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F Smedts

Publications and source records attributed to F Smedts.

At least 19 recordsLinked to original sources
PubMed2006

Genomic integration of oncogenic HPV and gain of the human telomerase gene TERC at 3q26 are strongly associated events in the progression of uterine cervical dysplasia to invasive cancer.

Recently proposed events associated with the progression of cervical intraepithelial neoplasia (CIN) 2/3 to cervical carcinoma include integration of human papillomavirus (HPV) into the host genome, genomic instability, and an increase in chromosome 3q copy number. In particular, the gene coding for the RNA component of telomerase (TERC) at 3q26 has been implicated as a possible candidate gene. Since it is not known to date how these events are temporally related during cervical carcinogenesis, the aim of the present study was to assess the correlation between TERC gene copy number and the physical status of HPV during progression in cervical neoplasia. Solitary precursor lesions of the uterine cervix (CIN 2/3, n = 17), lesions associated with a micro-invasive carcinoma (CIN 3&mCA, n = 13), and advanced invasive carcinomas (invCA, n = 7) were analysed by fluorescence in situ hybridization (FISH) to determine the physical status of the virus and TERC gene copy number. The TERC gene was increasingly gained with progression of CIN 2/3 (3 of 17) through CIN 3&mCA (7 of 13) to invCA (5 of 7). In the lesions exhibiting gain of TERC, the virus was predominantly integrated. This was seen in eight of ten diploid lesions, indicating that these events can occur prior to aneuploidization and are strongly associated with the progression of CIN 3 to mCA and invCA (p < 0.001). With progression to carcinoma, a number of these lesions show polyploidization, resulting in aneuploidy and high TERC gene copy numbers. In conclusion, genomic integration of oncogenic HPV and gain of the human telomerase gene TERC appear to be important associated genetic events in the progression of uterine cervical dysplasia to invasive cancer.

Cell Transformation, Neoplastic↗
PubMed2001

Proliferative activity and branching morphogenesis in the human prostate: a closer look at pre- and postnatal prostate growth.

BACKGROUND: To gain further insight into the molecular cell biologic features of prostate development, we investigated the proliferative activity of prostate epithelial and stromal cells and their topographic relationship with neuroendocrine (NE) cell distribution and regional heterogeneity. METHODS: Consecutive sections from 43 prostates taken during autopsy representing fetuses (12-38 weeks of gestation), infants, prepubertal males and adults were double stained for chromogranin A and MIB-1. MIB-1 labeling index (LI) was calculated in the budding tips, forming acini, major collecting ducts, adjacent and non-adjacent stromal compartments. Furthermore, the topographic relationship between proliferating cells and NE cells was evaluated. RESULTS: In the first half of gestation, cell proliferation as revealed by MIB-1 LI was significantly higher in epithelial structures and stroma than in older fetuses and other age groups. MIB-1 LI was higher in budding tips than in other epithelial regions. MIB-1 LI in stroma adjacent to budding tips was not higher than that adjacent to other epithelial branching segments. Co-expression of chromogranin A and MIB-1 staining was not observed. MIB-1 LI was lower in cells in the direct vicinity of chromogranin A positive NE cells than at a distance from NE cells. CONCLUSIONS: Prostate development in the first half of gestation is explosive. Thereafter, the prostate basically is a slow-growing organ. Budding tips are the major growth foci during early prostate development, while stromal growth is evenly distributed throughout the prostate, probably indicating that stromal-epithelial interactions do not manifest in enhanced proliferation at their interface. NE cells may have an inhibitory effect on proliferation of exocrine epithelial cells and are probably only associated with differentiation of prostate exocrine cells in the prostate.

Adult↗
PubMed2001

Branching activity in the human prostate: a closer look at the structure of small glandular buds.

