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R A Morton

Publications and source records attributed to R A Morton.

At least 37 records · Page 2Linked to original sources
PubMed1996

Metastatic prostate cancer in a transgenic mouse.

We have previously reported the development of a transgenic mouse model for prostate cancer derived from PB-Tag transgenic line 8247, henceforth designated the TRAMP (transgenic adenocarcinoma mouse prostate) model. We now describe the temporal and spatial consequences of transgene expression and report the identification and characterization of metastatic disease in the TRAMP model. TRAMP mice characteristically express the T antigen oncoprotein by 8 weeks of age and develop distinct pathology in the epithelium of the dorsolateral prostate by 10 weeks of age. Distant site metastases can be detected as early as 12 weeks of age. The common sites of metastases are the periaortic lymph nodes and lungs, with occasional metastases to the kidney, adrenal gland, and bone. By 28 weeks of age, 100% harbor metastatic prostate cancer in the lymph nodes or lungs. We have also demonstrated the loss of normal E-cadherin expression, as observed in human prostate cancer, as primary tumors become less differentiated and metastasize. The TRAMP model provides a consistent source of primary and metastatic tumors for histopathobiological and molecular analysis to further define the earliest molecular events involved in the genesis, progression, and metastasis of prostate cancer.

Adenocarcinoma↗
PubMed1996

Hypermethylation of chromosome 17P locus D17S5 in human prostate tissue.

PURPOSE: Under normal conditions genomic CpG islands are not methylated. Hypermethylation of a CpG island in the 5' regulatory region of a gene has the capacity to silence gene transcription. Recently, hypermethylation of a CpG island at D17S5 on chromosome 17P13.3 has been shown to be a frequent tumor-specific event. When it has been observed, hypermethylation of D17S5 occurs solely in neoplastic tissues. Consequently, it has been hypothesized that hypermethylation of D17S5 may be an important carcinogenic event in the organs in which it occurs (colon, kidney, and brain). In this study we examine D17S5 hypermethylation in DNA from the prostate, a gland which is unique in that it undergoes hyperplastic or neoplastic growth or both in virtually all aging men. MATERIALS AND METHODS: The methylation sensitive restriction enzyme Notl, a cDNA probe specific for the D17S5 locus, and Southern blotting were used to assay for hypermethylation of D17S5 in DNA derived from normal, benign hyperplastic and malignant prostate tissues. RESULTS: We find that methylation of Notl restriction sites at D17S5 is a very common occurrence in prostate cancers (25 of 26 cases examined). Surprisingly, we found that methylation of these sites at D17S5 also occurred in histologically normal prostate and benign hyperplastic (BPH) tissue from glands which both did and did not contain cancer. In contrast, seminal vesicle, an androgen-dependent male sex accessory tissue that rarely undergoes pathological overgrowth, was devoid of hypermethylation at this locus. CONCLUSIONS. These data demonstrate that hypermethylation of D17S5 is a tissue-specific event in prostate DNA, and we hypothesize that methylation of this and/or related loci may play a role in the extreme predilection of this gland to neoplastic growth.

Base Sequence↗
PubMed1995

Chromosome 5 suppresses tumorigenicity of PC3 prostate cancer cells: correlation with re-expression of alpha-catenin and restoration of E-cadherin function.

