[Histologic forms of benign prostatic hyperplasia: focus on fibroblastic factors].
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Fibroblast Growth Factor 2↗
Biomedical subjects
O Cussenot
Publications and source records attributed to O Cussenot.
Clinical relevance of genetic instability in prostatic cells obtained by prostatic massage in early prostate cancer.
We investigated whether genetic lesions such as loss of heterozygosity (LOH) are detected in prostatic cells obtained by prostatic massage during early diagnosis of prostate cancer (CaP) and discussed their clinical relevance. Blood and first urine voided after prostatic massage were collected in 99 patients with total prostate-specific antigen (PSA) between 4 and 10 ng ml(-1), prior to prostate biopsies. Presence of prostatic cells was confirmed by quantitative RT-PCR analysis of PSA mRNA. Genomic DNA was analysed for LOH on six chromosomal regions. One or more allelic deletions were found in prostatic fluid from 57 patients analysed, of whom 33 (58%) had CaP. Sensitivity and specificity of LOH detection and PSA free to total ratio <15% for positive biopsy were respectively 86.7 and 44% (P=0.002) for LOH, and 55 and 74% (P=0.006) for PSA ratio <15%. Analysis of LOH obtained from prostatic tumours revealed similar patterns compared to prostatic fluid cells in 86% of cases, confirming its accuracy. The presence of LOH of urinary prostatic cells obtained after prostatic massage is significantly associated with CaP on biopsy and may potentially help to identify a set of patients who are candidates for further prostate biopsies.
Aged↗
In vivo retroviral mediated gene transfer into bladder urothelium results in preferential transduction of tumoral cells.
OBJECTIVES: Superficial bladder tumours are at high risk for recurrence, relapse after resection, escape to intravesical immunotherapy and they may become invasive. New therapeutics are therefore needed to achieve cure. Thus, gene therapy is an attractive new treatment modality for malignant bladder tumours. The purpose of this study was to evaluate the feasibility and the efficiency of retroviral mediated reporter gene transfer into malignant urothelial cells both in vitro and in vivo. METHODS: We evaluated the feasibility of the transfection of bladder tumour with direct intravesical instillation of a defective retrovirus. The vector was derived from LXSN. The efficiency of transduction with the Moloney Leukaemia Murine virus-based vector, amphotrophic retroviral vector, was monitored through the expression of two marker genes (nls-LacZ and NeoR). The canine animal was chosen since it can present with spontaneous bladder carcinomas mimicking human pathology. Primary cultures of two normal canine bladder urothelium and two canine primary bladder tumours were first studied. We then investigated in vivo, in two normal and two spontaneous tumour bearing dogs, the transduction of urothelial cells following direct intravesical instillation of 2.10(4) to 3.10(6) of the retroviral vector. RESULTS: Transduced cells were evidenced in all primary cultures of canine normal urothelium and transitional cell carcinoma. Bladder biopsies from sound dogs instilled with the viral solution showed long lasting transduction up to 60 days long. Bladder cryosections from tumour-bearing dogs displayed transduction of superficial layers of urothelial cancer cells without passing through lamina propria. In vivo transduction was evidenced in 1 to 15% (mean 5%) of the cells in the tumours and preferentially addressed malignant cells. Normal epithelium either originating from sound or tumour-bearing animals was not transduced. CONCLUSION: These results demonstrate for the first time the feasibility of in vivo retroviral transduction of bladder cancer using a clinically relevant procedure.
Administration, Intravesical↗
Prostate cancer genetics.
Prostate cancer (PC) is the most frequent malignant tumor among men over 50 years old. Its incidence varies according to countries and ethnic groups. Known risk factors are race and positive family history of the disease. Familial aggregation (at least 2 cases in the family) is observed in about 20% of cases and a hereditary form of PC, compatible with a Mendelian inheritance, in 5%. This proportion increases with younger age at diagnosis. Eight putative loci are already identified for hereditary PC but undoubtedly, others will be found in forthcoming studies. The genetic heterogeneity observed in hereditary PC reflects variety of origins of the studied families. Agreggation of PC and other cancers in some families suggests the involvement of common susceptibility genes. In other familial form and in sporadic cases, the genetic component should be polygenic: PC wouldn't result from segregation of a major gene mutation transmitted according to a monogenic inheritance, but rather to sharing of alleles at many loci, each contributing to a small increase in cancer risk. Indeed, several genetic polymorphisms were associated with an increased risk of developing PC and could explain the variations of PC incidence observed between populations.
