H Bonkhoff

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

Are you H Bonkhoff?

Claim your profile

Publications (76)210.82 Total impact

  • Source
    Helmut Bonkhoff
    [show abstract] [hide abstract]
    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.
    Prostate cancer. 01/2012; 2012:593241.
  • Helmut Bonkhoff, Richard Berges
    [show abstract] [hide abstract]
    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 09/2009; 70(1):100-12. · 3.84 Impact Factor
  • Source
    Helmut Bonkhoff, Richard Berges
    [show abstract] [hide abstract]
    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. · 10.48 Impact Factor
  • H Bonkhoff, T Fixemer
    [show abstract] [hide abstract]
    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. · 0.62 Impact Factor
  • H Bonkhoff
    [show abstract] [hide abstract]
    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. · 0.62 Impact Factor
  • H Bonkhoff
    [show abstract] [hide abstract]
    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. · 0.62 Impact Factor
  • H Bonkhoff, T Fixemer
    [show abstract] [hide abstract]
    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. · 0.62 Impact Factor
  • H Bonkhoff
    [show abstract] [hide abstract]
    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. · 0.62 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Basal cell tumours of the prostatic gland are rare, and the classification is difficult. In the present case report, a large, tumour-like proliferation of atypical basaloid cells was found incidentally in a prostatectomy specimen that otherwise contained a conventional acinar adenocarcinoma. The basaloid cells displayed a solid or adenoid-cystic growth pattern and strongly expressed high-molecular-weight cytokeratins and bcl-2. A high Ki-67 index was recorded within the atypical basaloid cells, by far exceeding the one counted in the conventional adenocarcinoma. However, there were no definite criteria for a malignant behaviour of the basal cell tumour. Comparative genomic hybridisation from microdissected tumour cells yielded losses at the short arms of chromosomes 8 and 12 in the conventional adenocarcinoma and a normal karyotype in the basal cell tumour. The pathological findings favoured the diagnosis of an atypical basal cell hyperplasia.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 04/2005; 446(3):338-41. · 2.68 Impact Factor
  • H. Bonkhoff, T. Fixemer
    [show abstract] [hide abstract]
    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.
    Pathologe. 01/2005; 26(6):461-468.
  • [show abstract] [hide abstract]
    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. · 2.41 Impact Factor
  • H. Bonkhoff, T. Fixemer
    [show abstract] [hide abstract]
    ABSTRACT: Die gewhnlichen Adenokarzinome der Prostata bestehen berwiegend 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 bersicht fasst neue zellbiologische Daten zusammen, die fr die Androgen- und Strahlenresistenz des neuroendokrinen (NE-)Phnotyps im Prostatakarzinom sprechen. Die NE-Tumorzellen, die sich immunhistochemisch mit dem panendokrinen Marker ChromograninA nachweisen lassen, befinden sich in der G0-Phase des Zellzyklus und sind weitgehend resistent gegenber dem programmierten Zelltod. Sie entstehen ber einen Prozess der intermediren Differenzierung aus dem exokrinen Tumorzelltyp. Den NE-Tumorzellen fehlt konstitutionell der Androgenrezeptor. Sie produzieren aber eine Reihe von hormonellen Wachstumsfaktoren, die die Proliferationsaktivitt in benachbarten exokrinen Tumorzellen ber parakrine (androgenunabhngige) Regulationsmechanismen beeinflussen knnen.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 fr den Patienten die Option auf eine Androgenentzugs- bzw. Strahlentherapie besteht.Neuroendocrine (NE) differentiation frequently occurs in common prostatic malignancies and has attracted increasing attention in contemporary prostate cancer research .This particular phenotype, however, usually escapes pathological and clinical detection in routine practice.The present review focuses on the biological properties of NE tumor cells that make them resistant to androgen deprivation and radiation therapy. NE cells produce a number of hormonal growth factors (e.g., serotonin) that may act through endocrine, paracrine, and autocrine mechanisms. Morphogenetic studies have