OBJECTIVE: Knowledge regarding cell biologic characteristics of small solid glandular buds in the prostate and their relationship with branching activity in the human prostate is still fragmentary. Our object was to demonstrate, on the basis of immunophenotype, loci that harbor the potential for branching activity within the adult human prostate. MATERIALS AND METHODS: Semiserial sectioning was performed on 13 adult prostates in an effort to identify structures in the prostate that could be considered foci of growth. Selected slides were stained with biomarkers for basal/luminal cells (keratins), proliferation (MIB-1), apoptosis inhibitor (bcl-2), intercellular adhesion (E-cadherin), and stromal-epithelial interactions (tenascin-C). Results were compared with fetal and prepubertal human prostates and microdissected rat prostates. RESULTS: Five histologic epithelial structures were identified in 19 paraffin blocks, which on serial sectioning showed morphologic transitions with a common pattern, consisting of reduction in number and caliber of acini until small solid buds of epithelial cells were reached. Immunophenotypically, the small solid glandular buds had a basal-cell keratin phenotype, expression of bcl-2 in virtually all cells, high proliferative activity, prominent intracellular localization of E-cadherin, and enhanced periglandular tenascin-C immunoreactivity. The budding tips in fetal and prepubertal prostates revealed an immunostaining pattern identical to the small solid glandular buds in the adult, but different to the rat prostate. CONCLUSIONS: Our data suggest that dispersed small solid glandular buds have a capacity for growth, and as such may be considered foci of resumed reawakening branching activity with in the adult human prostate.

Adult↗
PubMed2000

Neuroendocrine cells during human prostate development: does neuroendocrine cell density remain constant during fetal as well as postnatal life?

BACKGROUND: Knowledge concerning differentiation of neuroendocrine (NE) cells during development of the human prostate is rather fragmentary. Using immunohistochemistry combined with a morphometric method, we investigated the distribution and density of NE cells in the developing human prostate, with special emphasis on the topographical relationship of NE cells with the developing gland. METHODS: Consecutive sections from a total of 42 human prostates taken during autopsy of fetuses (12-38 weeks of gestation), prepubertal males, and young adults were immunostained for chromogranin A and serotonin. Computer-assisted image analysis was used to assess the total number of cells in the different parts of the branching glandular anlage, i.e., budding tips and acini/ducts. Next, the number of NE cells was counted manually. The NE cell density (NE cell index) was then determined. RESULTS: NE cells could first be detected in the prostate from 13 weeks of gestation. By 21 weeks of gestation, all prostates contained NE cells. NE cells were mainly confined to the acinous/ductal regions, while most of the budding tips lacked NE staining. NE cell indexes of individuals were highly variable, mostly in the youngest age group. CONCLUSIONS: In the normal prostate, NE cell density probably remains constant in acini/ducts from fetuses to young adulthood. The presence of neuroendocrine cells in well-developed glandular structures at such an early fetal age and their absence in the less differentiated budding tips possibly indicates that differentiation of NE cells is associated with glandular maturation. NE cells occur preferentially in the acinous/ductal region, implying a paracrine function during secretory differentiation of exocrine epithelial cells.

Adolescent↗
PubMed1999

Can histopathology predict treatment outcome following high-energy transurethral microwave thermotherapy of the prostate? Results of a biopsy study.

BACKGROUND: Despite good results of high-energy transurethral microwave thermotherapy (TUMT) in the treatment of benign prostatic hyperplasia, it is still difficult to predict the response to treatment on an individual basis. Besides clinical baseline parameters, intrinsic histological parameters are suggested to play a role in the response variance after TUMT. In this study we analyzed histological parameters (vessel density and epithelium-stroma (E/S) ratio) in patients who were selected for high-energy TUMT and related these parameters to clinical outcome. METHODS: We treated 42 patients with high-energy TUMT, who prior to treatment agreed upon ultrasonographic investigation of the prostate in combination with biopsies of the peripheral and transitional zones of the prostate. For all separate biopsy locations, the histological stained prostate slides were morphometrically quantified with computer assistance and analyzed for E/S ratio and vessel density. Response to treatment was measured by using standardized response evaluation criteria and was correlated with histological outcome. RESULTS: The E/S ratio in the inner gland biopsies tended to be higher in the good response group compared to the very poor responders. Furthermore, a clear trend was seen towards a lower vessel density in good responders. Large prostates and prostates with a high E/S ratio responded well to the high-energy thermotherapy. CONCLUSIONS: Histopathological parameters of the prostate tend to be moderately predictive for clinical response in this research population. Poor responders appeared to have a somewhat higher vessel density in all prostate biopsy sides, and there was also a trend towards a lower E/S ratio in these patients.

