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Biomedical subjects

C L Eaton

Publications and source records attributed to C L Eaton.

At least 19 recordsLinked to original sources
PubMed2005

The expression and regulation of ADAMTS-1, -4, -5, -9, and -15, and TIMP-3 by TGFbeta1 in prostate cells: relevance to the accumulation of versican.

BACKGROUND: Benign prostatic hyperplasia (BPH) is characterized by a proportional increase in the size of the stromal compartment of the gland, involving alterations to extracellular matrix (ECM) components. Some of these changes have been associated with the activity and expression of transforming growth factor beta1 (TGFbeta1). Versican (chondroitin sulphate proteoglycan-2) is overexpressed in BPH and prostate cancer and potentially contributes to disease pathology. A sub-group of the ADAMTS lineage of metalloproteases possess versican-degrading properties and are potential regulators of proteoglycan accumulation associated with BPH. These enzymes have one major inhibitor in the ECM, tissue inhibitor of metalloproteinases (TIMP)-3. METHODS: The effect of TGFbeta on mRNA expression in prostatic stromal cells was determined by real-time qRT-PCR using primers to ADAMTS-1, -4, -5, -9, -15, versican, and TIMP-3. MMP-inhibitory potential (TIMP activity) of conditioned medium was measured using a fluorometric peptide substrate. RESULTS: Prostatic stromal cell cultures consistently expressed ADAMTS-1, -4, -5, -9, -15 and TIMP-3, in contrast to PC3, DU145, and LNCaP cells which failed to express at least two ADAMTS transcripts. In stromal cells, TGFbeta1 decreased ADAMTS-1, -5, -9, and -15 transcripts and increased ADAMTS-4, versican, and TIMP-3. TGFbeta also increased TIMP activity in conditioned medium. CONCLUSIONS: The induction of versican expression by TGFbeta in BPH stromal cells is in agreement with histological studies. The negative effect of TGFbeta1 on ADAMTS-1, -5, -9, and -15 coupled with increases in their inhibitor, TIMP-3 may aid the accumulation of versican in the stromal compartment of the prostate in BPH and prostate cancer.

ADAM Proteins↗
PubMed2004

Osteoprotegerin (OPG) produced by bone marrow stromal cells protects breast cancer cells from TRAIL-induced apoptosis.

Advanced breast cancer is often associated with metastatic bone disease, causing a number of serious complications for the patients such as hypercalceamia, pain, nerve compression and fractures. The formation of bone metastases depends on complex interactions between tumour cells and the cells of the bone microenvironment, but the precise molecular mechanisms involved in the development of tumour-induced bone disease have not been identified. We have investigated the ability of bone marrow stromal cells (BMSC) isolated from breast cancer patients to generate osteoprotegerin (OPG), a molecule involved both in bone turnover and cell survival. The potential survival effects of OPG are mediated through binding to a member of the TNF super family, TNF-related Apoptosis Inducing Ligand (TRAIL), preventing association between TRAIL and its death-inducing receptors present on a number of tumour cell types. In the present report we show that bone marrow stromal cells isolated from breast cancer patients produce OPG when grown in culture. The levels of OPG present in BMSC conditioned medium is sufficient to protect breast cancer cells from undergoing TRAIL induced apoptosis. Our data suggest that bone-derived OPG may increase survival of breast cancer cells that reach the bone microenvironment as part of the metastatic process.

Apoptosis↗
PubMed2001

Role of endogenous transforming growth factor beta (TGFbeta)1 in prostatic stromal cells.

BACKGROUND: In this study, defined culture conditions were used to examine the effects of recombinant TGFbeta1 on prostatic stromal cells and to determine the role of endogenous TGFbeta produced by these cells. METHODS: Cells were grown +/- recombinant TGFbeta1 and cell population sizes in replicate cultures determined. In other experiments, TGFbeta1 production by prostatic stromal cells was examined and the effects of neutralization of this activity on cell population sizes and apoptosis evaluated. RESULTS: At > 1 ng/ml, TGFbeta1 reduced cell population sizes while at 0.01 ng/ml cell numbers were increased cf. controls. Stromal cells produced up to 10 ng/ml/48 hr of latent TGFbeta1 of which < 0.2% was biologically active. When cells were treated with anti-TGFbeta1 antibodies, cell numbers decreased cf. controls and the proportion of apoptotic cells increased. CONCLUSIONS: These observations suggest that TGFbeta1 is an autocrine factor made by prostatic stromal cells in which it inhibits apoptosis at the activity levels produced.