Considerable evidence now exists to support an important role for the E-cadherin-mediated cell-cell adhesion pathway as a suppressor of the invasive phenotype in adenocarcinoma cells. Previous studies have found that this pathway is frequently aberrant in prostate cancers, particularly those that are likely to metastasize. In this study, we report on the effects of re-establishment of this pathway in a prostate cancer cell line, PC-3, in which this adhesion system is dysfunctional by virtue of a deletion of the gene that codes for alpha-catenin, an E-cadherin-associated protein necessary for normal E-cadherin function. Re-expression of alpha-catenin was accomplished either by transfection of PC-3 cells with a copy of the alpha-catenin cDNA under the control of a heterologous promoter or by microcell-mediated transfer of chromosome 5, which contains the alpha-catenin gene and its normal regulatory elements. In both cases, re-expression of alpha-catenin is associated with a similar, dramatic alteration in cell morphology, whereby extensive cell-cell contact is observed. In the case of transfection of the cDNA, this expression is only transient, because the transfected cells either cease to proliferate or, more commonly, revert to the parental phenotype with concomitant cessation of alpha-catenin expression. In contrast, cells containing one or more copies of microcell-transferred chromosome 5 express alpha-catenin in a stable manner and continue to proliferate. Upon injection into nude mice, these latter cells are no longer tumorigenic, or form only slowly growing tumors with greatly extended doubling times when compared to the parental PC-3 cells. During passage in culture, clones that contain only one transferred copy of chromosome 5 reproducibly revert to the parental phenotype. This reversion is associated with loss of the chromosome 5 region containing the alpha-catenin gene and consequent loss of alpha-catenin expression, as well as re-emergence of tumorigenicity. Transfer of chromosome 5 into prostate cancer cells that are E-cadherin negative does not result in either morphological transformation or suppression of tumorigenicity, suggesting that these effects of alpha-catenin expression are dependent upon concomitant expression of E-cadherin. These data demonstrate the tumor suppressive ability of chromosome 5 in the PC-3 prostate cancer cells and suggest that re-expression of alpha-catenin with resultant restoration of E-cadherin function plays a critical role in this process.

Animals↗
PubMed1995

The E-cadherin cell-cell adhesion pathway in urologic malignancies.

Alterations in the E-cadherin-mediated cell-cell adhesion pathway are commonly observed in urologic malignancies. This issue has been addressed most thoroughly in prostate cancer. Whereas both cadherin and catenin dysfunction have been seen in human prostate cancers, only down-regulation of E-cadherin has been shown for bladder cancer and renal-cell carcinoma. Although studies in bladder cancer and renal-cell carcinoma are less mature than studies in prostate cancer, they support the hypothesis that immunostaining for E-cadherin may be of significance for both diagnostic and prognostic purposes. Finally, the E-cadherin-mediated cell-cell adhesion pathway may represent a novel chemotherapeutic target for bladder cancer, prostate cancer, and renal-cell carcinoma. Obviously, more work lies ahead to translate these important observations from the bench to the bedside.

Cadherins↗
PubMed1995

Molecular biology of prostate cancer progression.

A number of genetic changes have been documented in prostate cancer, ranging from allelic loss to point mutations and changes in DNA methylation patterns (summarized in Fig. 1). The most consistent changes seen are those of allelic loss events, with the majority of tumours examined showing loss of alleles from at least one chromosomal arm. The short arm of chromosome 8, followed by the long arm of chromosome 16, seem to be the most frequent regions of loss, suggesting the presence of novel tumour suppressor genes. Deletions of one copy of the RB and TP53 genes are less frequent as are mutations of the TP53 gene, and accumulating evidence suggests the presence of an additional tumour suppressor gene on chromosome 17p, which is frequently inactivated in prostate cancer. Alterations in the E-cadherin/alpha catenin mediated cell-cell adhesion mechanism appear to be present in almost half of all prostate cancers and may be critical to the acquisition of metastatic potential of aggressive prostate cancers. Finally, altered DNA methylation patterns have been found in the majority of prostate cancers examined, suggesting widespread alterations in methylation modulated gene expression. The presence of multiple changes in these tumours is consistent with the multistep nature of the transformation process. Finally, efforts to identify prostate cancer susceptibility loci are under way, which may elucidate critical early events in prostatic carcinogenesis.

Cadherins↗
PubMed1994

Cytidine methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic carcinogenesis.

