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O Cussenot

Publications and source records attributed to O Cussenot.

At least 73 records · Page 4Linked to original sources
PubMed1998

Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2-43.

There is genetic predisposition associated with >=10% of all cancer of the prostate (CaP). By means of a genomewide search on a selection of 47 French and German families, parametric and nonparametric linkage (NPL) analysis allowed identification of a locus, on chromosome 1q42.2-43, carrying a putative predisposing gene for CaP (PCaP). The primary localization was confirmed with several markers, by use of three different genetic models. We obtained a maximum two-point LOD score of 2.7 with marker D1S2785. Multipoint parametric and NPL analysis yielded maximum HLOD and NPL scores of 2.2 and 3.1, respectively, with an associated P value of . 001. Homogeneity analysis with multipoint LOD scores gave an estimate of the proportion of families with linkage to this locus of 50%, with a likelihood ratio of 157/1 in favor of heterogeneity. Furthermore, the 9/47 families with early-onset CaP at age <60 years gave multipoint LOD and NPL scores of 3.31 and 3.32, respectively, with P = .001.

Age of Onset↗
PubMed1998

Hereditary prostate cancer and other genetic predispositions to prostate cancer.

The incidence of prostate cancer (CaP) and its increase in the last 10 years vary both from country to country and according to the ethnic group, with the highest incidence reported for Afro-Americans and the lowest for Asian men. To date, only three risk factors have been established for CaP: age; familial aggregation of CaP, and ethnic origins. No dietary or environment-related cause has been established. However, some variations in endogenous genetic factors may help explain differences in risk among ethnic groups or geographic areas. Similarly, certain genetic polymorphisms of genes encoding for 5alpha-reductase, androgen receptor or vitamin D, have been associated with different levels of CaP risk, and could explain the variations observed between populations. Different studies support the view that familial CaP may truly be hereditary, and not due to a similar lifestyle. Thus, familial inheritance is a parameter that needs to be considered in recommending screening for high-risk families. Indeed, when 1, 2, and 3 first-degree relatives are affected, the relative risk of first-degree relatives of CaP patients may increase to 2, 5, and 11%, respectively. Some familial forms appear to be associated with transmission of a rare putative dominant gene with a high penetrance (88% at age 85), with the cumulative proportion of CaP attributable to this gene being more marked for younger patients (a 43 versus a 34% risk of CaP appearing before the age of 55 versus 70 years). Using this transmission model and linkage analysis, a predisposing locus on chromosome 1q24-25 (HPC-1) has been described. Moreover, recessive and X-linked transmission has been suggested, showing that a large proportion of familial CaP may not be due to segregation of a few major gene mutations, but rather to familial sharing of alleles at many loci, each contributing to a small increase in cancer risk. Candidate genes may be the same suppressor genes that are involved in other cancers and in sporadic CaP.

Aged↗
PubMed1998

Evaluation and clinical value of neuroendocrine differentiation in human prostatic tumors.

BACKGROUND: Prostate cancer, like other solid tumors, is a rather heterogeneous entity. More than 50% of all malignant prostatic tumors contain neuroendocrine-like cells, which cannot be attributed to small cell prostatic carcinoma or carcinoid-like tumors, which represent only 1-2% of all prostatic malignancies. Several investigators have reported that histopathologic determination of neuroendocrine differentiation in prostate carcinomas may have prognostic implications, while others have not confirmed these results. However, on the basis of experimental data, neuroendocrine-like cells appear to be involved in the emergence of androgen-independent cells and could be a target for new prostate cancer therapeutic strategies. METHODS: The literature on the neuroendocrine phenotype of prostatic carcinoma is reviewed. This review summarizes most of the accumulated experimental and clinical data on the neuroendocrine phenotype in prostate cancer. We analyze the putative functions of neuroendocrine-like cells in prostate cancer progression and discuss the place of neuroendocrine phenotype biomarkers as diagnostic and prognostic factors in prostate cancer. RESULTS: The fact that focal, patchy and heterogeneous clusters of neuroendocrine-like cells are frequently identified in organ-confined prostatic carcinoma probably accounts for the various evaluations of the predictive value of neuroendocrine histological patterns for the clinical outcome at this stage of the disease. The amount of neuroendocrine cells required to produce a detectable elevation in plasma chromogranin A has not yet been determined, but it is correlated with the number of chromogranin A-positive neuroendocrine (NE) cells. Despite the obvious current limitations of the application of neuropeptides as a serological test, this overview will try to more accurately define the possible roles of specific neuropeptides as prostatic cancer markers in diagnostic and monitoring protocols. The plasma chromogranin A level, in comparison with neuron-specific enolase (NSE), chromogranin B (CBG), pancreastatin, or secretogranin levels, appears to be the most useful neuroendocrine marker for determination of neuroendocrine differentiation of advanced prostatic adenocarcinoma. CONCLUSIONS: Future studies on neuroendocrine should confirm whether neuroendocrine biomarkers, especially the chromogranin family of peptides, can be used as prognostic markers during the course of prostate cancer or for the selection of patients suitable for evaluation of new antineoplastic drugs known to be active against specific and aggressive subpopulations of tumor cells.