Antibodies↗
PubMed1999

Regulation of prostatic stromal cell growth and function by transforming growth factor beta (TGFbeta).

BACKGROUND: The majority of the overgrowth in benign prostatic hyperplasia (BPH) specimens is comprised of connective tissue. Factors that control stromal growth in the prostate are poorly understood; however, members of the transforming growth factor beta (TGFbeta) family may be of particular importance in the etiology of BPH. METHODS: Thirty-two low-passage stromal cultures were generated from human prostatectomy specimens. Their stromal origin was confirmed and expression of TGFbetas analyzed by duplex reverse transcription-polymerase chain reaction (RT-PCR). Challenge experiments were designed to study the effects of exogenous TGFbeta1 on stromal cell growth and synthesis of extracellular matrix components. RESULTS: The expression of TGFbetas 1, 2, and 3 was demonstrated in all 32 cell strains. The stromal origin of the cell lines was confirmed. Exogenous TGFbeta1 added to stromal cultures resulted in inhibition of cell growth and increased production of type I collagen. CONCLUSIONS: The prostatic stromal cell strains we have developed are a reliable mod- el for investigating prostatic connective tissue biology. The challenge experiments with TGFbeta1 provide further evidence for the involvement of TGFbetas in prostatic enlargement, as modulators of the extracellular matrix in the absence of growth stimulation.

Amino Acid Sequence↗
PubMed1998

Fibroblast growth factors and their receptors in parathyroid disease.

Fibroblast growth factors (FGFs) comprise a family of polypeptide growth factors implicated in the control of proliferation of glandular tissues. The aim of this study was to determine whether FGFs are produced in normal and abnormal parathyroid glands and if these tissues have the potential to respond to this growth factor family. We have examined the expression of FGF receptor (FGF-R) types 1 and 2 and of FGFs 1, 2, 3, and 7 in a series of human parathyroid tissues using the reverse transcription polymerase chain reaction (RT-PCR). Samples of 10 parathyroid adenomas and 10 hyperplastic glands from patients with renal hyperparathyroidism (HPT) were compared with samples from normal parathyroid glands from patients with primary HPT in the study. FGF-R1 was expressed in all samples and FGF-R2 in most. FGF1 and FGF2 were expressed in all samples at variable levels, with no correlation between disease type and amplified RT-PCR product levels. FGF7 was expressed in normal parathyroid tissue and in all adenomas but was absent in all but one of the hyperplastic parathyroid glands from renal failure patients. FGF3 was expressed at low levels in normal tissue and variably expressed in diseased tissue, in some instances at high levels. These findings suggest that parathyroid tissue is potentially responsive to FGFs. The absence of FGF7 expression in all but one of the renal parathyroid samples compared with normal and adenomatous tissue requires further investigation. The presence of elevated levels of FGF3 expression in abnormal parathyroid tissue may be significant, as the FGF3 gene (int-2 proto-oncogene) is located on chromosome 11q13.3, a region already identified as being susceptible to rearrangement/mutation in parathyroid disease.

Adenoma↗
PubMed1997

Effect of n-6 polyunsaturated fatty acids on growth and lipid composition of neoplastic and non-neoplastic canine prostate epithelial cell cultures.

BACKGROUND: Polyunsaturated fatty acids (n-6) are reported to selectively kill malignant cells. Most investigations, however, did not compare neoplastic with non-neoplastic cells from the same tissue type. Here we evaluate the effects of n-6 fatty acids on a non-neoplastic epithelium cell line (CAPE) and a spontaneous carcinoma cell line (CPA) derived from the canine prostate. METHODS: Cell lines were cultured in DME in the presence of fatty acids and their effects on cell proliferation monitored by coulter counting. Lipids were extracted and quantitized by gas chromatography. RESULTS: Cell proliferation was reduced more in CAPE. A neoplastic strain (CPA-GLA) tolerant to prolonged culture in 18:3n-6 was isolated. CPA grown in an 18:2n-6 or 18:3n-6 supplemented media accumulated 20:3n-6 and contained little 20:4n-6. CONCLUSIONS: Polyenoic n-6 fatty acids are not specifically inhibitory to neoplastic cells which exhibited a marked alteration in the metabolism of 20:4n-6.

