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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A longstanding goal has been to determine whether androgen receptor (AR) levels could be used to predict the clinical response of metastatic prostate cancer to androgen withdrawal therapy. A major limitation of previous studies was the use of homogenized tissue, which yields an average AR content for all cells. By AR immunohistochemical study using an antibody specific for AR the authors assessed nuclear AR content specifically in the malignant epithelial cells of prostate needle biopsy specimens of 17 patients with Stage D prostate cancer. The authors found that prostate cancer contains AR-positive and AR-negative malignant cells before androgen withdrawal therapy, but the percentage of AR-positive cells did not predict the time to tumor progression after therapy. There was no significant correlation between the percentage of AR-positive malignant cells and the time to tumor progression. When patients were divided into two groups based on the median time to progression, the percentage of AR-positive nuclei was not significantly different in poor responders versus good responders. When patients were divided into two groups based on the median percentage of receptor-positive nuclei, Kaplan-Meier estimates of the progression-free interval revealed no significant difference between the group of patients with AR-poor tumors and patients with AR-rich tumors. Potential explanations for these results are discussed. The authors conclude that the percentage of AR-positive nuclei is not a sufficient criterion to predict tumor behavior.
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PMID:Immunohistochemical study of androgen receptors in metastatic prostate cancer. Comparison of receptor content and response to hormonal therapy. 171 May 37

The Dunning R-3327 rat prostatic adenocarcinoma and its sublines have been developed as a model system to study prostate tumor progression. We have used this system to study the changes in androgen receptor (AR) and AR mRNA expression which occur during tumor progression from androgen dependent to androgen independent growth. Dorsal prostate and all tumor sublines contained a 10-kilobase AR mRNA on Northern blot analysis. The levels of AR mRNA in each subline compared to dorsal prostate (100%) were: H (75%) greater than G (48%) greater than HI (25%) greater than HI-F = AT-1 = AT-3 = MAT-Lu = MAT-Ly-Lu = less than 5%. Immunocytochemistry showed AR predominantly in acinar epithelial cells of dorsal prostate and the androgen sensitive H subline. In the H subline, both acinar epithelial cells and locally invasive adenocarcinoma cells within the stroma showed positive immunostaining. The androgen responsive, anaplastic G subline also showed strong positive immunostaining. The androgen resistant AT-1 and MAT-Lu sublines lacked immunostaining for the AR. Steroid autoradiography revealed a similar cellular distribution of AR. These data suggest that in the Dunning system the loss of androgen binding and responsiveness is primarily due to selective changes in gene expression and not to gene rearrangements or posttranscriptional or translational modification of the AR mRNA or protein.
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PMID:Expression and localization of androgen receptor in the R-3327 Dunning rat prostatic adenocarcinoma. 240 76

Amplification of HER-2 oncogene was analysed in DNAs obtained from 291 primary human mammary carcinomas. 52/291 (18%) were found to contain amplified HER-2 oncogene. Moderate amplification (2- to 5-fold) was noted in 36/291 (12%). Thirteen tumors (4.5%) had a copy number of 5 to 10. A 10- to 20-fold and greater than 20-fold amplification was observed in 2 and 1 patient, respectively. Sample sizes allowed the determination of estrogen receptor (ER) and progesterone receptor (PgR) levels in 253/291 primary breast cancers. HER-2 gene amplification was noted in 14% of ER+ patients and in 28% of ER- patients, respectively (P = 0.02). Similarly a significantly greater number of PgR- primary mammary carcinoma exhibited an amplification of the HER-2 gene compared to PgR+ cases (22% vs. 16%, P = 0.01). Although statistically not significant, tumors with HER-2 gene amplification were found to have lower levels of ER and PgR. No association of HER-2 amplification with the androgen receptor and EGF receptor was observed. Present data combine to suggest that tumor progression is more stringently controlled by the oncogene upon loss of hormone dependency. Differences found in HER-2 amplification between steroid receptor positive and negative tumors could be helpful to define a specific subset of women to whom adjuvant therapy should be directed.
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PMID:HER-2 amplification, steroid receptors and epidermal growth factor receptor in primary breast cancer. 291