Biomarkers, Tumor↗
PubMed1997

Androgens are not a direct requirement for the proliferation of human prostatic epithelium in vitro.

The androgen receptor pathway is known to be a key regulator of growth in the normal and pathological prostate. However, the precise mechanisms of this signaling pathway with respect to the different cellular compartments of the prostate remain largely unknown. We have used a primary culture system to grow human prostatic epithelial cells of normal, benign, tumor and metastatic origin, as well as immortalized human prostatic epithelial cell lines, to demonstrate the absence of a direct or indirect effect of androgens on cellular proliferation in vitro. In parallel to this observed androgen independence for growth, all cell systems lost significant expression of androgen receptor, prostate-specific antigen and prostatic acid phosphatase. Since the androgen receptor is expressed in the epithelium in situ, our results suggest that the androgen effect on epithelial cells may be one of prostatic differentiation rather than proliferation, and that the androgen receptor/growth factor pathway acts through mesenchymal-epithelial interactions.

Acid Phosphatase↗
PubMed1997

Pharmacological and molecular evidence for the expression of the two steroid 5 alpha-reductase isozymes in normal and hyperplastic human prostatic cells in culture.

BACKGROUND: Whereas the embryological development of the human prostate is clearly dependent on steroid 5 alpha-reductase (5 alpha-R) type 2 expression, the respective expression of the two known isoforms (types 1 and 2) of 5 alpha-R in the adult human prostate remains unclear. METHODS: 5 alpha-R isoform mRNA expression (Northern blots and reverse transcriptase-polymerase chain reaction [RT-PCR]) and enzyme activity were studied in immortalized epithelial cells (NE) and in fibroblasts from normal (NF) or hyperplastic (BPHF) human prostates. RESULTS: 5 alpha-R activity (fmol/microgram DNA/hr) was 1.43 +/- 0.5 in NE, 10.7 +/- 4.7 in NF, and 79 +/- 37 in BPHF. mRNAs for both 5 alpha-R isoforms were expressed in the three cell types, as shown by Northern blot and RT-PCR analysis. LY306089, a selective 5 alpha-R type 1 inhibitor, strongly inhibited 5 alpha-R activity in all cell types (IC50: 10 nM), confirming the predominant expression of 5 alpha-R type 1 in these cells. Finasteride, a 5 alpha-R type 2 inhibitor, was less efficient (IC50: 45, 35, and 65 nM in NE, NF, and BPHF, respectively). In addition, the inhibition by finasteride decreased with serial subculture in NF only, suggesting an effect of age in culture on the expression of 5 alpha-R type 2 in these cells. SKF105657, also a 5 alpha-R type 2 inhibitor, was a poor inhibitor in this system. CONCLUSIONS: These studies demonstrate that human prostate cells in culture express both isoforms of 5 alpha-R and suggest a balance in the expression of the two isoforms as a function of various regulatory factors.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1997

Constitutive expression of FGF2/bFGF in non-tumorigenic human prostatic epithelial cells results in the acquisition of a partial neoplastic phenotype.