Hypermethylation of regulatory sequences at the locus of the pi-class glutathione S-transferase gene GSTP1 was detected in 20 of 20 human prostatic carcinoma tissue specimens studied but not in normal tissues or prostatic tissues exhibiting benign hyperplasia. In addition, a striking decrease in GSTP1 expression was found to accompany human prostatic carcinogenesis. Immunohistochemical staining with anti-GSTP1 antibodies failed to detect the enzyme in 88 of 91 prostatic carcinomas analyzed. In vitro, GSTP1 expression was limited to human prostatic cancer cell lines containing GSTP1 alleles with hypomethylated promoter sequences; a human prostatic cancer cell line containing only hypermethylated GSTP1 promoter sequences did not express GSTP1 mRNA or polypeptides. Methylation of cytidine nucleotides in GSTP1 regulatory sequences constitutes the most common genomic alteration yet described for human prostate cancer.

Carcinoma↗
PubMed1994

Liver, serum and adipose tissue fatty acid composition in suckling Zucker rats.

Young adult obese Zucker rats have altered tissue fatty acid (FA) composition. The present study was aimed at determining whether such changes were seen in either liver, serum or adipose tissue obtained from 17-day-old obese (fafa) rats in comparison to both homozygous (FaFa) and heterozygous (Fafa) lean rats. Body weights of obese pups (30.3 g) were significantly greater than those of homozygous lean rats (25.2 g) (P < 0.05). Liver weight and lipid content were similar in all groups. Inguinal fat pad weight and lipid content were greatest in obese pups (573 mg) followed by heterozygous lean pups (303 mg); homozygous lean pups (146 mg) had the lowest values. There were no differences among the groups in hepatic FA composition in either triacylglycerol (TG) or phospholipid fractions. Serum TG was similar among the groups, while serum phospholipid was greater (P < 0.05) in obese (269 mg/dL) than in homozygous lean pups (184 mg/dL); heterozygous lean pups had an intermediate value not significantly different from either homozygous group. On a percent basis, there were no differences in FA composition in either serum lipid fraction among the three groups. There were a number of significant differences in adipose tissue FA composition between the groups on a percent basis. The adipose tissue FA composition on a percent basis reflected that of maternal milk. The results indicate that suckling obese Zucker rats do not have tissue FA profiles that are characteristic of essential FA deficiency.

Adipose Tissue↗
PubMed1994

Racial differences in adenocarcinoma of the prostate in North American men.

Black men represent a particularly high risk group for the development of prostate cancer. Current recommendations are that all men over age 50 be screened for prostate cancer annually with a digital rectal examination (DRE) and PSA. Moreover, it has been recommended that men in high risk groups, including blacks and men with a family history of prostate cancer, be screened at an earlier age. At the present time, no adequately performed prospective study has demonstrated a reduction in mortality rate attributable to annual prostate cancer screening. Preliminary reports have suggested that the proportion of men with organ confined tumors increases with PSA based screening, and that a reduction in prostate cancer mortality via screening is feasible. In light of these preliminary studies, increased efforts toward patient awareness and PSA screening are certainly warranted in the black community. Hopefully the result of such programs would be to increase the percentage of black men diagnosed with organ confined prostate cancer. However, the etiology of these striking racial differences remains to be defined. To date no consistent data have been presented which can explain these observations. It is likely that multiple factors will be involved including socioeconomic, environmental, dietary, and genetic. Lastly, little is known of the molecular genetic factors, tumor suppressor genes and/or oncogenes, that play a role in prostate cancer in black men. Increased research efforts are needed in order to understand this problem at the molecular level.

Adenocarcinoma↗
PubMed1994

Genetic alterations in prostate cancer.

