H Bonkhoff

Gemeinschaftspraxis für Pathologie Freiburg, Freiburg an der Elbe, Lower Saxony, Germany

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Publications (80)225.14 Total impact

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    ABSTRACT: Prostatic adenocarcinomas arising within the transition zone (Tz) are distinct from peripheral zone (Pz) tumors as regards biological aggression and mechanism of extraprostatic extension. Reliable biopsy identification of Tz tumors would allow targeted surgical approaches more likely to preserve erectile function without compromising surgical margins. Previous studies have demonstrated the presence of eosinophilic cytoplasmic granules (prostate secretory granules, or PSGs) after glutaraldehye fixation, with apparent depletion in neoplasia. We investigated PSG content, columnar cells, pale cytoplasm, and luminal secretions of both Pz and Tz tumors in 44 radical prostatectomies (RPs) and 135 biopsies fixed with gluteraldehyde-based fixative. Retention of PSG is characteristic of Tz carcinoma and infrequently seen in Pz tumors, and a combination of PSG greater than 30% with either columnar cells, pale cells, or secretions in biopsies is a reliable marker for Tz origin. When these criteria were prospectively applied to 3929 cases with follow-up RP, 510 Tz tumors were correctly identified on biopsy (sensitivity, 21.4%; specificity, 97.4%). Biopsy-identified Tz tumors had higher volumes (mean, 3.48 versus 1.81 cm(3); P < .001) and higher rates of margin positivity (22.5% versus 17.5%; P = .008) than did Tz tumors not identified preoperatively. Mean Tz tumor length in biopsies was 2.0 mm, with no correlation between tumor volume at RP and tumor length on biopsy. Tz tumors are reliably identified on biopsy, based on a combination of PSG retention with either columnar cells, pale cells, or secretion. Biopsy-identified Tz tumors may not be suitable for active surveillance because of an associated high probability of large tumor volume and increased risk of positive margins at RP.
    Human pathology 08/2013; 44(10). DOI:10.1016/j.humpath.2013.05.015 · 2.81 Impact Factor
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    ABSTRACT: BACKGROUND: Although the term "intraductal carcinoma of the prostate" (IDC-P) was introduced almost 40 years ago, there is still the lack of appreciation that this entity represents a clinically aggressive disease that continues to be misreported under the diagnostic category of high grade prostatic intraepithelial neoplasia (HGPIN). METHODS: Recent data obtained from histological, molecular, and clinical studies were reviewed to demonstrate that IDC-P significantly differs from HGPIN, and has a major impact in terms of diagnosis, prognosis and therapy of prostate cancer (PCa). RESULTS: HGPIN is the only accepted precursor of PCa. Its diagnosis in prostate biopsies has no prognostic implications, and does not dictate therapeutic decisions. By contrast, IDC-P correlates with a worse pathological and clinical outcome. IDC-P differs from HGPIN by distinct histological and molecular features. Recent clinical studies report that IDC-P is associated with neoadjuvant androgen deprivation therapy (ADT) and, chemotherapy (CT) failure as well as early disease recurrence after external beam radiation. Finally, IDC-P is associated with TMPRSS2-ERG gene fusion, which was reported to be regulated by estrogens and their receptors. CONCLUSIONS: IDC-P is an aggressive phenotype of prostate cancer and predicts poor response to ADT, CT, and external beam radiation. IDC-P should be separated from HGPIN and should be reported in prostate biopsies and prostatectomy specimens. Prostate © 2012 Wiley Periodicals, Inc.
    The Prostate 03/2013; 73(4). DOI:10.1002/pros.22579 · 3.57 Impact Factor
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    Helmut Bonkhoff
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    ABSTRACT: Tissue markers may be helpful in enhancing prediction of radiation therapy (RT) failure of prostate cancer (PCa). Among the various biomarkers tested in Phase III randomized trials conducted by the Radiation Therapy Oncology Group, p16, Ki-67, MDM2, COX-2, and PKA yielded the most robust data in predicting RT failure. Other pathways involved in RT failure are also implicated in the development of castration-resistant PCa, including the hypersensitive androgen receptor, EGFR, VEGF-R, and PI3K/Akt. Most of them are detectable in PCa tissue even at the time of initial diagnosis. Emerging evidence suggests that RT failure of PCa results from a multifactorial and heterogeneous disease process. A number of tissue markers are available to identify patients at high risk to fail RT. Some of these markers have the promise to be targeted by drugs currently available to enhance the efficacy of RT and delay disease progression.