Humans↗
S100A6 (Calcyclin) is a prostate basal cell marker absent in prostate cancer and its precursors.
S100A6 (Calcyclin) is a calcium-binding protein that has been implicated in a variety of biological functions as well as tumorigenesis. The aim of our study was to investigate the involvement of S100A6 during prostate cancer development and progression. Using immunohistochemistry, the expression of S100A6 was examined in benign (n=66), premalignant (n=10), malignant (n=66) and metastatic prostate (n=5) tissues arranged in a tissue-microarray or whole sections as well as in prostate cancer cell lines. The S100A6 immunostaining pattern in tissues was compared with that of cytokeratin 5 (a basal cell marker) and 18 (a benign luminal cell marker). In all cases of benign epithelium, intense S100A6 expression was seen in the basal cell layer with absent staining in luminal cells. In all cases of prostatic adenocarcinoma (matched), metastatic lesions and 3/10 high-grade prostatic intraepithelial neoplasia lesions, an absence of S100A6 was seen. Western blotting and RT-PCR analysis of cell lines showed S100A6 expression to be absent in LNCaP, LNCaP-LN3 and LNCaP-Pro5 but present in Du145, PC3, PC-3M and PC-3M-LN4. LNCaP cells treated with 5-Azacytidine, caused re-expression of S100A6 mRNA. Sequencing of bisulphite modified DNA showed CpG methylation within the S100A6 promoter region and exon 1 of LNCaP, LNCaP-LN3 and LNCaP-Pro5 cell lines but not in Du145 cells. Our data suggest that loss of S100A6 protein expression is common in prostate cancer development and may occur at an early stage. The mechanism of loss of expression may involve hypermethylation of CpG sites. The finding of intense S100A6 expression in the basal cells of benign glands but loss of expression in cancer could be useful as a novel diagnostic marker for prostate cancer.
Adenocarcinoma↗
Anatomical histological and mesoscopic study of the adipose tissue of the orbit.
Our study aimed to define the organization of the orbital adipose tissue, which is constituted from white adipose tissue. Six orbital samples were taken by dissection from fresh cadavers. After fixation and paraffin-embedding, the blocks were sectioned in the three spatial planes (two in the frontal, two in the sagittal, two in the horizontal). Semi-serial sections of 7 microm were then stained with hematein, eosin, safran or Masson trichrome green. We noticed strong areas of adhesion with orbital bones located at the lacrimal gland, the orbital trochlea and the inferior orbital fissure. Our mesoscopic and histological results allowed the description of two types of orbital adipose tissue corresponding to morpho-functional topographic variations. One was constituted of thick conjunctival septa with small adipocytes near muscles and the lacrimal gland. This was a supporting tissue that gave the points of rotation. The other was constituted of thin conjunctival septa with larger adipocytes near the optic nerve, allowing its movements in the orbit. These morphological differences appeared to be correlated with the mechanical role of these two areas. The dense appearance could correspond to the functional trochlea of rectus muscles described. In contrast we did not observe the systematic radial and concentric conjunctival meshwork classically described. This study underlines the specificity of orbital adipose tissue, which could be useful for a better understanding of its normal and pathological partition and its involvement in ocular motility.
Adipose Tissue↗
[Prostate cancer: Diagnosis and staging].