Fibroblast growth factor 2 (FGF2), also known as basic fibroblast growth factor (bFGF), belongs to the FGF family, which consists of at least 9 closely related members. FGF2 is a potent mitogen for fibroblasts derived from normal prostate and, to a lesser extent, for prostatic epithelial cells. Its role in the physiology of the normal prostate seems to be limited to stromal cells, whereas in prostate cancer FGF2 may also have an autocrine/paracrine effect on epithelial cells. In order to better understand the effects of FGF2 on the prostatic epithelium, especially its role in the progression of prostate cancer by establishing an autocrine-stimulation loop, we transfected FGF2 cDNA into a human prostatic epithelial cell line, PNT1A, immortalized with SV40 large-T antigen. This cell line is non-tumorigenic and expresses a high-affinity FGF2 receptor, FGFR1/flg. We characterized 3 independent FGF2-transfected clones and found that the establishment of an FGF2 autocrine loop on these cells led to (i) serum-independent growth, (ii) increased proliferation and (iii) anchorage-independent growth. Such results argue in favor of the possible action of FGF2 on progression of prostate cancer via an FGF2 autocrine loop on epithelial cells.

Animals↗
PubMed1997

Loss of heterozygosity at chromosome 16q in prostate adenocarcinoma: identification of three independent regions.

Loss of heterozygosity (LOH) on chromosome arm 16q is one of the most consistent genetic alterations in sporadic prostate cancer and may be involved in cancer development through inactivation of tumor suppressor genes. A candidate tumor suppressor gene on this chromosome arm, CDH1 at 16q22.1, is dysregulated in prostate cancer. However, no specific deletion map has been constructed from prostate tumors to determine whether CDH1 is the potential target gene for the observed LOH on 16q. To narrow down the region of 16q loss, we constructed a detailed deletion map that incorporates CDH1. We examined the pattern of allelic imbalance in prostate tissue from 22 patients with confined prostate tumors, 22 with local extracapsular extension, and 15 with metastatic forms, using 14 CA microsatellite repeats on 16q. Thirty-five of the 59 tumors tested showed LOH for at least one marker. We found evidence of 16q monosomy in 5 cases and partial allelic loss in 30. Our data provide evidence that three different target regions on 16q might be involved in the pathogenesis of prostate cancer. The first region is telomeric and lies at 16q24.3 between markers D16S520 and D16S413; the second, the most centromeric region in the 16q22.1 band, and limited by markers D16S347 and D16S318, is close to the CDH1 gene; the third, intermediate region, at 16q23.2, is bracketed by loci D16S518 and D16S507. The rate of LOH at 16q24.3 was significantly higher in metastatic forms (80%; 12 of 15) than localized forms (32%; 7 of 22), pointing to a gene related to invasiveness in prostate cancer.

Adenocarcinoma↗
PubMed1997

In utero eyeball development study by magnetic resonance imaging.

The aim of this study was to measure fetal ocular development and to determine a growth curve by means of measurements in utero. Fetal ocular development was recorded by analysis of the results of magnetic resonance imaging (MRI). An anatomic study allowed definition of the best contrasted MRI sequences for calculation of the ocular surface. Biometric analysis of the values of the ocular surface in the neuro-ocular plane in 35 fetuses allowed establishment of a linear model of ocular growth curve in utero. Evaluation of ocular development may allow the detection and confirmation of malformational ocular anomalies such as microphthalmia.

Embryonic and Fetal Development↗
PubMed1997

Co-ordinated changes in expression of cell adhesion molecules in prostate cancer.

The expressions of E-cadherin, the integrin subunits beta 1, beta 2, beta 3, CD44 and alpha-catenin were studied in parallel by immunohistochemistry in a series of 40 prostate biopsies comprising one normal, 11 benign prostatic hyperplasia (BPH), and 28 prostatic adenocarcinomas. As reported by others, there was a consistent loss of E-cadherin expression with increasing tumour grade and de-differentiation. However, a significant proportion of losses occurred at earlier grades than previously reported. The parallel nature of this study showed, for the first time in human prostate carcinoma, a reciprocal expression pattern of E-cadherin and beta 1 integrin in the higher grades of prostate cancer. A reciprocal expression pattern was also found for E-cadherin and CD44 between moderately and poorly differentiated tumours. alpha-Catenin expression was downregulated only in those cells which had previously lost E-cadherin expression, and beta 2 and beta 3 integrin were rarely expressed in prostate tumours. A loss of expression of the luminal epithelial specific keratins CK8 and CK18 was also observed in advanced stage, poorly differentiated carcinomas.