    01/2012; 2012(2090-3111):593241. DOI:10.1155/2012/593241
  • Helmut Bonkhoff, Richard Berges
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    ABSTRACT: Significant progress in understanding the molecular basis of castration resistant prostate cancer (CRPCa) has been achieved in recent years. Despite this progress, CRPCa still remains a lethal disease. Early detection and prevention of CRPCa may provide a new strategy to improve survival of patients diagnosed with PCa at risk to fail standard androgen deprivation therapy (ADT). Herein, we review pathogenetic mechanisms implicated in PCa progression toward castration resistant disease that are detectable in hormone naive PCa to define relevant therapeutic targets for prevention. Upregulation of androgen receptor (AR) expression has been recognized a major determinant for the development of CRPCa. This hypersensitive pathway is further boosted by the increase of intratumoral androgen synthesis. AR mutants bind promiscuous steroids, and may convert AR antagonists to agonists. Various non-hormonal growth factor receptors transactivate the AR, even in absence of androgens (outlaw pathway). Finally, PCa cells can bypass the AR through various mechanisms, including BCL-2, COX-2, neuroendocrine differentiation. Most of these pathogenetic factors involved in the development of CRPCa are detectable in hormone naive PCa tissue even at the time of initial diagnosis, and could be targeted by drugs currently available. CRPCa is the end-stage of a multifactorial and heterogeneous disease process. Pathogenetic factors responsible for the development of the CRPCa phenotype are detectable in the patient's PCa tissue long before the clinical onset of the disease. This approach provides opportunity for early detection and prevention by targeting pathways relevant for the individual disease process.
    The Prostate 01/2010; 70(1):100-12. DOI:10.1002/pros.21042 · 3.57 Impact Factor
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    Helmut Bonkhoff, Richard Berges
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    ABSTRACT: Oestrogens were proven effective in the hormonal treatment of advanced prostate cancer (PCa) >60 yr ago and are still used as second-line hormonal therapy. Paradoxically, oestrogens might also be involved in the development and progression of PCa. To examine mechanisms of how oestrogens may affect prostate carcinogenesis and tumour progression. Recent data obtained from animal, experimental, and clinical studies were reviewed. The human prostate is equipped with a dual system of oestrogen receptors (oestrogen receptor alpha [ERalpha], oestrogen receptor beta [ERbeta]) that undergoes profound remodelling during PCa development and tumour progression. In high-grade prostatic intraepithelial neoplasia (HGPIN), the ERalpha is upregulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models. Preliminary clinical studies with the ERalpha antagonist toremifene have identified the ERalpha as a promising target for PCa prevention. The partial loss of the ERbeta in HGPIN indicates that the ERbeta acts as a tumour suppressor. The ERbeta is generally retained in hormone-naïve PCa but is partially lost in castration-resistant disease. The progressive emergence of the ERalpha and the oestrogen-regulated progesterone receptor (PR) during PCa progression and hormone-refractory disease suggests that these tumours can use oestrogens and progestins for their growth. The TMPRSS2-ERG gene fusion recently reported as a potentially aggressive molecular subtype of PCa is regulated by ER-dependent signalling. TMPRSS2-ERG expression has been found to be increased by ERalpha agonist (oestrogens) and decreased by ERbeta agonists. Oestrogens and their receptors are implicated in PCa development and tumour progression. There is significant potential for the use of ERalpha antagonists and ERbeta agonists to prevent PCa and delay disease progression. Tumours equipped with the pertinent receptors are potential candidates for this new therapeutic approach.
    European Urology 11/2008; 55(3):533-42. DOI:10.1016/j.eururo.2008.10.035 · 12.48 Impact Factor
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    ABSTRACT: Prostatic adenocarcinoma growing within acinar-ductal spaces (intraductal carcinoma) in contrast to high-grade prostatic intraepithelial neoplasia (HG-PIN) impacts negatively on patient outcome. There is currently no generally accepted definition of this lesion nor is it classified in the current prostate cancer grading system (Gleason). To define intraductal carcinoma of the prostate (IDC-P) with major and minor diagnostic criteria that clearly separate it from HG-PIN. The implications of such a lesion are discussed with proposals to incorporate this entity into the Gleason grading system. We reviewed all published data referring to intraductal spread of prostate carcinoma. Articles discussing endometrial, endometrioid, and ductal carcinoma are included. Intraductal carcinoma of the prostate as defined by major criteria that include enlarged gland structures, neoplastic cells spanning the gland lumen, central comedonecrosis, and further supported by minor diagnostic criteria including molecular biological markers, separate this entity from HG-PIN. Despite its perimeter basal cells, IDC-P should be interpreted as biologically equivalent to Gleason pattern 4 or 5 adenocarcinoma. Several hypotheses are proposed as to the evolution of IDC-P, which is almost always a late event in prostate carcinoma progression. Diagnosis of IDC-P on needle biopsy should prompt therapeutic intervention rather than surveillance or repeat biopsy, as is the case for HG-PIN.
