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H Bonkhoff

Publications and source records attributed to H Bonkhoff.

At least 55 records · Page 3Linked to original sources
PubMed1996

Differentiation pathways and histogenetic aspects of normal and abnormal prostatic growth: a stem cell model.

A stem cell model is presented for the organization of the prostatic epithelium that may explain normal and abnormal growth in the human prostate. This model is based on recent data indicating that: 1) The three basic cell types encountered in the prostatic epithelium--i.e., secretory luminal, basal, and endocrine paracrine (EP) cells--are linked in the precursor progeny relationship. 2) The proliferative compartment of the normal and hyperplastic epithelium is located in the basal cell layer. 3) The proliferative compartment of the prostatic epithelium is androgen-independent but contains andro-responsive target cells. 4) During the malignant transformation of the prostatic epithelium, the proliferative zone is inverted and shifts to luminal cell types. 5) Formation of neoplastic basement membrane (BM) material is crucial for the development of the invasive phenotype in prostate cancer. 6) The proliferative activities in prostate cancer are exclusively restricted to exocrine cell types, whereas endocrine differentiated tumor cells are postmitotic cells. 7) The majority of exocrine tumor cells are androgen-responsive in contrast to endocrine differentiated cell types that consistently lack the nuclear androgen receptor (AR). In this model, a small stem cell population located in the basal cell layer gives rise to all epithelial cell lineages encountered in the normal, hyperplastic, and neoplastic prostate. The differentiating process from basal cells to secretory luminal cells via intermediate phenotypes is induced by circulating androgens, and largely depends on the presence of androgen-responsive target cells in the basal cell layer. Accordingly, the abnormal growth of the secretory epithelium in benign prostate hyperplasia (BPH) may be related to an increase in the total number of androgen-responsive basal cells in the proliferative compartment. Prostate cancer derives from transformed stem cells located in the basal cell layer that acquire secretory luminal characteristics under androgenic stimulation. During tumor invasion, the malignant phenotypes adhere via specific receptors to newly formed BM-material, which, in turn, may facilitate their passage through the extracellular matrix. The occurrence of endocrine differentiation in prostate cancer reflects the pluripotency of its stem cells. The widespread absence of nuclear AR in endocrine differentiated tumor cells clearly indicates that this phenotype belongs to those cell clones in prostate cancer, that are initially androgen-independent and refractory to hormonal therapy. Accordingly, the progressive emergence of endocrine cell clones during tumor progression may represent one mechanism by which prostate cancer cells escape hormonal control.

Adenocarcinoma↗
PubMed1996

Differential expression of 5 alpha-reductase isoenzymes in the human prostate and prostatic carcinomas.

BACKGROUND: Steroid 5 alpha-reductase is essential for the intracellular accumulation of dihydrotestosterone (DHT), which mediates androgen effects on target tissue. METHODS: In the present study, we describe the differential expression and cellular localization of 5 alpha-reductase 1 and 2 isoenzymes in the human prostate, and untreated and hormone-resistant prostatic carcinomas. The secretory epithelium of normal and hyperplastic glands showed strong nuclear 5 alpha-reductase 1 reactivity. Accordingly, the DHT forming 5 alpha-reductase process in secretory luminal cell types may be mediated predominantly by the type 1 isoenzyme. The androgen-independent basal cell layer variably expressed type 1 and 2 isoenzymes in nuclear and cytoplasmatic compartments. This suggests that circulating androgens are involved to control the basal cell layer, which represents the proliferative compartment of the human prostate. RESULTS: When compared with benign prostate tissue, increased 5 alpha-reductase reactivity was detected in prostate cancer, particularly in high-grade tumors and androgen-insensitive states of the disease. In cancerous lesions, the type 1 isoenzyme tended to shift to the cytoplasm, while the nuclear staining remained unchanged or slightly increased. Referring to the type 2 isoenzyme, increased cytoplasmatic and nuclear enzyme activity was detected in malignant cells when compared with adjacent benign prostate tissue. Even endocrine differentiated tumor cells that consistently lacked the nuclear androgen receptor variably expressed 5 alpha-reductase immunoreactivity. CONCLUSIONS: Although the functional significance of the differential subcellular localization of type 1 and 2 isoenzymes is currently unknown, the present data suggest that prostate cancer retains the DHT forming 5 alpha-reductase process in high-grade lesions and recurrent disease. Accordingly, circulating androgens may be still significant in these hormone-refractory malignancies.