Aged↗
PubMed1999

Can keratin 8 and 17 immunohistochemistry be of diagnostic value in cervical cytology? A feasibility study.

BACKGROUND: Based on results from evaluation of tissue sections from premalignant lesions of the uterine cervix, the authors examined the hypothesis that immunostaining of Papanicolaou-stained cytologic smears with monoclonal antibodies to keratins 8 and 17 allows detection of cervical intraepithelial neoplasia (CIN) with progressive potential. They also investigated whether detection of these two keratin subtypes could be of help in the analysis of normal and/or poor quality cytology smears. METHODS: Sixty-one Papanicolaou-stained smears, representing 25 normal smears, 8 CIN 1, 7 CIN 2, 18 CIN 3, and 3 cervical carcinomas, were stained with CAM 5.2 and E3, which are capable of detecting keratin 8 and 17, respectively. The percentages of immunoreactive normal, metaplastic, dysplastic, and malignant epithelial cells were determined. RESULTS: In normal cervical smears, keratin 8 was detected in endocervical columnar cells and sporadically in immature squamous metaplastic cells. Keratin 17 was identified in reserve cells and frequently in immature squamous metaplasic cells. In CIN, the number of cases in which keratin 8 was present increased with the severity of the lesion. Keratin 17 was found in the majority of CIN lesions, irrespective of grade. Intensity of immunostaining and number of cells stained per lesion varied and were also not related to the severity of CIN. CONCLUSIONS: The use of the keratin 8 antibody in normal cervical smears enabled the detection of endocervical cells in cases where they were thought to be absent, particularly in cases with severe inflammation. Staining with keratin 17 enabled the identification of reserve cells or immature metaplastic cells, which were often misinterpreted as parabasal cells. The application of antibodies to these subtypes of keratins in cervical cytology can to a certain extent help in the identification of CIN and may in future be tested in automated screening.

Carcinoma, Squamous Cell↗
PubMed1999

Transient tenascin enhancement is an early event after androgen ablation in rat prostate.

Tenascin (tenascin-C), a mesenchymal glycoprotein, is expressed in many tissue remodeling processes. We evaluated tenascin expression during androgen-deprivation-related involution of the rat prostate. At set intervals following castration and subsequent testosterone repletion, prostates were removed in 30 adult rats. Each prostate was immunostained with a polyclonal antiserum against rat tenascin and keratin antibodies specifically directed against exocrine basal cells and luminal cells in the prostate glandular structure. Morphologic impressions were semiquantatively evaluated using a computer-assisted image analysis system. Rat prostates showed a transient increase in the periglandular tenascin expression directly following castration that reached a maximum at day 3. At day 6, tenascin expression was similar to control prostates. This was accompanied by a decrease of cells in the luminal cell layer. The weakest tenascin immunoreactivity was noted on day 14 after androgen withdrawal. This process was reversed by androgen repletion. This study shows that in the rat prostate tenascin expression may be androgen dependent and that during androgen deprivation-related involution tenascin expression is probably associated with tissue remodeling by stromal-epithelial interactions.

Androgens↗
PubMed1999

Relationship between human papillomavirus type 16 in the cervix and intraepithelial neoplasia.

OBJECTIVE: To evaluate a temporal relationship between the presence of cervical human papilloma virus (HPV) type 16 and the risk of developing cervical intraepithelial neoplasia (CIN). METHODS: Fifty-four women with HPV 16 polymerase chain reaction (PCR)-positive tests were selected from the gynecologic outpatient clinic of the Reinier de Graaf Hospital, Delft, The Netherlands. At least three successive PCR tests were performed in each woman at intervals of 6 months. The PCR HPV 16 assay was performed in conjunction with cervical smear, and colposcopy and biopsy, if indicated. Women with at least three consecutive positive PCR tests were defined as having persistent HPV 16 infections. Women with one positive test followed by two negative tests were defined as having transient infections. Subdivided into two groups, 25 women had persistent infections and 29 had transient infections. RESULTS: In significantly more women in the persistent group compared with the transient group, CIN developed (11 of 25 versus six of 29, P = .036). Lesions in women with persistent HPV 16 infection were more severe (six of 11 were CIN III versus one of six P = .041). CONCLUSION: Persistent infection with HPV 16 is associated with a higher risk of developing CIN, which is often high-grade.