Adenocarcinoma↗
PubMed1997

New experimental model of ureteropelvic junction obstruction allowing easy access for percutaneous surgery.

To assess the usefulness of an experimental model of ureteropelvic junction (UPJ) obstruction designed to facilitate subsequent percutaneous surgery, a right UPJ obstruction was created in 10 pigs by an open retroperitoneal surgical approach. With the pig in the left lateral decubitus position, a 0.038-inch Terumo guidewire was inserted via a 1-cm longitudinal upper-third ureterotomy and advanced up and down so as to bridge the UPJ from the flank to the urogenital opening. A UPJ obstruction was then induced by securing two 2-0 chromic gut ties, separated by an interval of 1 cm, over the Terumo guidewire and a 6F ureteral catheter, which was removed immediately after this procedure. After closure of the ureterotomy, the kidney was anchored horizontally to the muscle wall, and the Terumo guidewire was coiled subcutaneously in the flank and fixed to the urogenital opening. Each pig developed marked hydronephrosis, diagnosed by ultrasonography, after a mean interval of 8.3 days. Retrograde ureteropyelography confirmed this pronounced dilation of the right collecting system above a tight UPJ stricture (mean length 1.17 cm). Subsequent percutaneous access to the UPJ over the Terumo guidewire in the lateral decubitus position was facilitated by the almost-horizontal plane of dilation (mean operating time 14 minutes). Pathologic examination of the UPJ revealed mild periureteral fibrosis, but the muscle layer and urothelium remained normal. We have developed a reliable and reproducible model of secondary UPJ obstruction especially designed for percutaneous surgery. This model should provide a better understanding of current endoscopic techniques such as endopyelotomy and could help to promote new treatment concepts such as percutaneous endoscopic pyeloplasty.

Anastomosis, Surgical↗
PubMed1997

Evaluation of optimal stent size after antegrade endopyelotomy: an experimental study in the porcine model.

OBJECTIVES: To investigate the influence of two sizes of internal ureteral stents, 7 F and 12 F, on ureteropelvic junction (UPJ) healing after antegrade endopyelotomy. METHODS: A right UPJ stricture was created in 10 pigs using an open surgical retroperitoneal approach. This model of obstruction consists of initially bridging the UPJ with a Terumo guide wire through an upper third ureterotomy and securing two 2.0 chronic gut ties around the UPJ over the guide wire and a 6 F ureteral catheter. The ureteral catheter is then withdrawn and the guide wire left in situ coiled up within the lumbar wall and fixed to the urogenital opening. Eight days later, each UPJ stricture was incised percutaneously using the invagination technique. Five pigs received a 7 F double-pigtail ureteral stent, while the remaining 5 pigs received a 12/7 F internal endopyelotomy stent. These stents were removed 1 week later. Retrograde ureteropyelography was performed at three months and the UPJ were examined grossly and harvested for histologic studies. RESULTS: One of the 5 pigs in each study group developed a recurrent stricture. The two groups were not statistically different in terms of histologic findings, although fibrosis of the muscle layer was more pronounced in the 12 F group. CONCLUSION: The use of a large caliber stent after experimental antegrade endopyelotomy does not provide any advantage over the use of a smaller easily positioned 7 F stent.

Animals↗
PubMed1997

[Growth factors and prostatic tumors].

