Differential Cytokeratin Expression in Normal, Hyperplastic and Malignant Epithelial Cells From Human Prostate

Sherwood, Edward R.; Berg, Lori A.; Mitchell, Nancy J.; McNeal, John E.; Kozlowski, James M.; Lee, Chung

doi:10.1016/s0022-5347(17)39903-2

Cited by 108 publications

(78 citation statements)

References 18 publications

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“…Exocrine, terminally differentiated luminal cells, express cytokeratin 18 (Sherwood et al, 1990) and PSA, and show androgen dependence. Basal cells express cytokeratin 5 and are androgen independent.…”

Section: Introductionmentioning

confidence: 99%

Identification of a stem cell candidate in the normal human prostate gland

Schmelz

Moll

Hesse

et al. 2005

European Journal of Cell Biology

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Stem cells of the human prostate gland have not yet been identified utilizing a structural biomarker. We have discovered a new prostatic epithelial cell phenotype-expressing cytokeratin 6a (Ck6a+ cells). The Ck6a+ cells are present within a specialized niche in the basal cell compartment in fetal, juvenile and adult prostate tissue, and within the stem cell-enriched urogenital sinus. In adult normal prostate tissue, the average abundance of Ck6a+ cells was 4.9%. With proliferative stimuli in the prostate organ culture model, in which the epithelial-stromal interaction was maintained, a remarkable increase of Ck 6a expression was noticed to up to 64.9%. The difference in cytokeratin 6a expression between the normal adult prostate and the prostate organ culture model was statistically significant (p<0.0001). Within the prostate organ culture model the increase of cytokeratin 6a-expressing cells significantly correlated with increased proliferation index (r = 0.7616; p = 0.0467) The Ck6a+ cells were capable of differentiation as indicated by their expression of luminal cell markers such as ZO-1 and prostate specific antigen (PSA). Our data indicate that Ck6a+ cells represent a prostatic epithelial stem cell candidate possessing high potential for proliferation and differentiation. Since the development of benign prostatic hyperplasia and prostate carcinogenesis are disorders of proliferation and differentiation, the Ck6a+ cells may represent a major element in the development of these diseases.

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Section: Introductionmentioning

confidence: 99%

Identification of a stem cell candidate in the normal human prostate gland

Schmelz

Moll

Hesse

et al. 2005

European Journal of Cell Biology

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“…NE cells are rare (Ͻ1% of the total), have distinctive projections that allow them to contact epithelial neighbors located several cell diameters away, and secrete a variety of neuropeptides and neurotransmitters (14)(15)(16)(17). Conventional adenocarcinoma of the prostate (CaP) is the most commonly diagnosed cancer and the second leading cause of cancer death in males (18): it displays features common to luminal͞secretory cells (19)(20)(21)(22)(23). Pure NE cell tumors of the prostate are rare but aggressive (2).…”

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confidence: 99%

An integrated functional genomics and metabolomics approach for defining poor prognosis in human neuroendocrine cancers

Ippolito

Jain

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

104

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Human neuroendocrine (NE) cancers range from relatively indolent to highly aggressive. In this study, we combine functional genomics with metabolomics to identify features of NE cancers associated with a poor outcome. Analysis of GeneChip datasets of primary prostate tumors, as well as lymph node and liver metastases from transgenic mice with a NE cell cancer, plus derived NE cell lines yielded a signature of 446 genes whose expression is enriched in neoplastic mouse prostatic NE cells. This signature was used for in silico metabolic reconstructions of NE cell metabolism, directed liquid chromatography͞tandem MS analysis of metabolites in prostatic NE tumors and cell lines, and analysis of GeneChip datasets of human NE tumors with good or poor prognoses. The results indicate that a distinguishing feature of poor-prognosis NE tumors is a glutamic acid decarboxylase-independent pathway for production of GABA and a pathway for production of imidazole-4-acetate that involves dopa decarboxylase and a membraneassociated amine oxidase, amiloride-binding protein 1. Electrophysiological studies disclosed that imidazole-4-acetate can bind and activate GABAA receptors expressed by transformed NE cells, thus providing a previously uncharacterized paradigm for NE tumor cell signaling. Transcriptional, metabolic, and electrophysiologic features of transformed mouse NE cells are also evident in neural progenitor cells.GABA signaling ͉ MS ͉ metastatic neuroendocrine cancers ͉ polyamine metabolism ͉ transcriptome-directed metabolomics H uman neuroendocrine (NE) cancers (NECs) can arise in neuroectodermal tissues or in endoderm-derived epithelia (e.g., pheochromocytomas and small cell lung cancers, respectively). Many types of NECs are aggressive and diagnosed only after metastatic spread (1, 2). In addition, the appearance of NE features in cancers arising from cells that do not normally express neural or endocrine fates is often associated with more aggressive disease (3-5). A panel of biomarkers and mediators of tumorigenesis is needed for better diagnosis and stratification of NECs and new, more efficacious therapeutic approaches. In this report, we present one approach for addressing this issue that uses a combination of transgenic mice with a metastatic cancer arising from their prostatic NE cell lineage, NE cell lines established from this cancer, human NE tumors with varying degrees of aggressiveness, functional genomics, and MS-based metabolomics.The prostate contains three epithelial lineages: secretory, basal, and NE (6). The secretory or luminal cell is the most abundant type and requires continuous exposure to androgens for its survival (7-11). Basal cells represent the primary proliferating epithelial population and are not androgen-dependent (12, 13). NE cells are rare (Ͻ1% of the total), have distinctive projections that allow them to contact epithelial neighbors located several cell diameters away, and secrete a variety of neuropeptides and neurotransmitters (14-17). Conventional adenocarcinoma of the prostate (C...