Adult↗
PubMed1998

Identification of intermediate cell types by keratin expression in the developing human prostate.

BACKGROUND: The secretory acini of the adult human prostate contain basal, luminal, and intermediate types of exocrine cells. Intermediate cells are thought to play an important role in normal growth and neoplastic transformation. In this study we investigated whether this cell type is present in early stages of prostate development, using keratin antibodies specific for them. METHODS: Autoptic tissue from 11 prepubertal and 5 normal adult prostates was immunohistochemically stained with four keratin antibodies capable of specifically detecting basal, luminal, or intermediate cell types. RESULTS: Morphologically, in fetal prostate cells differentiation was often not evident. However, basally located cells usually displayed a basal-cell keratin-phenotype. Morphologically similar cells with more luminal localization expressed keratins typical of luminal cells, or of intermediate cells. CONCLUSIONS: 1) In early stages of prostate development, cells with intermediate keratin-phenotype can be identified. 2) Their large numbers comply with a hierarchical pathway of cellular differentiation from basal to luminal cells. 3) The presence of intermediate cells at such an early fetal age may reflect their regulatory function in prostate development.

Adult↗
PubMed1998

Applications of the microbiopsy technique in non-cervical cytology: where cytology and histology meet.

AIM: To evaluate a recently developed technique allowing the removal and processing for histology of thick tissue fragments, called microbiopsies, from noncervical cytology specimens. METHODS AND RESULTS: Forty-five non-cervical smears from malignant tumours which contained microbiopsies were selected and processed. Sufficient sections could be cut in most cases for haematoxylin and eosin and an extensive panel of immunostaining. Seventy-one per cent of histological slides from the microbiopsies were representative of the tumour and confirmed the diagnosis. In 29% of the cases they were too small, contained non-representative tissue or showed extensive necrosis. Surprisingly, immunostaining results were at least the same and often better than those observed in routine formalin-fixed, paraffin-embedded tissue. Immunostaining profiles allowed distinction of tumour subtypes. Antigen retrieval techniques could be avoided in all cases. CONCLUSIONS: Application of the microbiopsy technique in routine cytology smears containing microbiopsies is helpful, particularly in those cases in which the diagnosis is not clear on the basis of the cytology smear and in cases in which there are not enough cytology slides for immunohistochemical examination.

Biomarkers, Tumor↗
PubMed1998

Expression of periglandular tenascin-C and basement membrane laminin in normal prostate, benign prostatic hyperplasia and prostate carcinoma.

OBJECTIVE: To evaluate the structural relationship of the distribution between tenascin (tenascin-C, an extra-cellular matrix glycoprotein involved in stromal-epithelial interactions in both normal and pathological conditions) and laminin, an important component of the basement membrane, in normal and neoplastic human prostate, and to establish whether changes in the basement membrane are accompanied by changes in tenascin staining. MATERIALS AND METHODS: Seventy-five snap-frozen prostate samples representing normal glands, nodular benign prostatic hyperplasia and prostate carcinoma were stained for tenascin. From these, 15 samples were selected for dual-immunofluorescence staining and a confocal laser scan microscope was used to simultaneously visualize tenascin and laminin immunoreactivity. RESULTS: Tenascin was expressed in the extracellular matrix, mainly at the periphery of the glands, in tumour foci and blood vessels. In cases with intact basement membranes, e.g. normal glands and hyperplastic lesions, tenascin expression was weak. Low- and moderate-grade tumours were characterized by strong tenascin expression, while laminin expression was weak and/or showed discontinuities, indicating disturbances in basement membrane composition. High-grade tumours had sparse tenascin staining and a marked loss of laminin immunoreactivity. CONCLUSION: These results indicate that periglandular tenascin expression correlates with the integrity of the basement membrane in the human prostate. By influencing stromal-epithelial interactions, tenascin may play a role in maintaining tissue homeostasis in the prostate.