Prostate growth factor (PGF) was the first growth factor isolated from the prostate. Because of its proliferative effect on fibroblasts and its affinity for heparin, it was first recognized as belonging to the family of fibroblastic growth factors then identified as bFGF (basic fibroblast growth factor) by Story in 1980. The presence of paracrine signals between the fibromuscular stroma and the epithelial tissue in the prostate were first demonstrated in 1970 by the incapacity of epithelial cells to grow without the presence of mesenchymal tissue. These paracrine relations are established during embryogenesis of the prostate and are required for its development and functional control in the adult. Keratinocyte growth factor (KGF), also called FGF-7, could be a stomal androgen mediator with a mitogenic paracrine effect on the epithelium. Dysregulation of growth factors has been suggested to be involved in the development of prostate tumors in elderly men (benign hypertrophy and cancer of the prostate). FGFs probably play an important role in benign prostate hypertrophy. Several studies have demonstrated an important rise in mRNA levels for these factors in benign hyperplastic tissue compared with "normal" tissue. This increased level would be associated with fibromuscular proliferation in periglandular tissue and could explain, at least in prat, the epithelial hyperplasia often associated with the paracrine stimulating effect. In prostate cancer, different families of growth factors have been associated with acquisition of aggressive tumor functions. The EGF receptor and its ligands, the IGF family, beta TGF and certain neuropeptides could be partially implicated in androgen-independent autocrine growth. Heparin-related growth factors (FGFs, Midkine family), VEGF or endothelin could be more particularly implicated in metastatic progression by stimulating cell motility, angiogenesis and metastatic implantation by a two-way cooperation between the tumor and the stroma in which it is implanted. Several of these factors are found in the blood stream and have been proposed as biological markers of poor prognosis. Knowledge of peptides regulating prostate growth or of growth factor antagonists has led to the concept of antipeptidergic therapy as an adjuvant in antiprostate tumor regiments.

Aged↗
PubMed1996

Identification of endothelin receptors in normal and hyperplasic human prostate tissues.

Specific endothelin-1 (ET1) binding sites have been demonstrated in membranes derived form normal (NP) and benign hyperplasic (BPH) human prostate using an 125I-ET1 binding assay. 125I saturation experiments and Scatchard analysis demonstrated the existence of a homogeneous population of binding sites with high affinity (Kd(app)) and density (B(max)), respectively, 106 +/- 15 pM and 1086 +/- 399 fmol/mg protein for NP (n = 5) and 168 +/- 26 pM and 964 +/- 445 fmol/mg protein for BPH (n = 5). We demonstrated the presence of two subtypes of ET1 receptors, ETA and ETB, by means of the following ET1 competitors: ET2, ET3, and BQ123 (which is selective for the ETA receptor), and IRL1620 and sarafotoxine c (S6c) (which are selective for the ETB receptor). The displacement curves allowed us to conclude that the large majority (85%) of the ET1 receptors in normal and hyperplasic human prostate are of the A subtype.

Binding, Competitive↗
PubMed1996

Establishment of permanent human endothelial cells achieved by transfection with SV40 large T antigen that retain typical phenotypical and functional characteristics.

The plasmid pMK16 containing-SV40 replicated origin defective gene was efficiently introduced into early-passage human umbilical vein endothelial cells (HUVEC) using positively charged liposomes. The resulting cell line acquired an almost infinite lifespan, was morphologically unchanged, expressed SV40-antigen, and coexpressed von Willebrand factor (vWF), tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), angiotensin conversion enzyme (ACE), and endothelin converting enzyme (ECE). In addition, these are the first immortalized human endothelial cells, to our knowledge, that biosynthesized and secreted interleukins (IL-1 beta and IL-6) in both a constitutive and regulated fashion and endothelin-1 (ET-1), the most potent vasoactive peptide, which has been suggested to be implicated in the pathogenesis of hypertension. Interestingly enough, both of the immortalized cells and the early-passage HUVEC from which the immortalized cells were obtained biosynthesized and secreted the same levels of ET-1 suggesting full maintenance of its biosynthetic pathway including the presence of active ECE, which cleaves big endothelin-1 (big-ET-1) to ET-1 and regulation factors. Moreover, the immortalized cells retained the ability to express the functional specific amino acid Na(+)-independent system Y+ transporter, which mediates L-arginine transport into endothelial cells from which endothelium-derived relaxing factor (EDRF, nitric oxide) is formed via the action of nitric oxide-synthase. Obtaining these immortalized human endothelial cells without alteration of the differentiated characteristics constitutes a useful model: (a) to study ET-1 secretion, gene regulation, and human ECE, which may be an important therapeutic target in disease conditions in which ET-1 is to be implicated; (b) to study L-arginine transport, which is a key step in the formation of EDRF; (c) to study IL-1 beta and IL-6 secretions, and gene regulations; (d) to substitute large quantities of HUVEC; and, finally, (e) to reproduce, starting with different primary endothelial cells both from human and animal origin.