    Archives of pathology & laboratory medicine 08/2007; 131(7):1103-9. DOI:10.1043/1543-2165(2007)131[1103:APOTIH]2.0.CO;2 · 2.88 Impact Factor
  • H Bonkhoff, T Fixemer
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    ABSTRACT: Neuroendocrine (NE) differentiation frequently occurs in common prostatic malignancies but usually escapes pathological and clinical detection. The present review focuses on biological properties of NE tumor cells making them resistant to androgen deprivation and radiation therapy. Recent data have shown that NE prostate cancer cells (as defined by the most commonly used endocrine marker chromogranin A) are arrested in the G0-phase of the cell cycle and do not undergo apoptosis. This particular phenotype consistently lacks the nuclear androgen receptor in both benign and malignant conditions but produces a series of hormonal growth factors exerting mitogenic stimuli on adjacent, exocrine tumor cells. Neoplastic NE cells devoid of the nuclear androgen receptor constitute an androgen-insensitive cell population in prostate cancer. The absence of proliferative and apoptotic activity makes NE tumor cells particularly resistant towards cytotoxic drugs and radiation therapy. Pathological and clinical detection of NE features is recommended for all prostate cancer patients for whom radiation therapy and androgen deprivation is being considered.
    Der Pathologe 12/2005; 26(6):453-60. DOI:10.1007/s00292-005-0791-0 · 0.64 Impact Factor
  • H Bonkhoff
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    ABSTRACT: Prostate cancer offers a wide spectrum ranging from clinically insignificant to aggressive and fatal disease. The Gleason grade is a powerful prognostic indicator and does influence treatment decision. Educational programs and websites are currently available to improve reproducibility and reliability of Gleason grading. A major problem in reporting of Gleason grading in needle biopsy is undergrading. The Gleason grade 3 is the lowest grade which can be assigned reliably in needle biopsies. The major prognostic shift is between Gleason grades 3 und 4 which is characterized by fusion of the glandular formations. Reporting the proportion of Gleason grades 4 and 5 in needle biopsies may be critical in terms of treatment decisions. The present review deals with diagnostic criteria of the Gleason grades and its clinical implications.
    Der Pathologe 12/2005; 26(6):422-32. · 0.64 Impact Factor
  • H Bonkhoff, T Fixemer
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    ABSTRACT: The recent discovery of the estrogen receptors alpha and beta (ERalpha, ERbeta) and the progesterone receptor (PR) in human prostate tissue offers new insights into the role of estrogens and their receptors in prostate cancer development and tumor progression. The differentiation compartment of the prostatic epithelium (secretory luminal cells) expresses high levels of ERbeta, while the ERalpha is restricted to the proliferation compartment (basal cells). In high grade prostatic intraepithelial neoplasia (HGPIN), ERalpha gene expression extends to luminal cells and thus may mediate cancerogenic effects of estrogens on the dysplastic epithelium. Conversely, the ERbeta is downregulated in HGPIN indicating that the chemopreventive effects of phytoestrogens mediated by the ERbeta are partially lost. Irrespective of grades and stages, prostate cancer retains high levels of the ERbeta which is partially lost in androgen-insensitive stages of the disease. In contrast with breast cancer, the presence of the ERalpha and the PR is a late event in prostate cancer progression. At least 30% of metastatic and androgen-insensitive tumors express high levels of the PR indicating that these tumors harbor a functional ERalpha. The antiestrogen Raloxifene has growth-inhibitory effects on androgen-insensitive prostate cancer cells in vitro and induces the apoptotic cell death in a dose-dependent fashion. These data provide a rational for clinical trials to study the efficiency of antiestrogens in the medical treatment of advanced prostate cancer.