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“…44 The basal cells express predominantly high molecular weight cytokeratins (CK5 and CK14), the luminal secretory cells express predominantly low molecular weight cytokeratin (CK8 and CK18) and the intermediate cells express a combination of basal and luminal cytokeratins. [45][46][47][48] There is increasing evidence that basal epithelial cells differentiate into luminal epithelial cells. 49 The expression level of high and low molecular weight cytokeratins in intermediate cells is heterogeneous, indicating that this compartment contains different cell populations possibly along a linear differentiation pathway.…”

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confidence: 99%

Normal and Malignant Prostate Epithelial Cells Differ in Their Response to Hepatocyte Growth Factor/Scatter Factor

Gmyrek

Walburg

Webb

et al. 2001

The American Journal of Pathology

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Hepatocyte growth factor/scatter factor (HGF/SF) promotes the proliferation, differentiation, motility, and invasion of epithelial cells by binding to its cell surface receptor, the Met tyrosine kinase. In the prostate, Met is expressed predominantly by prostate epithelial cells (PrEC), whereas HGF/SF is synthesized by prostate stromal cells (PrSCHepatocyte growth factor/scatter factor (HGF/SF) 1,2 has been implicated in the communication between stromal and epithelial cells of many different organs. HGF/SF is secreted predominantly by stromal cells and binds to its receptor, Met 3,4 mostly expressed on epithelial cells. Activation of the Met receptor tyrosine kinase affects a wide range of cellular processes, including growth and differentiation, morphogenesis and invasiveness. [5][6][7] The critical function of HGF/SF-Met in early development and during organogenesis is illustrated by the expression of Met in human embryonic tissues and by the identical phenotypes of HGF/SF and Met targeted knockout mice with early placental and hepatic defects. 8 -10 Gerald Cunha and collaborators 11,12 demonstrated the reciprocal nature of interactions between the stroma and epithelium in the determination of final organ structure. Several studies have suggested that mechanisms mediating the inductive interactions between the stroma and normal epithelium may also stimulate neoplastic cells during carcinogenesis and metastasis. 11,[13][14][15] This occurs through inappropriate expression or activation of receptors for stromal derived growth factors in tumor cells. 16 One of these receptors is Met which is aberrantly expressed or activated in a variety of human cancers. [17][18][19][20] Met was originally identified by its oncogenic potential in gene transfer experiments with DNA from transformed osteogenic sarcoma cells using the NIH 3T3 cell focus forming assay. 3 Dimerization of the cytoplasmic Met kinase activates its oncogenic function. 4,21 Constitutive Met activation is achieved through germline or somatic mutations in the Met kinase domain as detected in familial papillary renal cell carcinomas. 22,23 Transgenic expression of two independent strongly activating Met mutations as well as transgenic expression of tpr-met resulted in mammary carcinogenesis. 24,25 Furthermore, Met can be persistently activated through autocrine stimulation in tumor cells co-expressing Met and HGF/ SF. 26 -31 Based on the ability of HGF/SF to cause the dissociation of tumor cells from the primary tumor mass, to stimulate cell motility, and to elicit the activation of proteolytic cascades that degrade the extracellular matrix, 32-34 the HGF/SF-Met ligand-receptor system is a likely regulator of tumor metastases. As previously demonstrated, autocrine secretion of HGF/SF promotes metastases in a mouse model of tumor metastasis and Supported by Department of the Army grant DAMA-17-98-1-8592 (to B.S.K.).

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Differential Cytokeratin Expression in Normal, Hyperplastic and Malignant Epithelial Cells From Human Prostate

Cited by 108 publications

References 18 publications

Identification of a stem cell candidate in the normal human prostate gland

Identification of a stem cell candidate in the normal human prostate gland

An integrated functional genomics and metabolomics approach for defining poor prognosis in human neuroendocrine cancers

Normal and Malignant Prostate Epithelial Cells Differ in Their Response to Hepatocyte Growth Factor/Scatter Factor

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