Androgens↗
PubMed1996

Ischemia-reperfusion-induced pancreatic microvascular injury. An intravital fluorescence microscopic study in rats.

With the concept that ischemia-reperfusion injury may contribute to the pathogenesis of acute pancreatitis, we have quantitatively analyzed the pancreatic microcirculation of rats during postischemic reperfusion using intravital fluorescence microscopy. Ischemia to the pancreas of Sprague-Dawley rats (N = 7) was induced by clamping the arteriae gastroduodenalis, lienalis, gastrica sinistra, and gastricae breves for 60 min followed by 120 min of reperfusion. Ischemic conditions were verified by measurement of microvascular hemoglobin oxygenation using reflection spectrophotometry (n = 9). Postischemic reperfusion was characterized by a significant (P < 0.05) reduction of functional capillary density to approximately 69% of baseline (no reflow). Reperfusion-induced inflammatory response was reflected by a marked increase (100-fold; P < 0.01) of the number of permanently adherent leukocytes in postcapillary venules (reflow paradox). Postischemic reperfusion was further associated with increased serum lipase activities, and histomorphological analysis revealed alterations, similar as known in acute interstitial pancreatitis, ie, neutrophil infiltration, interstitial edema, and hemorrhagic lesions. We, therefore, conclude that ischemia-reperfusion- associated events, ie, no reflow and reflow paradox, may be considered as trigger mechanisms in the manifestation of distinct types of acute pancreatitis, in particular posttransplant pancreatitis.

Acute Disease↗
PubMed1996

Role of the basal cells in premalignant changes of the human prostate: a stem cell concept for the development of prostate cancer.

OBJECTIVES: Prostatic intraepithelial neoplasias (PIN) result from abnormal differentiation and proliferation processes within the prostatic epithelial cell system. Recent data indicate that basal cells are essentially involved in normal and abnormal growth patterns of the human prostate. RESULTS: The basal cell layer represents the proliferative compartment and most probably houses the prostatic stem cell population. Basal cells are targets of several regulatory factors including estrogens, androgens, epidermal growth factor and other nonsteroidal growth factors. During the malignant transformation of the prostatic epithelium (PIN), the basal cell layer loses its proliferative function which is transferred to secretory luminal cell types. These proliferative abnormalities are attended by severe regulatory disorders of the programmed cell death within the prostatic epithelial cell system. The Bcl-2 oncoprotein which blocks the programmed cell death in the proliferative compartment (basal cell layer) in normal conditions, extends to the secretory luminal cell types in high-grade PIN lesions. This, in turn, may increase the genetic instability of the dysplastic epithelium. During the process of tumor invasion, the transformed cells lose their basal cell-specific phenotype and acquire features of exocrine cell types which represent the major phenotype in common prostate cancer. At the point of stromal invasion, the transformed cells produce neoplastic basement membrane material which allows them to penetrate the extracellular matrix. CONCLUSION: These data provide theoretical bases for a stem cell concept in the development of prostate cancer and highlights the importance of basal cells in this multifactorial process.

Basement Membrane↗
PubMed1995

Differential expression of the pS2 protein in the human prostate and prostate cancer: association with premalignant changes and neuroendocrine differentiation.