    Der Pathologe 12/2005; 26(6):461-8. · 0.64 Impact Factor
  • H Bonkhoff
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    ABSTRACT: Prostate cancer offers a wide range of growth patterns depicted in the classical Gleason diagram. For each Gleason pattern exist a number of benign and malignant mimickers that can simulate prostatic adenocarcinoma. In the present review, the use of immunohistochemical markers is discussed with emphasis to a pattern-based approach to differential diagnosis in prostate pathology. Basal cell markers (34betaE12 and P63) are very useful to analyze histo-architectural features of small and large glandular lesions. AMACR (P504 s) is helpful not only in identifying small amount of cancer in needle biopsies but also in the diagnosis of high grade prostatic intra epithelial neoplasia (HGPIN). A number of lesions which may be confused with small acinar adenocarcinoma (Cowper's gland, nephrogenic metaplasia, mesonephric glands) and poorly differentiated prostate cancer (urothelial neoplasia, mucinous colon cancer and other metastatic lesions) lacks convincing PSA immunoreactivity. Basal cell markers and the nuclear androgen receptors are important markers to differentiate Gleason grade 5 A und 5 B patterns from prostatic involvement by transitional cell carcinoma. Finally, a selected panel of markers is useful to classify prostatic stromal lesions. In each case, immunohistochemical findings should be interpreted in context with the various patterns on routine microscopy.
    Der Pathologe 12/2005; 26(6):405-21. · 0.64 Impact Factor
  • H Bonkhoff
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    ABSTRACT: Since several therapeutic options are currently available for clinically organ-confined prostate cancer, morphological parameters have rapidly emerged as prognostic factors to stratify patients into different therapeutic modalities. In addition to the PSA value, pathologic stage, as defined by the TNM system, Gleason grade and the surgical margin status, other markers have prognostic implications. This includes the percent pattern 4/5 cancer, tumor volume, intraductal spread, large volume perineural invasion and molecular markers. This review discusses the methods of sampling and reporting in prostate pathology with an emphasis on well established and new prognostic factors.
    Der Pathologe 12/2005; 26(6):433-43. · 0.64 Impact Factor
  • H. Bonkhoff, T. Fixemer
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    ABSTRACT: Durch verbesserte Detektionsmethoden und neue Antikörper können heute in prämalignen Prostataveränderungen und im Prostatakarzinom (PCa) verschiedene Östrogenrezeptoren und östrogenregulierte Zielgene nachgewiesen werden. Die Östrogenrezeptoren α und β (ERα, ERβ) werden in funktionell unterschiedlichen Kompartimenten des Prostataepithels exprimiert: ERα im Proliferationskompartiment (Basalzellschicht), ERβ im Differenzierungskompartiment (sekretorisches Epithel). In der High-grade prostatischen intraepithelialen Neoplasie (HGPIN) verlagert sich die ERα-Expression in das Differenzierungskompartiment und vermittelt als Onkogen kanzerogene Effekte auf das Prostataepithel. Der ERβ, ein potenzieller Tumorsuppressor, geht in der HGPIN partiell verloren.
    Der Pathologe 11/2005; 26(6):461-468. DOI:10.1007/s00292-005-0790-1 · 0.64 Impact Factor
  • H. Bonkhoff
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    ABSTRACT: Das klinische Spektrum des Prostatakarzinoms (PCa) umfasst eine breite Palette, die von den klinisch unbedeuteten bis hin zu den hoch malignen und letal verlaufenden Tumorerkrankungen reicht. Die Bestimmung des Gleason-Grades durch den Pathologen liefert wichtige Informationen über den individuellen Verlauf und die Wahl der Therapie. Durch die Einrichtung von Gleason-Schulen wird international versucht, die Reproduzierbarkeit und Verlässlichkeit des Gleason-Gradings zu verbessern. Ein Problem ist die Untergraduierung in Stanzbiopsien. Der primäre Gleason-Grad 3 ist der niedrigste Grad, den man in Stanzbiopsien verlässlich diagnostizieren kann. Prognostisch wichtig ist die Abgrenzung gegenüber dem Gleason-Grad 4, der durch die Fusion von Tumordrüsen gekennzeichnet ist. Der prozentuale Anteil der Gleason-Grade 4 und 5 der in der Stanzbiopsie erfassten Läsion ist in vielen Fällen ein entscheidendes Kriterium für die Wahl der Therapie. In der vorliegenden Übersicht werden die diagnostischen Kriterien der primären Gleason-Grade und ihr Stellenwert in der Prostatadiagnostik besprochen.