The discovery and the use of serum prostate specific antigen (PSA) has considerably improved the diagnosis of prostate cancer during the past 20 years. Before PSA era, early diagnosis was only based on the digital rectal examination (DRE) of which the Limitations have been evidenced; over half of the tumours diagnosed by such means had already spread out of the prostate and were incurable. Assessment of serum PSA has allowed the diagnosis to be made at an earlier stage of the disease, curable by current treatments. Whichever the diagnostic tools, transrectal ultrasound (TRUS) prostatic biopsies remain necessary for diagnosis ascertainment, taking into account the low specificity of PSA assessment. The feasibility of a diagnosis at an early and curable stage of the disease has logically resulted in screening procedures aimed at reducing the high mortality related to prostate cancer. The numerous publications on prostate cancer screening provide precise information on the accuracy of available diagnostic means (PSA, DRE, TRUS, combined PSA and DRE), on the characteristics of screened tumours (stage and differentiation), and also on the population of men likely to benefit from the screening (age at beginning and end of the screening, frequency of PSA testing, identification of the men with ethnic and/or genetic predisposition). In those early diagnosed prostate cancers, the assessment of loco-regional cancer extension (extracapsular and/or, microscopic nodal involvement), remains unsatisfactory because no imaging technique (ultrasonography, CT scan, MRI,...) allows visualising the tumour itself or microscopic metastases. Nevertheless, the combination of multiple parameters such as DRE data, PSA level, biopsy data and tumour differentiation helps approaching with an increasing precision (nomograms) the true pathologic stage of the disease. Such advances allow distinguishing, among the very heterogeneous group of prostate cancers, tumours that differ from one to another in terms of disease stage, progression and prognosis, which is helpful for the determination of an adapted therapeutic strategy.
Aged↗
[Prostate cancer. Treatment].
The discovery and the utilisation of the prostate specific antigen (PSA) that allows early diagnosis of prostate cancer, have considerably improved the management of this disease. Before the PSA era, prostate cancer was just a disease of the old man, generally detected at an advanced stage and incurable, with a fatal outcome delayed by the androgenic deprivation. Since early 1990's, prostate cancer has become primarily a disease of the man of 60 years, detectable earlier, and curable provided no extraprostatic dissemination has occurred. Early treatment of prostate cancer has benefited from important advances in surgical and radio-therapeutic techniques (conformational irradiation, brachytherapy), with, as principal goal, the combination of a better survival and the reduction of the potential adverse effects that alter quality of life. A better definition of the characteristics of the tumours in terms of progression regarding various parameters (clinical stage, PSA, tumoral differentiation) have resulted, despite the heterogeneity of the disease, in the determination of subgroups of tumours with different prognosis, which leads to an improved therapeutic strategy. The assessment of men's life expectancy (< or > 10 years) is the second primary parameter on which is based the indication for curative or non curative therapy in case of localized tumour. Roughly, before the age of 75, a curative therapy is indicated whereas after this age a surveillance is reasonable as first-line treatment, followed by hormone therapy in case of onset of symptoms indicating some progression of the disease (urinary symptoms, bone lesion). At a Later stage, in case of a metastatic or locally advanced cancer, hormone therapy by androgenic deprivation is highly indicated. The hormone sensitivity characterizes prostate cancer; it has been discovered more than 50 years ago by Charles Huggins (Nobel prize-winner). This hormone therapy is a palliative treatment since its efficacy is transient (ineluctable occurrence of hormone resistance in a variable time delay), but it constitutes an essential therapeutic means with a well-established efficacy. Hormone therapy has progressively improved, with the renunciation of oestrogen therapy and surgical castration which has been replaced by luteinizing hormone-releasing hormone (LH-RH) analogues, and/ or anti-androgens. Numerous works have resulted in a better rationalization of the prescription (date of treatment initiation, interest of combined androgenic deprivation, ...) but uncertainties remain, such as the therapeutic interest of intermittent treatment, or of earlier hormone therapy combined with the treatment of the primitive tumour (adjuvant hormone therapy). Finally, at the time of the hormonal escape of which the molecular mechanisms remain unclear, no therapy has proven any efficacy in survival lengthening, and the treatment remains palliative and symptomatic. Although improved knowledge of prostate cancer aetiology is expected for a real disease prevention, early diagnosis at a curable stage of the disease (by PSA assessment) remains the only means for mortality reduction.
Aged↗
[Prostate cancer. Epidemiology. Risk factors. Pathology].