Animals↗
PubMed1997

Comparative studies of the mitogenic effects of epidermal growth factor and transforming growth factor-alpha and the expression of various growth factors in neoplastic and non-neoplastic prostatic cell lines.

BACKGROUND: The role of growth factors in prostate cell growth has been investigated as these peptides may be involved in the autonomous growth of hormone-independent prostate cancer. METHODS: Responses of neoplastic (PC-3 and CPA) and non-neoplastic (CAPE) prostatic cell lines to epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) were determined using clonogenic and growth curve analysis. The constitutive expression of EGF, TGF-alpha, and TGF-beta 1-3 mRNA was examined using Northern blotting and EGF and TGF-alpha protein levels were determined immunohistochemically. RESULTS: Growth curve and clonogenic analysis indicated that EGF and TGF-alpha were mitogenic in each cell line. The magnitude of the clonogenic response varied between the cell lines, with CPA cells showing the greatest growth increases. CPA cells also displayed the highest levels of EGF and TGF-alpha mRNA and protein. TGF-beta 1 mRNA was detected in the order of magnitude, PC-3 > CPA > CAPE. Furthermore, PC-3 and CPA cells expressed TGF-beta 3 and TGF-beta 2 transcripts respectively. In each cell line, the expression of any growth factor mRNA was not affected by exogenous EGF. CONCLUSIONS: The growth responses of the cell lines to EGF and TGF-alpha did not correlate with their constitutive levels of EGF and TGF-alpha mRNA and protein, thus whilst growth factors may be important in malignant cell growth, other pathways may also be involved in the autocrine regulation of cell proliferation.

Animals↗
PubMed1997

Response of cell growth and retinoic acid receptor expression to retinoic acid in neoplastic and non-neoplastic prostate cell lines.

BACKGROUND: Retinoic acid (RA) is recognized as an inhibitor of tumorigenesis, but conversely, has also been shown to act as a tumor enhancer, therefore its role in prostate tumor cell growth was investigated. METHODS: The response of two human prostate tumor cell lines (PC-3 and DU-145), and cell lines derived from a well-differentiated canine prostate adenocarcinoma (CPA) and normal canine prostate epithelium (CAPE) to all-trans RA was determined using growth curve analysis. Additionally, the constitutive expression and RA-challenged expression of retinoic acid receptors (RARs) -alpha, -beta, and -gamma mRNA was examined using Northern blotting techniques. RESULTS: In response to all-trans RA, the PC-3 and DU-145 cell lines showed considerable growth promotion, while CAPE and CPA cell growth was dramatically inhibited. Each cell line expressed RAR alpha and RAR gamma, with either negligible or no RAR beta transcripts being detected. RAR alpha and -gamma mRNAs detected in the four cell lines were variably regulated in response to RA, and no distinct patterns of RAR regulation that could be related to cell growth responses were observed. CONCLUSIONS: The data indicates that no simple association exists between the expression or regulation of RAR subtype mRNAs and the divergent growth responses to RA displayed by the prostate cell lines.

Adenocarcinoma↗
PubMed1994

Transforming growth factor beta 1 expression in benign and malignant prostatic tumors.

The expression of transforming growth factor beta 1 (TGF-beta 1) in prostate specimens obtained from patients with benign prostatic hyperplasia (BPH, n = 32) and prostate carcinoma (n = 66) was investigated using Northern blot analysis and immunohistochemistry. Northern blot analysis revealed TGF-beta 1 message (2.5 kb) in virtually all of the samples examined, reflecting the ubiquitous nature of this growth factor. No statistical difference was found between the levels of mRNA detected in benign and malignant tissues due, in part, to the inherent heterogeneity of prostate tissue. Immunohistochemical methods using an antibody to native TGF-beta 1 revealed a novel pattern of immunoreactivity. Staining observed only in certain epithelial cells of benign glands was associated with areas of infection rather than tumorigenesis. Interestingly, intense staining was also seen in polymorphonuclear leukocytes. No correlation was found with the mRNA results, suggesting that this antibody is binding to TGF-beta 1 activated in response to infection rather than detecting sites of synthesis of latent TGF-beta 1.

Blotting, Northern↗
PubMed1993

Relationship between EGF-R, c-erbB-2 protein expression and Ki67 immunostaining in breast cancer and hormone sensitivity.