A number of genetic changes have been documented in prostate cancer, ranging from allelic loss to point mutations and changes in DNA methylation patterns (summarized in Fig. 1). To date, the most consistent changes are those of allelic loss events, with the majority of tumors examined showing loss of alleles from at least one chromosomal arm. The short arm of chromosome 8, followed by the long arm of chromosome 16, appear to be the most frequent regions of loss, suggesting the presence of novel tumor suppressor genes. Deletions of one copy of the Rb and p53 genes are less frequent, as are mutations of the p53 gene, and accumulating evidence suggests the presence of an additional tumor suppressor gene on chromosome 17p, which is frequently inactivated in prostate cancer. Alterations in the E-cadherin/alpha-catenin-mediated cell-cell adhesion mechanism appear to be present in almost half of all prostate cancers and may be critical to the acquisition of metastatic potential of aggressive prostate cancers. Finally, altered DNA methylation patterns have been found in the majority of prostate cancers examined, suggesting widespread alterations in methylation-modulated gene expression. The presence of multiple changes in these tumors is consistent with the multistep nature of the transformation process. Finally, efforts to identify prostate cancer susceptibility loci are under way and may elucidate critical early events in prostatic carcinogenesis.

Cadherins↗
PubMed1994

Molecular biology of prostate cancer.

A number of genetic changes have been documented in prostate cancer, ranging from allelic loss to point mutations and changes in DNA methylation patterns (summarized in Fig 1). To date, the most consistent changes are those of allelic loss events, with the majority of tumors examined showing loss of alleles from at least one chromosomal arm. The short arm of chromosome 8, followed by the long arm of chromosome 16 appear to be the most frequent regions of loss, suggesting the presence of novel tumor suppressor genes. Deletions of one copy of the Rb and p53 genes are less frequent as are mutations of the p53 gene, and accumulating evidence suggests the presence of an additional tumor suppressor gene on chromosome 17p, which is frequently inactivated in prostate cancer. Alterations in the E-cadherin/alpha catenin mediated cell-cell adhesion mechanism appear to be present in almost half of all prostate cancers, and may be critical to the acquisition of metastatic potential of aggressive prostate cancers. Finally, altered DNA methylation patterns have been found in the majority of prostate cancers examined, suggesting widespread alterations in methylation-modulated gene expression. The presence of multiple changes in these tumors is consistent with the multistep nature of the transformation process. Finally, efforts to identify prostate cancer susceptibility loci are underway and will hopefully elucidate critical early events in prostatic carcinogenesis.

Cadherins↗
PubMed1993

Reduction of E-cadherin levels and deletion of the alpha-catenin gene in human prostate cancer cells.

The cadherins are a family of transmembrane glycoproteins responsible for calcium-dependent cell-cell adhesion. This adhesion is mediated by a group of cytoplasmic proteins, the catenins, which act inside the cell to couple the cadherin molecule to the microfilament cytoskeleton. Dysfunction of E-cadherin-dependent cell-cell adhesion has been demonstrated to contribute to the acquisition of invasive potential of malignant adenocarcinoma cells. The potential role of alterations of catenin expression in tumor cell invasion is largely unexplored. We have previously found that E-cadherin is frequently down-regulated in clinical samples of prostate cancer (Umbas, R., Schalken, J. A., Aalders, T. W., Carter, B. S., Karthaus, H. F. M., Schaafsma, H. E., Debruyne, F. M. J., and Isaacs, W. B. Cancer Res., 52: 5104-5109, 1992). In this study, we further investigate this adhesion system in both benign and malignant human prostate cells in culture. Using antibodies to E-cadherin and its cytoplasmic accessory protein, alpha-catenin, we find that 5 of 6 human prostate cancer cell lines have reduced or absent levels of one or the other or both of these molecules when compared to normal prostatic epithelial cells. Only the LNCaP prostate cancer cell line is indistinguishable from normal prostate epithelium with respect to its E-cadherin-alpha-catenin complement. Interestingly, the PC-3 line is characterized by the presence of E-cadherin, but the complete lack of alpha-catenin found at both the RNA and protein level. This lack of alpha-catenin gene expression is explained by Southern analysis, which reveals a homozygous deletion of a large portion of the alpha-catenin gene in PC-3 cells. This loss of alpha-catenin is functionally manifested by negligible Ca(2+)-dependent aggregation of these cells in vitro, when compared to LNCaP cells. These results confirm that E-cadherin-dependent cell-cell adhesion is frequently aberrant in prostate cancer cells, and suggest that in a subset of prostate cancers, this adhesion may be inactivated by loss of alpha-catenin rather than E-cadherin itself. Furthermore, these results demonstrate that mutational inactivation of the alpha-catenin gene is one mechanism responsible for the loss of normal cell-cell adhesion in prostate cancer.