Prostate cancer (prostate adenocarcinoma) has become an important concern in terms of public health these past fifteen years; recent French epidemiological data revealed 10,104 deaths due to this disease in 2000. The two main factors involved are the serum prostatic specific antigen (PSA), routinely used since late 1980's and which allows early diagnosis (before symptom onset), and the lengthened duration of life. Such cancer is rare before the age of 50, but its frequency increases with age, making it the most frequent type of cancer in French men. Although the aetiology of this disease is unknown, the ethnic origin, and a familial history of prostate or breast cancer are known risk factors. Predisposing genes to such hereditary types remain to be identified. Other genetic factors (polymorphisms), combined with environmental factors such as nutrition, have been incriminated, which is likely to explain the geographical variations of this affection. At the molecular level, the mechanisms involved in the tumoral initiation and progression remain unclear. Various genetic alterations have been identified among the genome of cancerous cells, at various stages of the affection: intraepithelial neoplasia, localized, locally advanced, metastatic or hormone refractory stage -, hormonal escape). However, the precise sequence and nature of the complex molecular events remain to be determined prior to their routine utilisation in the determination of subjects at risk, or as prognostic factors, and even as therapeutic targets. The anatomopathology is a key for the diagnosis. Intraepithelial neoplasia is the pre-cancerous lesion observed in most adenocarcinomas; these are localized in the peripheral part of the prostate gland in 70% of the cases. Gleason's classification is the current gold standard for the determination of tumoral aggressiveness and categorisation of the adenocarcinomas which are basically heterogeneous (coexistence of tumors cells with different degrees of differenciation in the same tumor). This anatomopathological classification allows distinguishing the tumours in terms of potential progressiveness and prognosis, and hence, to orientate the therapeutic strategy in case of localised or locally advanced prostate cancer.
Adenocarcinoma↗
Microsatellite instability as indicator of MSH2 gene mutation in patients with upper urinary tract transitional cell carcinoma.
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Aged↗
DNA microarrays in clinical practice: past, present, and future.
Gene expression is a central concept in molecular biology and forms part of our knowledge of the role of genes in human diseases. Genome-wide monitoring of gene expression using DNA microarrays (allowing the simultaneous assessment of the transcription of tens of thousands of genes, and of their relative expression between normal cells and pathological cells) represents one of the latest breakthroughs in experimental molecular biology and provides unprecedented opportunity to explore the biological processes underlying human diseases by providing a comprehensive survey of a cell's transcriptional landscape. This revolutionary technology ultimately leads to the discovery of new biomarkers for disease diagnosis and prognosis prediction, and of new therapeutic tools. This paper provides an overview of microarray technology and describes some of its recent applications in medicine.
Gene Expression↗
Segregation analysis of prostate cancer in France: evidence for autosomal dominant inheritance and residual brother-brother dependence.
Four segregation analyses concerning prostate cancer (CaP), three conducted in the United States and one in Northern Europe, have shown evidence for a dominant major gene but with different parameter estimates. A recent segregation analysis of Australian pedigrees has found a better fit of a two-locus model than single-locus models. This model included a dominantly inherited increased risk that was greater at younger ages and a recessively inherited or X-linked increased risk that was greater at older ages. Recent linkage analyses have led to the detection of at least 8 CaP predisposing genes, suggesting a complex inheritance and genetic heterogeneity. To assess the nature of familial aggregation of prostate cancer in France, segregation analysis was conducted in 691 families ascertained through 691 CaP patients, recruited from three French hospitals and unselected with respect to age at diagnosis, clinical stage or family history. This mode of family inclusion, without any particular selection of the probands, is unique, as probands from all previous analyses were selected according to various criteria. Segregation analysis was carried out using the logistic hazard regressive model, as incorporated in the REGRESS program, which can accommodate a major gene effect, residual familial dependences of any origin (genetic and/or environmental), and covariates, while including survival analysis concepts. Segregation analysis showed evidence for the segregation of an autosomal dominant gene (allele frequency of 0.03%) with an additional brother-brother dependence. The estimated cumulative risks of prostate cancer by age 85 years, among subjects with the at-risk genotype, were 86% in the fathers' generation and 99% in the probands' generation. This study supports the model of Mendelian transmission of a rare autosomal dominant gene with high penetrance, and demonstrates that additional genetic and/or common sibling environmental factors are involved to account for the familial clustering of CaP.
Age of Onset↗
A candidate gene approach within the susceptibility region PCaP on 1q42.2-43 excludes deleterious mutations of the PCTA-1 gene to be responsible for hereditary prostate cancer.