    Der Pathologe 11/2005; 26(6):422-432. DOI:10.1007/s00292-005-0793-y · 0.64 Impact Factor
  • H. Bonkhoff
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    ABSTRACT: Bei den verschiedenen therapeutischen Optionen, die heute bei klinisch organbegrenzten Prostatakarzinomen (PCa) zur Verfügung stehen, spielen histopathologische Selektionskriterien eine zunehmende Rolle. Es geht beim Prostatakarzinom nicht nur um die Diagnose, sondern auch um prognostische Informationen für eine stadiengerechte Therapieentscheidung. Neben den klassischen Prognosefaktoren (PSA-Wert, TNM, Gleason-Grad, R-Status), gibt es eine Reihe von neueren Prognosefaktoren (Tumorvolumen, Anteil der Gleason-Grade 4 und 5, zystische Nervenscheideninvasionen, intraduktale Tumorausbreitung) und molekulare Marker, die heute beachtet werden sollten. Die vorliegende Übersicht befasst sich mit den etablierten und neuen Prognosefaktoren sowie den aktuellen Standards der Aufarbeitung und Befundung in der histopathologischen Diagnose des Prostatakarzinoms.
    Der Pathologe 11/2005; 26(6):433-443. DOI:10.1007/s00292-005-0792-z · 0.64 Impact Factor
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    ABSTRACT: Life expectancy for patients suffering from prostate cancer is inversely correlated with the degree of extraprostatic metastasis. In order to find pharmacological tools to treat this aggressive growth it is important to define targets whose expression not only correlates with the malignancy of the cancerous cells, but that are also amenable to pharmacological intervention. In this review, we would like to focus on the potential role of a distinct class of ion channels that may be involved in this process.
    Biochemical and Biophysical Research Communications 11/2004; 322(4):1359-63. DOI:10.1016/j.bbrc.2004.08.042 · 2.28 Impact Factor
  • H. Bonkhoff, T. Fixemer
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    ABSTRACT: Die gewöhnlichen Adenokarzinome der Prostata bestehen überwiegend aus exokrinen (PSA–produzierenden) Tumorzellen. An zweiter Stelle stehen die neuroendokrinen Tumorzellen. Sie kommen disseminiert und wechselnd ausgedehnt in nahezu allen Prostatakarzinomen vor, entziehen sich aber der histopathologischen und klinischen Routinediagnostik.Die vorliegende Übersicht fasst neue zellbiologische Daten zusammen, die für die Androgen- und Strahlenresistenz des neuroendokrinen (NE-)Phänotyps im Prostatakarzinom sprechen. Die NE-Tumorzellen, die sich immunhistochemisch mit dem panendokrinen Marker Chromogranin A nachweisen lassen, befinden sich in der G0-Phase des Zellzyklus und sind weitgehend resistent gegenüber dem programmierten Zelltod. Sie entstehen über einen Prozess der intermediären Differenzierung aus dem exokrinen Tumorzelltyp. Den NE-Tumorzellen fehlt konstitutionell der Androgenrezeptor. Sie produzieren aber eine Reihe von hormonellen Wachstumsfaktoren, die die Proliferationsaktivität in benachbarten exokrinen Tumorzellen über parakrine (androgenunabhängige) Regulationsmechanismen beeinflussen können.Die neuroendokrinen Tumorzellen bilden somit eine androgeninsensitive Zellpopulation im Prostatakarzinom und sind als G0-Zellen relativ strahlenresistent und potenziell unsterblich. Ihre besonderen zellbiologischen Eigenschaften spiegeln sich auch in den klinische Studien wider, in denen neuroendokrine Serummarker diagnostisch genutzt werden.In der klinischen und histopathologischen Routinediagnostik sollte deshalb gezielt nach der neuroendokrinen Differenzierung gefahndet werden, wenn für den Patienten die Option auf eine Androgenentzugs- bzw. Strahlentherapie besteht.