The distribution of the estrogen inducible pS2 protein was investigated in benign and malignant prostate tissue by the avidin-biotin complex method. Prostate tissue obtained from 20 patients without clinical and histological evidence of malignant disease consistently lacked pS2 immunoreactivity. Conversely, nonneoplastic tissue from 36 total prostatectomies with locally advanced prostate cancer showed a variable degree of pS2 reactivity in normal or hyperplastic glands and in prostatic intraepithelial neoplasia (PIN) adjacent to the cancerous lesions. This suggests that the pS2 gene expression detected in nonmalignant tissue may be related to early premalignant changes of prostate glands harboring significant carcinomas. In prostate cancer the pS2 protein was detected in close association with neuroendocrine (NE) differentiation as assessed by Chromogranin A (Chr A) immunoreactivity. Double labeling techniques showed that pS2 immunoreactivity recognizes both endocrine (Chr A-positive) and adjacent exocrine (Chr A-negative) cell types within NE foci. Whereas pS2 expression was consistently confined to NE differentiation in untreated tumors, carcinomas that relapsed after hormonal therapy showed increased pS2 immunoreactivity, even in the absence of NE features. The differential expression of the pS2 peptide in nonneoplastic tissue from patients with and without malignant disease indicates that pS2 immunohistochemistry may be useful in the diagnostic evaluation of negative biopsy specimens. Furthermore, the results suggest that the immunohistochemical spectrum of pS2 in prostate cancer may include endocrine differentiated and presumably related cell populations.

Carcinoma↗
PubMed1995

Endocrine-paracrine cell types in the prostate and prostatic adenocarcinoma are postmitotic cells.

Neuroendocrine (NE) differentiation frequently occurs in common prostatic malignancies and has potential prognostic and therapeutic implications. In a recent study we were able to provide immunohistochemical evidence that endocrine-paracrine cell types represent an androgen-insensitive cell population in prostate cancer, documented by the consistent lack of the pertinent receptor. In this study we investigated the proliferative activity of endocrine-paracrine cell types in normal, hyperplastic, and neoplastic prostate tissue. Using double-label techniques for the endocrine marker chromogranin A (chr A) and the proliferation-associated MIB-1 antigen, we evaluated the proliferative status of endocrine-paracrine cell types in the prostate and prostatic adenocarcinoma showing marked NE differentiation. In this series of carcinomas and in nonneoplastic tissue the proliferative activities were exclusively restricted to nonendocrine cell populations, whereas endocrine-paracrine cell types characterized by Chr A consistently lack MIB-1 immunoreactivity. This may indicate that prostatic endocrine-paracrine cell types do not participate in the cell cycle during normal, hyperplastic, and neoplastic prostatic growth. Based on the present information, the endocrine phenotype can be considered to be an androgen-insensitive, postmitotic subpopulation in the prostate and prostate cancer.

Adenocarcinoma↗
PubMed1995

Morphogenetic aspects of normal and abnormal prostatic growth.

Studies of cancerogenesis in the human prostate have been hampered by a number of factors, including the complex composition of the prostatic epithelium by three different cell types, the lack of good animal models and the relative inaccessibility of the gland. More information about the basic biology of epithelial cell types in the development of the various neoplastic disorders of the prostate gland is required. This article reviews recent data about differentiation and proliferation processes in the human prostate and proposes a stem cell model that may explain the morphogenisis of normal and abnormal prostatic growth.

Cell Differentiation↗
PubMed1994

The proliferative function of basal cells in the normal and hyperplastic human prostate.

To obtain more insight into the proliferative function of basal and secretory cell types in human prostate, we studied the immunoprofile of three well-characterized proliferation-associated antigens (Ki-67, PCNA, MIB 1) in normal and hyperplastic prostate tissue. Distinction between labeled basal and secretory cell types was made by simultaneous demonstration of the proliferation-associated antigens and basal cell-specific cytokeratins in identical sections. In normal and hyperplastic acini, approximately 70% of labeled cells were of the basal cell phenotype. These data clearly suggest that the proliferative compartment of the normal and hyperplastic epithelium is located in the basal cell layer. Compared to normal and hyperplastic conditions, severe proliferative abnormalities were detected in high-grade prostate intraepithelial neoplasias (PIN), as documented by the extension of the proliferative compartment up to the luminal border. Conversely, approximately 70% of proliferating cells detected in atypical hyperplasias that progressed in invasive carcinomas were localized in the remaining basal cell layer. These findings may indicate the proliferative role of basal cells in the epithelial renewal, and the development of hyperplastic and neoplastic disorders in the human prostate.