Basement Membrane↗
PubMed1998

Cell kinetics of prostate exocrine and neuroendocrine epithelium and their differential interrelationship: new perspectives.

The prostate gland consists of a complex ductal system lined with exocrine basal and luminal cells, and neuroendocrine epithelial cells. This paper reviews the histologic and molecular cell biologic characteristics of these cells, in normal adult tissue, during prostate morphogenesis, and in the development of benign and malignant neoplastic conditions. Expression of differentiation markers, as well as proliferation and apoptosis markers, growth factors and associated receptors, and abnormalities in genes and chromosomes are reviewed. Accumulating data indicate that (1) pluripotent immortal stem cells are located in the basal cell compartment of the prostate; (2) there is a subpopulation of epithelial cells in the prostate gland (intermediate cells) that have both structural and functional characteristics common to basal and luminal cells, which may be identified in various conditions; and prostate NE cells may have the same common origin as other exocrine cells, and share the same differentiation pathway. A stem cell model is proposed in which both exocrine and endocrine cells are derived from a subpopulation of basal cells (stem cell) that give rise to luminal cells through intermediate cells (pluripotent amplifying cells). These cells are also probably highly implicated in the early development of prostate benign and malignant neoplasia.

Adult↗
PubMed1997

A- and B-type lamins are differentially expressed in normal human tissues.

A selection of normal human tissues was investigated for the presence of lamins B1, B2, and A-type lamins, using a panel of antibodies specific for the individual lamin subtypes. By use of immunoprecipitation and two-dimensional immunoblotting techniques we demonstrated that these antibodies do not cross-react with other lamin subtypes and that a range of different phosphorylation isoforms is recognized by each antibody. The lamin B2 antibodies appeared to decorate the nuclear lamina in all tissues examined, except hepatocytes, in which very little lamin B2 expression was observed. In contrast to previous studies, which suggested the ubiquitous expression of lamin B1 in mammalian tissues, we show that lamin B1 is not as universally distributed throughout normal human tissues as was to be expected from previous studies. Muscle and connective tissues are negative, while in epithelial cells lamin B1 seemed to be preferentially detected in proliferating cells. These results correspond well with those obtained for lamin B1 in chicken tissues. The expression of A-type lamins is most prominent in well-differentiated epithelial cells. Relatively undifferentiated and proliferating cells in epithelia showed a clearly reduced expression of A-type lamins. Furthermore, most cells of neuroendocrine origin as well as most hematopoietic cells were negative for A-type lamin antibodies.

Antibodies, Monoclonal↗
PubMed1997

Histologic processing of microbiopsies from cervical smears is diagnostically useful in selected cases.

We analyzed the value in cervical cytology of a recently developed technique by which it is possible to remove thick tissue specimens, called microbiopsies, from cervical smears and to process them for histologic examination. In 12 (48%) of 25 cervical smears in which microbiopsies were found, the histologic sections from them confirmed the cytologic diagnosis. Most cases involved classification of lesions diagnosed as cervical intraepithelial neoplasia. In 13 (52%) of 25 smears, processing the microbiopsy allowed considerable modification of the cytologic diagnosis. In six of these cases, microbiopsies consisted of groups of columnar cells that were incorrectly classified as atypical on the basis of cytologic criteria. After histologic processing, the microbiopsies revealed nonatypical columnar cells in four cases and only mildly atypical columnar cells in two cases. In 3 of 13 smears, there were insufficient dispersed atypical cells for a conclusive diagnosis. Processing the microbiopsies in these cases allowed classification into one of the cervical intraepithelial neoplasia categories.

Biopsy↗
PubMed1997

Progressing imbalance between proliferation and apoptosis with increasing severity of cervical intraepithelial neoplasia.