The expression of the epidermal growth factor receptor (EGF-R), c-erbB-2 protein product and Ki67 have been evaluated in 105 breast cancers of known responsiveness to endocrine therapy using immunohistochemistry. EGF-R staining was observed in 62 of the tumours and was significantly associated with elevated rates of cell proliferation (%Ki67 positive cells) and loss of hormone sensitivity. In contrast, c-erbB-2 expression was not correlated with cell proliferation rates and was less strongly related to hormone insensitivity. Subdivision of the EGF-R data according to c-erbB-2 measurements revealed an association between c-erbB-2 immunostaining and worsened patient outlook and hormone insensitivity in moderately EGF-R-positive tumours. c-erbB-2 immunostaining in highly EGF-R-positive tumours did not further contribute to the already poor prognosis of these patients. These data confirm the prognostic importance of EGF-R measurements in breast cancer and may infer a functional interaction between this protein and the c-erbB-2 protein product in the aberrant growth of a subset of breast tumours.

Breast Neoplasms↗
PubMed1991

Steroids and the prostate.

Interelationships between steroid and growth factor regulation of cell proliferation has been examined in two androgen sensitive prostatic cell lines, grown in defined medium. The cell lines used were derived from normal (CAPE) and neoplastic (LNCaP) tissues. The growth of both cell lines was elevated by challenge with serum, androgens and epidermal growth factor (EGF) used as single agents. The effects of androgen in CAPE were small, but significant while the profound effects of these agents on the growth of LNCaP were confirmatory of other studies. Androgens upregulated EGF receptor expression in LNCaP measured by both ligand binding capacity and mRNA analysis. This was not observed in the CAPE cells. Addition of serum (whole or charcoal stripped) suppressed the observed androgenic stimulation of EGF receptor expression in LNCaP. This apparent anomaly is discussed in relation to the growth enhancing properties of serum in these cell lines and in the wider context of normal and neoplastic growth control in the prostate.

Androgens↗
PubMed1991

Steroid hormones and the pathogenesis of benign prostatic hyperplasia.

The pathogenesis of benign prostatic hyperplasia (BPH) is still poorly understood: there is, however, general acceptance that the condition is not premalignant and that it has an etiology distinct from that of cancer. Interest now focuses on the biochemistry of the target prostate cells and the propensity of the gland for uncontrolled growth. Dihydrotestosterone (DHT) is the active intracellular androgen formed from testosterone by 5 alpha-reductase. DHT concentrations appear a little higher in BPH tissue than in normal tissue, and there is no doubt that DHT-receptor complex modulates gene expression. Current studies suggest that DHT is essential but not sufficient for proliferation, and that other regulatory factors, including peptide growth factors, are prerequisite. The growth responsiveness of prostate tissue to androgens may be dependent on the balance between epithelial and stromal tissues, with biologic processes in the epithelium indirectly controlled by androgen-dependent mediators of stromal origin.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1990

The role of endocrine therapy in prostatic cancer.

When judged by randomized clinical trial, current endocrine therapies offer symptomatic relief to prostatic cancer patients for an average period of 1-2 years following initiation of therapy. Medical castration with LHRH analogues is a safe and effective way of achieving 'castrate' levels of circulating androgens without the undesirable aspects of surgery. While there is some evidence for the value of combined therapies using these agents in combination with anti-androgens for 'total androgen blockade' in some patients, overall this approach has not been shown to offer advantages over castration, either surgical or medical, alone in controlled trials. Secondary endocrine therapy does not offer convincing objective response rates, suggesting that disease progression is independent of androgens.

Androgen Antagonists↗
PubMed1989

Binding of epidermal growth factor by human normal, hypertrophic, and carcinomatous prostate.

Saturable binding sites for radioiodinated epidermal growth factor (EGF) have been quantified in surgical specimens of benign prostate hypertrophy (BPH), histologically normal (HN) prostate, and prostate cancer. Values for EGF binding did not differ significantly between HN prostate and prostate cancer, although dedifferentiated samples tended to higher levels. These were coincident with lower comparative levels of androgen receptors. Unfractionated BPH tissue contained lower levels of EGF binding than either HN or carcinomatous prostate, but in separated epithelial cells EGF binding fell into the same range. Saturation analyses showed two affinity classes of binding in all except dedifferentiated tissues.

Binding Sites↗
PubMed1989

Prostatic cancer: aetiology and endocrinology.

Prostate cancer is common in the male population, worldwide. Several therapies are currently available, but only greater understanding of the complex processes that govern the growth of the cancer will produce real progress in treatment.

Humans↗