Antigens, Polyomavirus Transforming↗
PubMed1996

Human prostatic cells in culture: different testosterone metabolic profile in epithelial cells and fibroblasts from normal or hyperplastic prostates.

The prostate gland depends on androgens for its development and the maintainance of its differentiated structures and secretory function. We have characterized the metabolic pathways of testosterone in isolated epithelial (NE) and fibroblast cultured cells from normal (NF) and hyperplastic (BPHF) prostates, in order to provide a tool for the study of androgen function in the prostate in defined conditions. In NE, 5 alpha-reductase (5 alpha-R) is the predominant metabolic pathway whereas in NF 17 beta-hydroxysteroid dehydrogenase (17 beta-OHSDHase) is the main activity. However, 5 alpha-R in NF is 5-10-fold higher than in NE. Furthermore, a striking increase in both enzyme activities is observed in fibroblasts from hyperplastic prostates (5 alpha-R x 8; 17 beta-OHSDHase x 250 relative to NF). delta 4-androstenedione could serve as a reservoir for testosterone or could be a tentative protective mechanism directing testosterone metabolism towards an inactive molecule. In conclusion, human epithelial and stromal cells maintain in culture their main metabolic characteristics. The knowledge derived from these studies should facilitate the reconstitution and analysis of their interactions, which in vivo may modify their respective metabolism.

17-Hydroxysteroid Dehydrogenases↗
PubMed1996

Percentage of free serum prostate-specific antigen: a new tool in the early diagnosis of prostatic cancer.

Prostate-specific antigen (PSA) is a protease able to bind to serum antiproteases as alpha 1 antichymotrypsin (ACT). Free PSA (FPSA) corresponds to the fraction of total PSA (TPSA) which is unbound to ACT. Specific detection of the FPSA seems to be a valuable tool in the distinction between prostatic cancer (PCa) and benign prostatic hyperplasia (BPH). Our aim was to evaluate retrospectively the FPSA/TPSA ratio in comparison to TPSA or FPSA determination, using two new immunoradiometric assays (PSA-RIACT and FPSA-RIACT, CIS bio international, Gif Sur Yvette, France) in the early diagnosis of PCa. 256 men, with TPSA levels between 0.7 and 44.7 ng/ml (median age = 69 years), including 164 sera obtained from patients with BPH and 92 sera from patients with untreated PCa were assayed. All diagnoses were histologically confirmed and patients tested before any adjuvant treatment. The evaluation of the median FPSA/TPSA ratio in the two groups showed significantly different values (BPH group: 24.2%, PCa group: 12.1%, P < 0.0001). By R.O.C. (Receiver-Operating-Characteristics) analysis, we show that the FPSA/TPSA ratio is the method of choice for discriminating BPH and PCa, since the area under curve is the greatest for the FPSA/TPSA ratio curve, as compared to the TPSA or FPSA curves (P < 0.0001). The best accuracy (number of true positive + true negative/total = 82.4%) was obtained with a FPSA/TPSA ratio < or = 15% with high odds ratio (20.5; confidence interval (CI): 11.2; 37.7). Of interest, similar results were also confirmed even in the subpopulation with serum TPSA levels between 2.5 and 10 ng/ml (161 patients including 99 BPH and 62 PCa). We thus confirm that combined serum measurement of FPSA and TPSA is of particular interest in the early diagnosis of PCa for patients with non-suspicious digital rectal examination and a TPSA value between 2.5 and 10 ng/ml. In those patients, biopsy should be reserved to the cases with FPSA/TPSA below 15%, which allows significant odds ratio (12.8; CI: 5.2; 31.4). Otherwise, to avoid the risk of missing any PCa, usual follow-up with combined TPSA and FPSA determination would be required with the same criteria of biopsy (i.e. FPSA/TPSA ratio < or = 15% when TPSA value is between 2.5 and 10 ng/ml; or TPSA > 10 ng/ml).

Adult↗