identified intermediate phenotypes between the three basic cell types of the prostatic epithelium indicating their common origin from stem cells located in the basal cell layer.Virtually all prostatic adenocarcinomas show NE differentiation as defined by the most commonly used endocrine marker chromogranin A. Clinical studies suggest that the extent of NE differentiation increases with tumor progression and the development of androgen insensitivity. NE differentiation exclusively occurs in the G0 phase of the cell cycle in which tumor cells are usually resistant to radiation therapy and cytotoxic drugs. In addition, NE tumor cells also escape programmed cell death. Even under androgen deprivation, only 0.16% of NE tumor cells show apoptotic activity. This indicates that the vast majority of NE tumor cells represent an immortal cell population in prostate cancer.Although NE tumor cells do not proliferate, they produce a number of NE growth factors with mitogenic properties that maintain cell proliferation in adjacent (exocrine) tumor cells through a paracrine mechanism. NE tumor cells consistently lack the androgen receptor and are androgen insensitive in all stages of the disease. They derive through a process of intermediate differentiation from exocrine tumor cells, the most prevalent phenotype in common prostatic adenocarcinoma. Elevated serum levels of chromogranin A in prostate cancer patients correlate with poor prognosis and are scarcely influenced by either androgen deprivation or chemotherapy. Looking for NE differentiation is recommended in the pathological and clinical evaluation of prostate cancer patients for whom radiation and androgen deprivation are therapeutic options.
    Der Urologe 06/2004; 43(7):836-842. · 0.46 Impact Factor
  • H Bonkhoff, H Motherby, T Fixemer
    [show abstract] [hide abstract]
    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. · 0.46 Impact Factor
  • Source
    H. Bonkhoff, H. Motherby, T. Fixemer
    [show abstract] [hide abstract]
    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. · 0.46 Impact Factor
  • Source
    [show abstract] [hide abstract]
    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. · 7.36 Impact Factor
  • Source
    [show abstract] [hide abstract]
    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. · 3.96 Impact Factor
  • Thomas Fixemer, Klaus Remberger, Helmut Bonkhoff
    [show abstract] [hide abstract]
    ABSTRACT: Estrogen signaling mediated by the estrogen receptor beta (ERbeta) has potential implications in normal and abnormal prostate growth. Few studies have addressed this issue in human prostate tissue leaving conflicting results on the immunolocalization of the ERbeta in benign and neoplastic lesions. Using a new monoclonal antibody, the current study reports on the differential expression of the ERbeta in tissue sections from 132 patients with prostate cancer. The prostatic epithelium expressed the ERbeta extensively in secretory luminal cell types and at lower levels in basal cells. Atrophic changes of the peripheral zone (PZ) were more immunoreactive than hyperplastic lesions of the transition zone (TZ). When compared with glandular tissue of the PZ, high-grade prostatic intraepithelial neoplasia (HGPIN) revealed decreased levels of the ERbeta in 30 of 47 cases and was unreactive in six lesions. In informative cases with suitable internal controls, all primary tumors (n = 60), lymph node (n = 7), and bone metastases (n = 5) expressed the ERbeta at variable degree. No correlation was found between the ERbeta status, the primary Gleason grade (P = 0.254), and the pathological stage (P = 0.157). Recurrent adenocarcinoma revealed markedly decreased levels in 15 of 40 cases and was ERbeta negative in five recurrent lesions. The secretory epithelium is a major target of ERbeta-mediated estrogen signaling in the human prostate. Its downregulation in HGPIN is consistent with chemopreventive effects that the ERbeta may exert on the prostatic epithelium. The continuous expression of the receptor protein at significant levels in untreated primary and metastatic adenocarcinoma indicates that these tumors can use estrogens through an ERbeta-mediated pathway. The partial loss of the ERbeta in recurrent tumors after androgen-deprivation may reflect the androgen-dependence of ERbeta gene expression in human prostate cancer.