Antibodies, Monoclonal↗
PubMed1994

DNA aneuploidy in prostatic adenocarcinoma: a frequent event as shown by fluorescence in situ DNA hybridization.

Fluorescence in situ hybridization (FISH) using specific DNA probes for chromosomes 1, 7, 10, and Y was performed on 53 prostatic tissue samples obtained from 33 radical prostatectomy specimens and two benign control specimens. The 53 samples from carcinomatous prostates included 33 cancerous and 20 noncancerous samples. Additionally, four metastatic lymph node specimens were examined. Clonal chromosome abnormalities were observed in 78% of the tumors studied. They were detected in a higher proportion in stage pT2 and pT3 tumors (86% and 88%, respectively) compared with stage pT1 tumors (25%). No stage pT4 tumor was analyzed. There was evidence of remarkable focal intratumoral heterogeneity documented by the study of two samples from the same tumor in three of six cases. Comparing FISH determined ploidy patterns with DNA flow cytometry (FCM) in 22 samples, FISH showed aneuploidy whereas FCM showed none.

Adenocarcinoma↗
PubMed1994

Multidirectional differentiation in the normal, hyperplastic, and neoplastic human prostate: simultaneous demonstration of cell-specific epithelial markers.

The prostatic epithelium is composed of three distinct cell populations: secretory luminal, basal, and endocrine-paracrine cells. It is currently unknown whether these basic epithelial cell types are related in a hierarchical pathway of differentiation or are independent and separate entities. In the present study we used double-label techniques for cell-specific markers to search for multidirectional differentiation in normal, hyperplastic, and neoplastic prostate tissue. In normal and hyperplastic conditions subsets of basal cells revealed synchronous expression of basal cell-specific cytokeratins and the prostate-specific antigen, indicating intermediate differentiation between basal and secretory luminal cell types. Furthermore, endocrine-paracrine cells of the closed type focally showed simultaneous expression of chromogranin A and basal cell-specific cytokeratins. These findings highlight the phenotypic plasticity of the basal cell layer in the human prostate. In prostatic adenocarcinoma co-expression of exocrine (prostate-specific antigen) and endocrine (chromogranin A) markers was detected frequently in subsets of malignant cells. Conversely, this amphicrine phenotype was rarely found in hyperplastic glands. The occurrence of multidirectional differentiation within the prostatic endocrine cell system may indicate that endocrine-paracine cells derive from pluripotent stem cells of endodermal origin. Furthermore, the phenotypic plasticity of basal cells suggests that this epithelial compartment houses stem cell populations that give rise to all epithelial cell lineages encountered in the normal, hyperplastic, and neoplastic human prostate.

Adenocarcinoma↗
PubMed1993

Genotypic characterization of prostatic carcinomas: a combined cytogenetic, flow cytometry, and in situ DNA hybridization study.

Cytogenetic studies were performed on 36 biopsies obtained from 26 primary prostatic adenocarcinomas. Following histopathological characterization of control sections, the biopsies were investigated using metaphase cytogenetics, DNA flow cytometry, and fluorescence in situ DNA hybridization. In 12 specimens, no carcinoma was found in control sections by histopathological means. In 24 carcinoma biopsies clonal aberrations were detected in 15 specimens. Tetraploidy as sole aberration was detected in five specimens. Loss of the Y chromosome was seen in eight samples. Only one tumor revealed structural abnormalities. Eight samples were found to be normal (46,XY). Remarkably, nonclonal chromosome aberrations, particularly marked chromosome loss, were frequently detected in prostatic carcinomas and premalignant lesions (prostatic intraepithelial neoplasia). In the series of biopsies investigated by means of cytogenetics and flow cytometry, biopsies with aneuploid DNA content were found to be cytogenetically normal. Conversely, the cytogenetically aberrant clones were found to be of diploid DNA content. Evidence of focal intratumoral heterogeneity was revealed by cytogenetics, flow cytometry, and in situ hybridization.