Heterogeneity in human androgen receptor (hAR) expression in prostate cancer is considered to be implicated in tumor progression. hAR expression was therefore studied immunohistochemically in localized and locally progressive, hormone refractory (HR) prostate cancer. Because altered functional activity of the hAR may be due to changes in the structural integrity of the hAR gene, exons 2 to 8 of the hAR gene were assessed for mutations by single-strand conformation polymorphism (SSCP) analysis and exon 1 was analyzed for the size of the CAG repeat. The hormone binding capacity, a prerequisite for ligand-regulated receptor function, was determined by a ligand binding assay. Coexpression of the hAR and prostate-specific antigen (PSA) was studied by a sequential double immunoenzymatic staining to verify whether PSA expression is a parameter of hAR function. Almost all human prostatic carcinomas revealed heterogeneous hAR expression, regardless of tumor differentiation and progression. Putative predominance of hAR-negative tumor areas in HR prostate cancer was not observed. No hAR gene mutations or major changes in the CAG repeat were found in the 18 HR carcinomas or in the 9 control samples. Moreover, all selected hAR-expressing cancers were able to bind the synthetic androgen methyltrienolone (R1881). Immunoenzymatic double staining revealed even PSA expression in hAR-negative tumor areas. PSA immunohistochemistry in human prostatic carcinomas therefore is of no use in determining hAR functional activity. Thus, most prostatic carcinomas, even when progressed to a state of hormone insensitivity, contain a structurally intact hAR gene, heterogeneously expressed with retained androgen binding capacity.
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PMID:Androgen receptor status in localized and locally progressive hormone refractory human prostate cancer. 751 91

Intracellular action of androgens is mediated by the androgen receptor (AR), which is a key element of the androgen signal transduction cascade and a target of endocrine therapy for prostatic carcinoma. Therefore, the qualitative and quantitative alterations of AR expression in prostatic carcinomas and their possible implications for tumor progression and treatment are of great interest. Findings in prostatic tumor cell lines of rat and human origin suggest a reduction of AR protein expression accompanied by an increase in tumor malignancy. However, immunohistochemical studies and binding assays demonstrated presence of ARs in all histological types of prostatic tumors, in therapy-responsive as well as in therapy-unresponsive ones. AR content of prostatic tumor specimens did not correlate with outcome of endocrine therapy of advanced prostatic carcinoma in these studies. Solely the degree of heterogeneity of AR expression may be useful as an indicator of responsiveness to therapy. AR mutations have been detected in the LNCaP cell line and in three primary prostatic tumor specimens. Three of them are point mutations in the hormone-binding domain of the AR, the fourth mutation is a CAG-microsatellite depression in the N-terminus. Evidence coming from studies on AR in prostatic cancer highlights the possibility that AR structural alterations may have significance in tumor progression.
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PMID:Androgen receptor alterations in prostatic carcinoma. 797 17

Neuroendocrine (NE) cells containing neurosecretory granules, rich in various peptide hormones and biogenic amines, are components of the human prostate epithelium and prostatic adenocarcinomas. Neuroendocrine differentiation in prostatic adenocarcinomas has been associated with a poor prognosis and, following androgen withdrawal therapy, tumor cell populations have been observed to become enriched with NE cells. We assessed androgen receptor (AR) expression in NE cells in benign and malignant prostatic tissue using double-labeling immunocytochemistry with validated monoclonal antibodies to the AR and to chromogranin A (a generic NE marker). Neuroendocrine cells in benign and malignant prostatic tissue generally showed nuclear staining with AR. Some distinct AR-negative nuclei were observed in normal NE cells. In prostatic adenocarcinomas with extensive NE differentiation, a subpopulation of AR-negative NE cells was demonstrated. In conclusion, benign and malignant prostatic tissue contain both AR-positive and AR-negative NE cells that may have significance in regards to androgen-independent tumor growth and tumor progression.
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PMID:The androgen receptor status of neuroendocrine cells in human benign and malignant prostatic tissue. 848 96

To date androgen receptor (AR) expression and structure in human prostatic cancer have been studied in primary tumor specimens and in cell lines. Investigation of alterations in the androgen-signalling transduction cascade in prostatic carcinoma metastases is important to improve our understanding of tumor progression towards androgen insensitivity. In the present study we have collected data comparing AR expression in both the primary tumors and the respective pelvic lymph node metastases. Formalin-fixed and paraffin-embedded tissues derived from the primary tumors and positive lymph nodes of 12 patients undergoing radical prostatectomy were immunostained for the AR and prostate-specific antigen (PSA). AR expression was evaluated with the polyclonal antibody PG-21, which is directed against amino acid 1-21 in the N-terminal region of the AR. All primary tumors stained for the AR. In 8 of the 12 lymph nodes examined more than 50% of the tumor cells were AR positive and displayed a uniform staining pattern; in one lymph node metastasis remarkable heterogeneity in AR expression was observed. In two cases less than 10% of the tumor cells stained for the AR. In one case the lymph node metastasis was immunohistochemically negative for the AR, whereas the primary tumor obtained from the same patient displayed intense staining for the AR. PSA was expressed in all metastases and primary tumors. Our data demonstrate that loss of the AR in lymph node metastases from prostatic carcinoma is a rare event.
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PMID:Androgen receptor status of lymph node metastases from prostate cancer. 860 94