    The Prostate 03/2003; 54(2):79-87. · 3.84 Impact Factor
  • Thomas Fixemer, Klaus Remberger, Helmut Bonkhoff
    [show abstract] [hide abstract]
    ABSTRACT: Neuroendocrine (NE) differentiation has been implicated in prostate cancer progression and hormone therapy failure. It has been shown that prostate cancer cells with NE features lack proliferation activity in vitro and in vivo. The current study reports on the apoptotic status of NE phenotypes in human prostate cancer. Double-label techniques were used for simultaneous demonstration of the endocrine marker chromogranin A (ChrA) and DNA fragmentation assessed by the terminal transferase-mediated biotinylated 16-desoxy-uridine-tri-phosphate (bio-16-dUTP) nick-end-labeling (TUNEL) assay. The material included primary prostatic adenocarcinoma (n = 18), lymph node metastases (n = 5), bone metastases (n = 2), and recurrent lesions (n = 10) showing NE differentiation at the immunohistochemical level. Irrespective of grades, stages, and the degree of NE differentiation, DNA fragmentation was restricted to exocrine (ChrA-negative) tumor cells and was undetectable in most of NE tumor cells expressing ChrA. At least 0.16% of ChrA-positive tumor cells revealed DNA fragmentation assessed by the TUNEL assay. The present data suggest that the vast majority of prostate cancer cells with NE features escapes programmed cell death. This escape may contribute significantly to their drug resistance and their malignant potential.
    The Prostate 11/2002; 53(2):118-23. · 3.84 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Solid-pseudopapillary tumor of the pancreas constitutes a very rare benign or low-grade malignant lesion occurring most commonly in young women and girls. It was first described by Frantz. Local infiltration, distant metastasis and recurrence are very rare. Until today, the histogenetic origin of the tumor cell remains to be elucidated. In 1996, solid-pseudopapillary tumor of the pancreas was introduced in the World Health Organization (WHO) classification of tumors of the exocrine pancreas. Our case report--like a recently published work by Lange et al.--intends to underline the significance of solid-pseudopapillary tumor in the differential diagnosis of a pancreatic mass.
    Klinische Pädiatrie 01/2002; 214(5):316-8. · 1.90 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: The recent discovery of the classical estrogen receptor alpha (ERalpha) in metastatic and recurrent prostatic adenocarcinoma suggests that estrogens are implicated in prostate cancer progression. To get more insight into estrogen signaling in prostate cancer tissue, the current study has examined the immunoprofile of the estrogen-inducible progesterone receptor (PR), and evaluated its relation to ERalpha gene expression. In primary tumors, the PR was detectable in 36% of primary Gleason grade 3 (5 of 14 cases), 33% of primary Gleason grade 4 (5 of 15 cases), and in 58% of primary Gleason grade 5 tumors (7 of 12 cases). None of the 41 primary tumors investigated revealed significant PR expression in more than 50% of tumor cells. Conversely, moderate to strong receptor expression was observed in 60% of metastatic lesions (9 of 15 cases), and in 54% of androgen-insensitive tumors (38 of 71 cases). Irrespective of grades and stages, the presence of the PR was invariably associated with high steady state levels of ERalpha mRNA, whereas the ERalpha protein was undetectable by immunohistochemistry (IHC) in a significant number of cases (58 of 97 cases). The progressive emergence of the PR during tumor progression obviously reflects the ability of metastatic and androgen-insensitive tumors to use estrogens through a ERalpha-mediated pathway. The present data provide a theoretical background for studying the efficiency of antiestrogens and antigestagens in the medical treatment of advanced prostate cancer.
    The Prostate 10/2001; 48(4):285-91. · 3.84 Impact Factor

Publication Stats

3k Citations
210.82 Total Impact Points

Institutions

  • 2004
    • Gemeinschaftspraxis für Pathologie Freiburg
      Freiburg an der Elbe, Lower Saxony, Germany
  • 1989–2003
    • Universität des Saarlandes
      • • Institut für Allgemeine und Spezielle Pathologie und Neuropathologie
      • • Zentrum für Pathologie und Rechtsmedizin
      Saarbrücken, Saarland, Germany