    Der Urologe 01/2004; 43(7). DOI:10.1007/s00120-004-0559-9 · 0.44 Impact Factor
  • H Bonkhoff, H Motherby, T Fixemer
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    ABSTRACT: The present review gives a survey on the differential expression of estrogen receptors alpha and beta (ERalpha, ERbeta) and the progesterone receptor (PR) in human prostate tissue and discusses their potential implications for normal and abnormal prostatic growth. The differentiation compartment of the prostatic epithelium (secretory luminal cells) expresses high levels of ERbeta, while the ERalpha is restricted to the proliferation compartment (basal cells). In high-grade prostatic intraepithelial neoplasia (HGPIN), ERalpha gene expression extends to luminal cells and thus may mediate cancerogenic effects of estrogens on the dysplastic epithelium. Conversely, the ERbeta is downregulated in HGPIN indicating that the chemopreventive effects of phytoestrogens mediated by the ERbeta are partially lost. Irrespective of grades and stages, prostate cancer retains high levels of the ERbeta, which is partially lost in androgen-insensitive stages of the disease. In contrast with breast cancer, the presence of the ERalpha and the progesterone receptor (PR) is a late event in prostate cancer progression. At least 30% of metastatic and androgen-insensitive tumors express high levels of the PR indicating that these tumors harbor a functional ERalpha. The antiestrogen raloxifene has growth-inhibitory effects on androgen-insensitive prostate cancer cells in vitro and induces apoptotic cell death in a dose-dependent fashion. These data provide a rationale for clinical trials to study the efficiency of antiestrogens in the medical treatment of advanced prostate cancer.
    Der Urologe 01/2004; 42(12):1594-601. · 0.44 Impact Factor
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    H. Bonkhoff, H. Motherby, T. Fixemer
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    ABSTRACT: In der vorliegenden bersicht werden neue Befunde ber die differenzielle Expression von strogenrezeptoren und strogenregulierter Zielgene in der Prostata und im Prostatakarzinom zusammengefasst und ihre Bedeutung fr die Tumorentstehung und Androgenresistenz diskutiert. Die beiden strogenrezeptoren und (ER, ER) werden in funktionell unterschiedlichen Kompartimenten des Prostataepithels exprimiert; der ER im Proliferationskompartiment (Basalzellschicht), der ER im Differenzierungskompartiment (sekretorisches Epithel).Bei der malignen Transformation des Prostataepithels (high-grade-prostatische intraepitheliale Neoplasie, HGPIN) verlagert sich die ER-Expression in das Differenzierungskompartiment und vermittelt als Onkogen kanzerogene Effekte auf das Prostataepithel. Der ER, ein potenzieller Tumorsuppressor, geht in der HGPIN partiell verloren, wodurch die protektive Wirkung der Phytostrogene auf das transformierte Prostataepithel abgeschwcht wird. Das Prostatakarzinom zeigt unabhngig von Grading und Staging hohe Expressoinsraten des ER. Erst im Stadium der Androgenresistenz geht der androgenregulierte ER partiell verloren. Im Gegensatz zum Mammakarzinom ist die Expression des klassischen ER und des Progesteronrezeptors im Prostatakarzinom ein sptes Ereignis in der Tumorprogression und ist maximal in Metastasen und hormonrefraktren Tumoren ausgeprgt. Etwa 30% der metastasierten und androgeninsensitiven Prostatakarzinome zeigen hohe Expressionsraten des ER regulierten Progesteronrezeptors. Das Antistrogen Raloxifen wirkt in androgeninsensitiven Prostatakarzinomzelllinien wachstumsinhibitorisch und induziert dosisabhngig den programmierten Zelltod.Aufgrund dieser Befunde sind Patienten mit androgeninsensitiven Prostatakarzinomen potentielle Kandidaten fr eine Antistrogen- bzw. Antigestagentherapie. Klinische Studien mssen die Effizienz einer solchen Therapie prfen.The present review gives a survey on the differential expression of estrogen receptors alpha and beta (ER, ER) and the progesterone receptor (PR) in human prostate tissue and discusses their potential implications for normal and abnormal prostatic growth. The differentiation compartment of the prostatic epithelium (secretory luminal cells) expresses high levels of ER, while the ER is restricted to the proliferation compartment (basal cells).In high-grade prostatic intraepithelial neoplasia (HGPIN), ER gene expression extends to luminal cells and thus may mediate cancerogenic effects of estrogens on the dysplastic epithelium. Conversely, the ER is downregulated in HGPIN indicating that the chemopreventive effects of phytoestrogens mediated by the ER are partially lost. Irrespective of grades and stages, prostate cancer retains high levels of the ER, which is partially lost in androgen-insensitive stages of the disease. In contrast with breast cancer, the presence of the ER and the progesterone receptor (PR) is a late event in prostate cancer progression. At least 30% of metastatic and androgen-insensitive tumors express high levels of the PR indicating that these tumors harbor a functional ER.The antiestrogen raloxifene has growth-inhibitory effects on androgen-insensitive prostate cancer cells in vitro and induces apoptotic cell death in a dose-dependent fashion. These data provide a rationale for clinical trials to study the efficiency of antiestrogens in the medical treatment of advanced prostate cancer.