Cadherins↗
PubMed1993

Vitamin B12 deficiency in patients with ileocolic neobladders.

The terminal ileum is widely used for reconstruction of the lower urinary tract. Since the terminal ileum exclusively absorbs vitamin B12, removal of ileum from the gastrointestinal trace for use in lower urinary tract reconstruction may predispose patients to vitamin B12 deficiency. In a prospective study serial vitamin B12 levels were obtained postoperatively in 24 patients who underwent cystectomy for malignancy and ileocolic neobladder urinary diversion with a mean followup of 25 months (range 6 to 53). Any patient who had a low vitamin B12 serum level (less than 200 pg./ml.) underwent a Schilling test to confirm malabsorptive vitamin B12 deficiency. Six patients (25%) had low serum vitamin B12 levels, of whom 3 (13%) had an abnormal Schilling test. No patient had megaloblastic anemia. One patient with malabsorptive vitamin B12 deficiency had neurological symptoms 53 months postoperatively. We conclude that vitamin B12 deficiency can occur following ileocolic neobladder reconstruction. Patients with true vitamin B12 deficiency should be identified and placed on lifelong parenteral vitamin B12.

Adult↗
PubMed1993

Evolution of Drosophila insecticide resistance.

The impact of insecticide resistance is well documented. It includes the toxic effects of pesticides on the environment and the cost of the increased amounts of insecticides required to effectively control resistant insects. Resistance evolves by the selection of genes that confer tolerance to insecticides. Several resistance genes have been identified and cloned in Drosophila, including genes for mutant target molecules and genes that increase insecticide degradation. Drosophila is a useful system to understand the evolution of quantitative traits in general as well as the population genetics of insecticide resistance. Through it, we may hope to understand the relationship between discrete genetic change and continuously varying characters. In addition, molecular genetic techniques developed using Drosophila can eventually be transferred to other insects in order to help control pest populations.

Acetylcholinesterase↗
PubMed1991

Impact of anatomical radical prostatectomy on urinary continence.

Urinary continence following an anatomical approach to radical prostatectomy was evaluated in 593 consecutive patients, 547 (92%) of whom achieved complete urinary control. Stress incontinence was present in 46 patients (8%), of whom 34 (6%) wore 1 or fewer pads per day and 2 (0.3%) required placement of an artificial sphincter. No patient was totally incontinent. Age, weight of the prostate, prior transurethral resection of the prostate, pathological stage and preservation or wide excision of the neurovascular bundles had no significant influence on preservation of urinary control. These data suggest that anatomical factors rather than preservation of autonomic innervation may be responsible for the improved urinary control associated with an anatomical approach to radical prostatectomy.

Adenocarcinoma↗
PubMed1991

Cancer control following anatomical radical prostatectomy: an interim report.

Cancer control following anatomical radical prostatectomy was evaluated in 586 men who were followed for 1 1/2 to 8 years (median followup 4 years, 166 men followed 5 years or longer). The 5-year actuarial rate was 4% for local recurrence alone, 5% for distant metastases alone, 2% for distant metastases in association with local recurrence and 3% for death of or with disease, while 10% of the men had elevated levels of prostate specific antigen without local recurrence or distant metastases. When the actuarial status at 5 years was evaluated by clinical stage there was local recurrence alone in 0% of men with a clinical stage A1 or B1 nodule, and 4% with stage B1, 7% with stage A2 and 8% with stage B2 disease. When evaluated by pathological stage at 5 years local recurrence alone was noted in 2% of men with organ-confined disease, 8% with specimen-confined disease and 8% in whom the disease involved the surgical margin, seminal vesicles or pelvic lymph nodes. Recognizing that two-thirds to three-quarters of all local recurrences occur within the first 5 years, these data suggest that the anatomical approach to radical prostatectomy is associated with local control rates that are equal to or greater than other series reported in the literature. However, without a randomized study it is impossible to compare one clinical series to another, and followup evaluations at 10 and 15 years will be necessary to confirm these findings.