Aged↗
PubMed1993

Widespread distribution of nuclear androgen receptors in the basal cell layer of the normal and hyperplastic human prostate.

The role of the basal cell layer in organogenesis, epithelial renewal and development of benign prostatic disorders is largely unknown. The objective of the present study was to investigate whether or not basal cells express the nuclear androgen receptor (AR). Computer-assisted image analyses of immunohistochemical double stainings were performed to localize AR and basal-cell-specific cytokeratins in identical sections. The results showed that the basal cells express nuclear AR widely in normal and hyperplastic conditions. When compared with the staining intensities detected in secretory luminal cells, the receptor was most frequently expressed at lower levels in basal cells, which may exhibit strong AR immunoreactivity focally. Basal cells with increased AR expression were most frequently detected in hyperplastic lesions including post-atrophic and atypical hyperplasia. The presence of nuclear receptors for both androgens and oestrogens or progestins in basal cells may indicate that these cells are targets of the hormonal imbalance which has frequently been implicated in the aetiology of benign prostatic hyperplasia.

Atrophy↗
PubMed1993

Androgen receptor status in endocrine-paracrine cell types of the normal, hyperplastic, and neoplastic human prostate.

Neuroendocrine differentiation is a frequent occurrence in common prostatic adenocarcinomas and may have prognostic implications in prostatic malignancies. In the present study, we used immunohistochemical double label methods to evaluate the nuclear androgen receptor (AR) status in endocrine-paracrine (EP) cells of normal, hyperplastic, and neoplastic prostate including tumours that recurred after hormonal and radiation therapy. In normal and hyperplastic glands, EP cells characterized by the panendocrine marker chromogranin A (Chr A) did not reveal AR-positivity. This may indicate that prostatic EP cells represent an androgen-independent cell population whose regulatory functions are not influenced by circulating androgens. Unequivocal co-expression of Chr A and AR was very rarely detected in subsets of endocrine differentiated tumour cells in treated and untreated specimens. The widespread absence of nuclear AR in neuroendocrine tumour cells suggests that this phenotype belongs to those cell clones in prostate cancer which are initially androgen-independent and refractory to hormonal therapy.

Adenocarcinoma↗
PubMed1993

Differential expression of alpha 6 and alpha 2 very late antigen integrins in the normal, hyperplastic, and neoplastic prostate: simultaneous demonstration of cell surface receptors and their extracellular ligands.

The very late antigens (VLAs) are alpha beta-heterodimeric transmembrane proteins that include surface cell receptors for laminin (VLA-6) and collagen (VLA-2), which mediate cell-matrix and cell-cell adhesion. We investigated the distribution of VLA-6 (alpha 6, beta 1) and VLA-2 (alpha 2, beta 1) proteins in normal, hyperplastic, and neoplastic human prostate tissue and lymph node metastases by the avidin-biotin complex method. In normal and hyperplastic glands we observed two staining patterns that differed according to the density of alpha 6- and alpha 2-receptors at the site of co-expression with their corresponding ligands (laminin, type IV collagen) in acinar basement membranes (BMs). Band-like deposits with high receptor density suggested strong anchorage of the prostate epithelium to acinar BMs, whereas the absence of this pattern most probably reflected reduced cellular attachment. Very late antigen-6 immunoreactivity showed the band-like pattern in approximately 70% of normal and hyperplastic glands compared with VLA-2, which showed the same pattern in only 5% of cases. In prostatic adenocarcinoma the band-like pattern significantly decreased with dedifferentiation and was consistently absent in grade III lesions. Compared with staining intensities in normal and hyperplastic conditions, grade I and II tumors maintained or overexpressed the VLA-6 receptor in 85% of cases, whereas the VLA-2 receptor was downregulated in approximately 70% of cases. Grade III tumors were characterized by a heterogeneous expression of VLA-6 and VLA-2 proteins, but frequently upregulated their receptors in corresponding lymph node metastases. Regardless of the staining intensity, all primary and metastatic carcinomas investigated expressed VLA-6 and VLA-2 receptors whose extracellular domains were extensively co-expressed with their ligands in neoplastic BM formations. These findings suggest that VLA-6 and VLA-2 receptors mediate attachment of tumor cells to neoplastic BM material, which, in turn, may endow these cells with an increased ability to invade the extracellular matrix.

