Helmut Bonkhoff

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 androgen‐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).

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.

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.

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

Steroid 5α‐reductase is essential for the intracellular accumulation of dihydrotestosterone (DHT), which mediates androgen effects on target tissue.

Differential expression of α6 and α2 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.

A Proposal on the Identification, Histologic Reporting, and Implications of Intraductal Prostatic Carcinoma

CONTEXTnProstatic 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).nnnOBJECTIVEnTo 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.nnnDATA SOURCESnWe reviewed all published data referring to intraductal spread of prostate carcinoma. Articles discussing endometrial, endometrioid, and ductal carcinoma are included.nnnCONCLUSIONSnIntraductal 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.

Cellular and Molecular Pathology of Prostate Cancer Precursors

Prostate cancer is usually heterogeneous and multifocal, with diverse clinical and morphologic manifestations. Current understanding of the molecular basis for this heterogeneity is limited, particularly for prostatic intraepithelial neoplasia (PIN), the only putative precursor which can be identified according to morphologic criteria. However, it is likely that prostatic adenocarcinoma might arise from precursor lesions other than PIN, although these cannot be recognized with certainty at the present time. In this review, we summarize the current state of knowledge regarding the cell-biological and genetic bases for linking PIN and prostatic adenocarcinoma. It is conceivable that a stem cell of basal phenotype, or an amplifying cell, is the target of prostatic carcinogenesis. Prominent genetic heterogeneity is characteristic of both PIN and carcinoma; and multiple foci of PIN arise independently within the same prostate. This observation suggests that a field effect probably underlies prostatic neoplasia. Multiple foci of cancer also often arise independently, lending additional support to this hypothesis. The strong genetic similarities between PIN and cancer strongly suggest that evolution and clonal expansion of PIN, or other precursor lesions, may account for the multifocal etiology of carcinoma. Uncertainties with respect to identification of those precursor lesions which are most likely to progress to invasive and metastatic prostate cancer reinforce the requirement for objective immunohistochemical or molecular biological markers of the aggressive phenotype.

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.

Morphogenetic concepts of normal and abnormal growth in the human prostate.

Abstractu2002Benign prostatic hyperplasia (BPH) and prostate cancer are multifactorial disease processes, involving a growing number of biochemical, genetic and epigenetic factors. Their pathogenesis, however, remains poorly understood. The present review examines current morphogenetic concepts of normal and abnormal growth in the human prostate. This includes the role of basal cells in organogenesis and cancerogenesis, the impact of cell–matrix interactions, and the importance of cellular heterogeneity in tumour progression and hormone-insensitive growth. Knowledge of morphogenesis and morphology is required in any scientific approach to BPH and prostate cancer.

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.