OBJECTIVE: The Prostate Carcinoma Tumor Antigen-1 (PCTA-1) is located at the prostate cancer susceptibility locus on chromosome 1q42.2-43 (PCaP). In this candidate gene approach, we searched for deleterious mutations within the PCTA-1 gene and its promoter. MATERIALS AND METHODS: Seventy-seven familial prostate cancer cases from 36 German and French pedigrees were screened for germline mutations in the PCTA-1 gene using enzymatic mutation detection (EMD). Putative missense mutations were genotyped by RPLP and ddNTP primer extension assays in 88 controls to assess allele frequencies and haplotypes. RESULTS: Several sequence variants were found but none of the findings indicated a deleterious mutation. Three affected brothers showed an intronic variation, which may interfere with correct splicing. Four non-conservative SNPs were characterized, coding for the amino acid alterations Y19F, C36R, V56M and S184R. All exchanges were found in controls with common allelic frequencies of at least 28%. Haplotype definition including six SNPs within the PCTA-1 gene revealed a complete linkage disequilibrium. Low haplotype diversity leads to a predominance of only two peptide variants of the PCTA-1 protein, coded by 95% of all chromosomes. CONCLUSIONS: PCTA-1 is not a classical high risk gene with deleterious mutations predisposing to hereditary prostate cancer. Its contribution to prostate cancer susceptibility as a low risk factor in sporadic disease has to be assessed in larger samples by association studies.
Galectins↗
Human prostatic cell line PNT1A, a useful tool for studying androgen receptor transcriptional activity and its differential subnuclear localization in the presence of androgens and antiandrogens.
The human immortalized prostatic cell line PNT1A has been proved to be a good model for analysis of cellular processes such as the prostatic epithelium proliferation in response to androgens and growth factors. Here we used this cell line for studying the transcriptional activity and trafficking of the androgen receptor (AR) by analyzing several actions of antiandrogens. Transient transfection experiments with PNT1A cells were performed with wild type human AR and an androgen-responsive gene reporter. We demonstrated that the transcription of reporter gene could be triggered by natural androgens (testosterone and dihydrotestosterone) in PNT1A cells as well as in the prostatic carcinoma cell line DU-145. With competitive experiments in the two cell lines, we observed no difference between the antagonistic capacity of cyproterone acetate (CPA) and hydroxyflutamide at 10(-7) M. At this concentration, bicalutamide antagonist activity was lower. In parallel, we compared the subcellular localization of the modified green fluorescent protein (EGFP)-AR in COS-7, PNT1A and DU-145 cell lines under fluorescence microscopy: we found different distributions between nucleus and cytoplasm, depending on the cell line and the culture medium. Androgen induced cluster formation within the nucleus of the PNT1A and DU-145 cells. However, the cytonuclear trafficking of androgen bound EGFP-AR in the same living cell and nuclear foci were easier to examine in the PNT1A cells. The antiandrogen capacity of bicalutamide was manifested by a slower androgen-dependent nuclear transfer of EGFP-AR and a homogeneous nuclear localization. A delayed advent of nuclear clusters was observed in presence of CPA. We conclude that the PNT1A cell line is a better model than the DU-145 cell line to analyze the trafficking of AR and the association of AR on the nuclear matrix, as well as to observe the action of antiandrogens on these critical steps in prostate cells.
Active Transport, Cell Nucleus↗
Prostate carcinoma risk and allelic variants of genes involved in androgen biosynthesis and metabolism pathways.