Adenocarcinoma↗
PubMed1993

[New aspects in histogenesis of hyperplasia and cancers of the prostate].

The prostatic epithelium has generally been described as consisting of three separate cell types--secretory, luminal, basal and endocrine-paracrine (EP) cells--that differ by their morphological features, functions and hormonal regulation. Compared with the gastrointestinal tract and other self-renewing tissue, little is known about differentiating and proliferative processes in the normal and hyperplastic human prostate. In the present report, we propose a stem cell model for the organization of the prostatic epithelium that may explain normal and abnormal growth in the human prostate. This model is based on recent data indicating that 1. the three basic cell types encountered in the prostatic epithelium are linked in precursor-progeny relationship as documented by the existence of intermediate phenotypes, 2. the basal cell layer represents the proliferative compartment in normal and hyperplastic conditions, 3. EP-cell types do not proliferate and lack the nuclear androgen receptor (AR), 4. basal cells may be potentially androgen-responsive as documented by the presence of AR, 5. formation of basement membrane (BM) deposits is crucial in the development of the invasive phenotype. In this model, a small stem cell population located in the basal cell layer gives rise to all epithelial cell lineages encountered in the normal, hyperplastic and neoplastic prostate. The differentiating process from basal cells to secretory luminal cells via intermediate phenotypes is induced by circulating androgens, and largely depends on the presence of responsive target cells in the basal cell layer. Accordingly, the abnormal growth of the secretory epithelium in benign prostatic hyperplasia may be related to an increase in the total number of androgen-responsive basal cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Distribution of basement membranes in primary and metastatic carcinomas of the prostate.

The presence of periacinar and pericellular basement membranes (BMs) has been reported recently in common prostatic adenocarcinomas. In this study we extended our investigations of BMs on lymph node and hematogenous metastases, primary prostatic cancer with unusual histologic features, and posttreatment tumors. In contrast to prostatic malignancies that derive from the transitional epithelium (squamous cell carcinoma, prostatic transitional cell carcinoma) and prostatic involvement by bladder cancer, inconspicuous stromal changes and distinct BM formations at the site of tumor invasion were observed in carcinomas deriving from the secretory epithelium (papillary ductal carcinoma) and from the basal cell (basal cell carcinoma). Even highly malignant anaplastic and small cell carcinomas, as well as irradiated and/or hormonally treated tumors, showed distinct BM formations in contact with the stroma. The same observations could be made in lymphatic and hematogenous metastases of different anatomic sites. These findings indicate that prostatic malignancies may retain BMs even in high-grade lesions, metastases, posttreatment tumors, and variants of prostatic adenocarcinoma.

Basement Membrane↗
PubMed1992

[Use of computer-assisted image analysis for the detection of immunohistochemical receptor status in breast cancer. Immunohistochemical densitometry receptor analysis--IRDA].

A method for the evaluation of the immunohistochemical staining score of steroid receptors in breast cancer using computer-based image analysis is presented. The optical density of tumour cell nuclei was measured using kryostat sections and, using a control section as reference, an objective threshold for specific staining was defined. In intensively stained sections, a good correlation with visual scoring was achieved, but in 9 out of 16 sections, which were regarded as receptor-negative by visual scoring, a specific receptor-positive staining was demonstrated by image analysis. Next to the percentage of positive cells (PP) and the mean staining intensity (SI), a histogram of the receptor concentration in positive nuclei was calculated. The method allows, besides an objective evaluation and documentation, an exact definition of a threshold for specific receptor measurement and furthermore shows the pattern of receptor concentration in the tumour cell nuclei. Hence, the method could contribute towards a more widespread use of immunohistochemical receptor analysis.

Breast↗