Antigens, Neoplasm↗
PubMed1991

Nutritional and gastrointestinal complications of the use of bowel segments in the lower urinary tract.

Almost all segments of the gastrointestinal tract have been used as urinary tract substitutes. The specific nutritional and gastrointestinal complications depend on the particular portion of bowel that is removed from the alimentary tract. The use of stomach theoretically may predispose the patient to hypergastrinemia and peptic ulcer disease, hypocalcemia, and iron deficiency or megaloblastic anemia. Resection of a large amount of jejunum causes malabsorption. Limited use of colon segments usually is well tolerated, but loss of large parts of the colon directly decreases available absorptive area, resulting in diarrhea. Resection of the ileum and ileocecal valve can lead to several disease states. One is mixed secretory-osmotic diarrhea. Decreased ileal reabsorption of bile salts results in fat malabsorption and steatorrhea. The presentation of increased amounts of bile salts and fatty acids to the colon decreases water absorption and stimulates active chloride and water secretion, producing a cholera-like high-volume secretory diarrhea. The loss of the ileocecal valve and ileum segment accelerates intestinal transit time, which does not allow for complete digestion and absorption of food. Water and electrolytes remain associated with undigested food particles and may overwhelm the absorptive capacity of the colon, resulting in an osmotic diarrhea. A second problem is vitamin B12 deficiency. Surgical reduction of sites in the terminal ileum for active and exclusive uptake of vitamin B12 might lead to hypovitaminosis. If this is unrecognized, patients may develop irreversible neurologic injury. A third problem is cholelithiasis. Derangements in bile salt metabolism can occur when as little as 10 cm of ileum is resected, and the propensity to form gallstones is increased. Pigment gallstones appear to be the predominant stone associated with ileal resections. The fourth possible problem is urolithiasis, the etiology of which is multifactorial in patients with ileal resections. With decreased availability of bile salts, fat malabsorption occurs. Fatty acids bind with calcium and magnesium to form soaps, resulting in increased levels of free oxalate available for absorption. Moreover, fatty acids directly increase colonic permeability to oxalate.(ABSTRACT TRUNCATED AT 400 WORDS)

Gastrointestinal Diseases↗
PubMed1990

Differential effects of growth factor antagonists on neoplastic and normal prostatic cells.

Growth factors such as epidermal growth factor and fibroblast growth factor have been suggested to be involved as paracrine or autocrine mediators of androgen action in normal and malignant prostatic cells. Suramin and protamine are potent in vitro growth factor antagonists. To evaluate the effect of growth factor antagonists on prostatic growth, suramin and protamine were administered to castrated rats simultaneously receiving exogenous testosterone replacement in an attempt to block androgen-dependent restoration of the normal rat ventral prostate. Using this prostatic restoration model, there was no statistical difference in the prostate wet weight or total DNA content attained between rats given testosterone alone and those given testosterone in combination with either suramin or protamine. In intact rats, suramin administration caused an 80% reduction in serum testosterone; concomitantly, these rats had a 40% reduction in mean prostate weight. This decrease in size could be blocked with androgen supplementation. To examine the effects of growth factor antagonists on neoplastic prostatic cell growth, rats bearing the androgen-independent AT-2 subline of the Dunning R-3327 tumor were treated with either suramin or protamine. The same dosing regimen found to be ineffective in blocking the restoration of the involuted prostate of castrated rats resulted in a significant reduction in the growth rate of AT-2 tumors. These results suggest that the growth factor antagonists suramin and protamine given in vivo have a differential ability to slow the growth of malignant vs. normal prostatic cells.

Animals↗