatous polyposis develop periampullary adenomas at a high rate. However, little is known regarding the factors that control the growth, the natural history, or the malignant potential of these tumors.. In this study, the authors systematically evaluated the expression of the intestinal peptide growth factor, transforming growth factor-alpha (TGF-alpha), and its corresponding receptor, epidermal growth factor-receptor (EGF-R), in 49 periampullary adenomas and 6 periampullary carcinomas from 29 patients. Tumor proliferation rates were evaluated with the MIB-1 antibody.. All periampullary adenomas and carcinomas (100%) had TGF-alpha expression, whereas 63% of adenomas and 67% of carcinomas expressed EGF-R. The extent of TGF-alpha expression was greater in carcinomas compared with adenomas and increased progressively in adenomas relative to the degree of dysplasia and villous architecture of these lesions. The extent of EGF-R expression correlated only with the degree of dysplasia in adenomas. With regard to proliferation kinetics, higher MIB-1 labeling indices were observed in adenomas that were larger, more severely dysplastic, and villous. Transforming growth factor-alpha, and to a lesser extent, EGF-R expression, correlated directly with the MIB-1 labeling indices.. These results support the adenoma-carcinoma sequence in the progression of malignancy in the duodenum in familial adenomatous polyposis, suggesting a possible involvement for TGF-alpha and EGF-R expression in this process.

Topics: Adenoma; Adenomatous Polyposis Coli; Adult; Cell Division; ErbB Receptors; Female; Growth Substances; Humans; Immunoenzyme Techniques; Male; Middle Aged; Transforming Growth Factor alpha

Hepatocarcinogenesis was initiated in rats with a single dose of either of two chemical mutagens--benzo[a]pyrene diolepoxide I and methyl(acetoxymethyl)nitrosamine--administered 15 h after partial hepatectomy. The development of hepatocellular foci and neoplasms was then promoted with dietary phenobarbital given for 45 or 62 weeks. Formalin-fixed tissue specimens that contained hepatic neoplasms and altered hepatocellular foci were screened for expression of the oncodevelopmental marker glutathione-S-transferase (placental form) (GSTP) and transforming growth factor-alpha (TGF-alpha) using immunohistochemistry. All (100%) hepatocellular carcinomas expressed both GSTP and TGF-alpha, as did most hepatocellular adenomas (greater than 80%). However, quantitative stereologic analysis of treated and control livers revealed that GSTP-positive foci were 10-30 times more frequent than TGF-alpha-positive foci. Foci with homogeneous expression of GSTP generally displayed heterogeneous expression of TGF-alpha with reaction product most prominent at their peripheries. Less frequently homogeneous TGF-alpha-positive foci were seen within GSTP-positive foci. The average volumes of those GSTP-positive foci that also expressed TGF-alpha were significantly greater than those of the entire sets of GSTP-positive foci. These results suggest that expression of TGF-alpha may distinguish a subset of GSTP-positive foci that have a growth advantage and increased probability of progression to neoplasia.

Topics: Adenoma; Animals; Carcinogens; Carcinoma; Cell Transformation, Neoplastic; Chrysenes; Dimethylnitrosamine; Glutathione Transferase; Liver Neoplasms, Experimental; Rats; Transforming Growth Factor alpha

A total of 117 colorectal tissue specimens were examined immunohistochemically for the production of immunoreactive (IR-) transforming growth factor (TGF)-alpha and IR-epidermal growth factor (EGF). IR-TGF-alpha was detected in 26/32 (81.3%) invasive cancers, 14/27 (51.9%) carcinomas in situ, and 14/58 (24.1%) adenomas. IR-EGF was detected in 14/32 (43.8%) invasive cancers, 12/27 (44.4%) carcinomas in situ, and 12/58 (20.7%) adenomas. The staining intensity of IR-TGF-alpha was related to the histologic grade of malignancy, but that of IR-EGF was not. These suggest that IR-TGF-alpha plays a more important role than IR-EGF in the growth of colorectal neoplasms, and that further study of these growth factors would be helpful in understanding the biology of colorectal carcinoma.

Topics: Adenoma; Carcinoma; Carcinoma in Situ; Colorectal Neoplasms; Epidermal Growth Factor; Humans; Immunohistochemistry; Transforming Growth Factor alpha