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.
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PMID:Differentiation pathways and histogenetic aspects of normal and abnormal prostatic growth: a stem cell model. 860 98

Progress in prostate cancer research has been hindered by the lack of well characterized, immortalized, human prostatic epithelial cell lines that express markers of normal prostatic epithelial cells and mimic normal growth and differentiation responses to androgens. The objectives of this study were to: (i) establish immortalized cell lines from non-neoplastic, adult human prostatic epithelium using adenovirus-12/simian virus-40 (Ad12-SV40) hybrid virus; (ii) establish their prostatic epithelial origin; (iii) demonstrate androgen responsiveness; and (iv) examine response to growth factors. Primary epithelial cell cultures derived from a non-neoplastic, adult human prostate were infected with the Ad12-SV40 virus. Several immortalized clones were isolated. Single cell cloning of one clone, free of cytopathic effects, gave rise to the PWr-1E cell line. An immortalized cell line PWR-1E, which expresses many characteristics of normal prostatic epithelial cells was established. Immunostaining showed that cells express cytokeratins 8 and 18 normally expressed by differentiated, secretory prostatic epithelial cells. The most remarkable characteristics of PWR-1E cells are growth stimulation, increased expression of androgen receptor and induction of prostate specific antigen (PSA) expression in response to androgens, which indisputably establish their prostatic epithelial origin. They are positive for SV40 large-T antigen and show strong nuclear staining for p53. Cells from passages 23 and 40 were not tumorigenic in nude mice even when co-injected with Matrigel. They grow in a serum-free defined medium and respond to EGF, bFGF and TGF-beta. Passage 42-cells showed a human male (XY), hyperdiploid karyotype. The PWR-1E cell line is the only known Ad12-SV40-immortalized human prostatic epithelial cell line. PWR-1E cells can be used to study (i) the etiology and the multistep process of carcinogenesis and tumor progression in the human prostate; (ii) normal prostate physiology and differentiation; and (iii) potential prostate cancer chemopreventive agents.
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PMID:Prostate specific antigen and androgen receptor induction and characterization of an immortalized adult human prostatic epithelial cell line. 876 20

Several immortalized and malignant adult human prostatic epithelial cell lines have recently been developed. The three most widely used carcinoma cell lines, DU-145, PC-3, and LNCaP, developed between 1977 and 1980, have greatly contributed to our present understanding of prostate cancer. Before a cell line can be accepted as having prostatic epithelial origin, some basic characteristics must be established. Expression of specific cytokeratins, but absence of desmin and factor VIII, should be first determined to establish epithelial origin. Responsiveness to androgens and expression of androgen receptor and prostate specific antigen should be examined under stringent culture conditions to establish prostatic epithelial origin. Response to growth factors and expression of their receptors facilitates further characterization of cell behavior. Cell lines immortalized by human papillomaviruses (HPVs) are of special interest because HPVs are involved in a variety of anogenital cancers and may also play a role in prostate carcinogenesis. Malignant transformation of HPV-18 immortalized cells with the ras oncogene provides cell systems for investigating the multistep process of carcinogenesis. Each cell line has some unique characteristics, whether it arose directly from a carcinoma or resulted from immortalization with simian virus 40 (SV40) or HPV or was transformed in vitro by oncogenes. Comparisons of these characteristics should facilitate elucidation of the mechanisms involved in initiation, promotion, and progression of prostate cancer. These cell lines will further serve as useful models for investigating tumor progression, invasion, metastasis, new therapeutic strategies, drug resistance, and its reversal and chemoprevention. This review will be published in three parts and will summarize cell markers necessary for characterization, as well as the characteristics and some applications of the immortalized as well as malignant adult human prostatic epithelial cell lines. Part 1 deals with cell markers and the immortalized, nontumorigenic cell lines.
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PMID:Immortalized and tumorigenic adult human prostatic epithelial cell lines: characteristics and applications. Part I. Cell markers and immortalized nontumorigenic cell lines. 897 36


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