BACKGROUND: Ethnicity, when it is used to mean shared genetic inheritance within a group, has become one of the most important factors in determining prostate carcinoma risk. Genetic polymorphisms were hypothesized to be the probable explanation for differences in risk among ethnic groups. The authors evaluated the association between polymorphisms in genes involved in the androgen biosynthesis and metabolism pathway and the risk of prostate carcinoma. METHODS: Two hundred twenty-six patients with the pathologic diagnosis of sporadic prostate tumor and 156 healthy matched (age, ethnic group) male controls from a large epidemiologic cohort were genotyped for previously described polymorphisms in the androgen receptor (AR), 5alpha-reductase type II (SRD5A2), p450c17 (CYP17), and aromatase (CYP19) genes. The different polymorphisms in prostate carcinoma patients also were analyzed according to age of onset, preoperative prostate-specific antigen level, tumor stage, and tumor grade. RESULTS: The distribution of the tetranucleotide simple tandem repeat polymorphism (STRP) in intron 4 of CYP19 was significantly different in control and cancer patients (P = 0.012). The 171 allele and the 187 allele were associated with prostate carcinoma risk (P = 0.05 and P = 0.045, respectively). Conversely, no association was observed between prostate carcinoma risk and the other polymorphisms studied as follow: the CAG repeat in exon 1 of AR, the (TA)n dinucleotide repeat polymorphism in the 3' untranslated region, and the A49T or V89L substitutions in SDR5A2, the single base pair (bp) (a T to C transition) polymorphism that creates an additional Sp1-type (CCACC box) promoter site in CYP17. In prostate carcinoma patients, CAG repeats of AR, and TA repeats of SDR5A2 are associated with age of onset (P = 0.05 and P < 0.001, respectively). CONCLUSIONS: The association between the 171-bp allele of CYP19 and prostate carcinoma risk suggests that aromatase could be used as a new indicator for prostate carcinoma prevention in men of White French ethnogeographic origin. Conversely, it is possible that an individual carries both a high- and a low-risk marker (e.g., CYP17 A2 allele and V89L in SRD5A2) resulting in no overall difference in risk observed across the population. For these reasons, the development of a polygenic model, incorporating multiple loci from the individual genes may maximize the chance of identifying individuals with high-risk genotypes.
Aged↗
No evidence of linkage to HPC20 on chromosome 20q13 in hereditary prostate cancer.
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Aged↗
Evaluation of androgen, estrogen (ER alpha and ER beta), and progesterone receptor expression in human prostate cancer by real-time quantitative reverse transcription-polymerase chain reaction assays.
Steroid hormones can have profound effects on prostate tumor development making it important to define steroid receptor expression in prostate tissues. For this purpose, androgen receptor (AR) and estrogen receptor (ER alpha and ER beta) expression was quantified in 12 clinically localized and 11 hormone-refractory sporadic prostate tumors, using real-time quantitative reverse transcription-PCR assays. To gain more insight into hormone-responsiveness, estrogen-regulated progesterone receptor (PGR) and androgen-regulated prostatic acid phosphatase (PAP) mRNA levels were also quantified. There is a decrease in expression of ER beta in both clinically localized and hormone-refractory tumors relative to normal prostate tissues. Moreover, hormone-refractory tumors display a decreased expression of ER alpha and an increased expression of AR. There is a positive association between ER alpha, ER beta, and PGR expression (P < 0.0001) and a negative association between AR and the androgen-regulated gene PAP expression in hormone-refractory tumors. Taken together, these data indicate that, although increased expression of the AR gene might play a key role in endocrine treatment failure, it cannot be considered as the sole actor of this unresolved dilemma, and abnormalities in ER alpha and/or ER beta expression may also modulate the growth response of prostate cancer to hormone withdrawal. Our results also suggest that ER alpha and ER beta expression status could be used to identify advanced prostate tumor patients who may respond to antiestrogen therapy.
Acid Phosphatase↗
In vivo model mimicking natural history of dog prostate cancer using DPC-1, a new canine prostate carcinoma cell line.
BACKGROUND: Dog prostate cancer is usually considered to be highly relevant to human prostate cancer. We report the isolation of a new canine prostate cancer epithelial cell line designated DPC-1. METHODS: Primary cultures were established from a canine poorly differentiated prostatic adenocarcinoma. Population doubling time was determined by counting nuclei after cell lysis. Tumorigenicity was assessed in nude mice and in one adult immunodeficient dog. Immunoscintigraphy was performed in both models using a monoclonal antibody (mAb) raised against the [44-62] sequence of human PSMA. RESULTS: DPC-1 cells have a rapid growth in vitro (doubling time, 27 hr) which is not stimulated by androgens. In addition, DPC-1 displays immunoreactivity to human PSA and PSMA. DPC-1 was found to be highly tumorigenic not only in nude mice but also for the first time after orthotopic seeding in an immunodeficient dog. This allograft mimicked, in a compressed form, the aggressive biological behavior of spontaneous dog prostate adenocarcinoma. Immunoscintigraphy using a (131)Iodine-labeled PSMA mAb clearly visualized induced tumors in nude mice and in the dog allograft. CONCLUSIONS: This study suggests that DPC-1 may constitute a powerful model for assessing new diagnostic and/or therapeutic tools in the management of prostate cancer.
Adenocarcinoma↗