The equilibrium between cell proliferation and protection against apoptosis was studied immunohistochemically using monoclonal antibodies against Ki-67-Ag and bcl-2, respectively, in consecutive sections from normal and metaplastic cervical epithelia and cervical intraepithelial neoplasia (CIN) lesions and cervical carcinomas. A high percentage of Ki-67-Ag positive cells was seen in the parabasal cells of normal ectocervical and mature squamous metaplastic epithelium, although the basal cells were virtually negative. In preneoplastic lesions, however, the basal cells showed high proliferative activity and an increasing frequency of Ki-67-Ag positive cells was observed in the higher epithelial layers with increasing severity of CIN. In squamous cell carcinomas, variable numbers of Ki-67-Ag positive cells were observed and in adenocarcinomas expression increased with the degree of anaplasia. bcl-2 expression was observed only in the basal cells of normal endo- and ectocervix including reserve cells. With increasing severity of CIN, staining intensity and number of bcl-2 positive cells gradually increased. Five of eight squamous cell carcinomas were variably positive. All five adenocarcinomas showed extensive bcl-2 expression. Increased expression of both Ki-67-Ag and bcl-2 with increasing severity of CIN indicates an increasing imbalance between cell proliferation and protection from apoptosis. It is therefore proposed that an increasing proliferative fraction combined with a higher number of cells protected from apoptotic cell death contributes to progression of CIN. This phenotype may identify premalignant lesions with the potential to transform to cervical cancer.

Adenocarcinoma↗
PubMed1997

Changes in keratin expression during the development of benign prostatic hyperplasia.

OBJECTIVE: The relationship between different types of epithelial cells in the prostate and the regulatory mechanism underlying benign prostatic hyperplasia (BPH) are still obscure as is the association between BPH and prostate carcinoma (PCa.) On the basis of keratin immunophenotyping, a subpopulation of cells in normal rat prostate and human PCa have been identified as candidates for the 'amplifying cell' in the stem cell model. In this model the basal cell is described as being associated with the stem cell. From this precursor an intermediate cell type develops which may differentiate into the luminal-type cell. In this study these different cell types are investigated in the development of isolated BPH and BPH associated with PCa, using monoclonal antibodies to intermediate filaments of the keratin class. METHODS: We immunohistochemically stained 64 snap-frozen human prostatic tissues, using monoclonal antibodies against keratin 14 (marker for putative 'stem cell'), keratin 18 (marker for putative 'transit cell'), and MAb RCK103 (marker for putative 'amplifying cell' or intermediate cell). RESULTS: In basal cell hyperplasia, an atypical form of BPH, keratins previously associated with intermediate cells were frequently detected. Cells with this keratin phenotype were detected in the luminal compartment of BPH, and were more prevalent in BPH adjacent to PCa. This keratin expression pattern was similar to that of PCa. CONCLUSION: On the basis of keratin phenotyping we demonstrated that large numbers of cells with the keratin expression pattern of so-called intermediate cells were identified in BPH associated with PCa, while in isolated BPH these cells were infrequently found. This supports the concept that BPH with intermediate phenotype may have premalignant potential. Furthermore this is suggestive of an etiologic relationship between the two diseases.

Antibodies, Monoclonal↗
PubMed1997

Prostatic neuroendocrine cells have a unique keratin expression pattern and do not express Bcl-2: cell kinetic features of neuroendocrine cells in the human prostate.

We investigated the keratin phenotype and bcl-2 immunoreactivity of neuroendocrine cells in the human prostate to determine whether the postmitotic status of these cells is associated with protection from apoptosis by bcl-2 protein expression and to elucidate the possible cell kinetic relationship between neuroendocrine cells and the other epithelial components of the prostate. Tissue specimens were selected from prostates of 19 patients harboring normal secretory glands (n = 15) and glandular benign prostatic hyperplasia (n = 10). Using a novel sequentially selective destaining immunoenzymatic cytochemical technique we were able to demonstrate the distribution of neuroendocrine cells, keratin markers identifying either basal, luminal, or intermediate cells, and the bcl-2 protein in single sections. Basal cell keratins were expressed in the minority of the neuroendocrine cells. In most of the cells, intermediate and luminal cell keratins were found and bcl-2 was constantly negative. Our findings indicate that neuroendocrine cells and other epithelial cells in the human prostate share a common keratin phenotype and probably originate from a common epithelial precursor. From the absence of bcl-2 we infer that the neuroendocrine cells have no progenitor cell characteristics.

Aged↗