    Der Urologe 11/2003; 42(12):1594-1601. DOI:10.1007/s00120-003-0438-9 · 0.44 Impact Factor
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    ABSTRACT: Members of the TRP superfamily of cation channels have homeostatic and regulatory functions in cells and changes in their expression may contribute to malignant growth. Previously, we have demonstrated that the gene of the Ca2+-selective cation channel CaT-L or TRPV6 is not expressed in benign prostate tissues including benign prostate hyperplasia, but is upregulated in prostate cancer. Here, we report on the differential expression of TRPV6 mRNA in prostate tissue obtained from 140 patients with prostate cancer. Using in situ hybridization, TRPV6 transcripts were undetectable in benign prostate tissue, high-grade prostatic intraepithelial neoplasia (n=57), incidental adenocarcinoma and all tumors less than 2.3 cubic centimeter (cc). In prostatectomy specimens from 97 clinically organ-confined tumors, TRPV6 expression correlated significantly with the Gleason score (P=0.032), pathological stage (P<0.001) and extraprostatic extension (P=0.025). Lymph node metastasis (n=17) and androgen-insensitive tumors (n=27) revealed TRPV6 expression in 63 and 67% of cases, respectively. The latter, however, revealed markedly and significantly decreased levels when compared with untreated tumors (P=0.044). In summary, the data demonstrate that TRPV6 expression is associated with prostate cancer progression. Accordingly, TRPV6 represents a prognostic marker and, as a plasma membrane Ca2+ channel, a promising target for new therapeutic strategies to treat advanced prostate cancer.
    Oncogene 11/2003; 22(49):7858-61. DOI:10.1038/sj.onc.1206895 · 8.56 Impact Factor
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    ABSTRACT: Because the mechanisms of telomerase activation in prostate cancer are mainly unknown, we investigated the relationships between telomerase activity and expression levels of human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) mRNA in benign and malignant alterations of the human prostate gland. Using the LightCycler technology, hTERT mRNA expression was quantified in 46 radical prostatectomy and 10 benign prostatic hyperplasia (BPH) cases; hTR expression was quantified in a subset of these tissue samples. Telomerase activity was measured using a quantitative telomeric repeat amplification protocol ELISA assay. Similar to hTR, which was expressed in all tissue samples tested, hTERT mRNA was detected in 98% of the prostate cancer samples and in 30% of the BPH samples. Regarding clinicopathologic variables, telomerase activity was significantly correlated with Gleason score (<7 vs > or =7, p = 0.02). No relationships emerged between normalized hTR or hTERT expression levels and tumor stage, Gleason score, lymph node status, or preoperative serum prostate-specific antigen. Remarkably, one third of all cancer and BPH tissue samples with hTR and hTERT expression lack telomerase activity. Quantitative analyses contradict the assumption that a certain threshold level of hTR or hTERT mRNA is required for telomerase activation, thus indicating that telomerase regulation in prostate cancer occurs more likely on a posttranscriptional level. Nevertheless, the observation that hTR and hTERT mRNA levels are significantly (p < 0.002) correlated suggests some common mechanisms in the up-regulation of hTR and hTERT expression. Because in situ hybridization revealed strong hTERT expression in all cells of the tumor glands but also in high-grade prostatic intraepithelial neoplasia foci, this up-regulation seems to occur early in prostate carcinogenesis.
    Laboratory Investigation 05/2003; 83(5):623-33. DOI:10.1097/01.LAB.0000069035.85309.30 · 3.83 Impact Factor

Publication Stats

3k Citations
225.14 Total Impact Points

Institutions

  • 2004
    • Gemeinschaftspraxis für Pathologie Freiburg
      Freiburg an der Elbe, Lower Saxony, Germany
  • 1990–2004
    • Universität des Saarlandes
      • • Institut für Allgemeine und Spezielle Pathologie und Neuropathologie
      • • Zentrum für Pathologie und Rechtsmedizin
      Saarbrücken, Saarland, Germany