Cathepsin D and chromogranin A as predictors of long term disease specific survival after radical prostatectomy for localized carcinoma of the prostate

Theodorescu, Dan; Broder, Stanford R.; Boyd, James C.; Mills, Stacey E.; Frierson, Henry F.

doi:10.1002/(sici)1097-0142(19971201)80:11<2109::aid-cncr10>3.0.co;2-2

Cited by 112 publications

(68 citation statements)

References 36 publications

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“…These findings notwithstanding, the relationship with survival is still controversial, since some studies demonstrated a negative prognostic role (Weinstein et al 1996, McWilliam et al 1997, Theodorescu et al 1997, while others did not (Noordzij et al 1995, Bubendorf et al 1997, Abrahamsson et al 1998, Ahlegren et al 2000, Bostwick et al 2002. All these studies involved hormonenaive patients.…”

Section: Introductionmentioning

confidence: 99%

Independent prognostic role of circulating chromogranin A in prostate cancer patients with hormone-refractory disease

Berruti

Mosca²,

Tucci³

et al. 2005

Endocr Relat Cancer

118

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The presence of neuroendocrine (NE) differentiation in the context of predominantly exocrine prostate cancer may play a key role in androgen-independent tumor growth. The prognostic significance of plasma chromogranin A (CgA) was assessed in a series of consecutive prostate cancer patients with hormone-refractory disease.One hundred and eight patients with newly diagnosed hormone-refractory prostate cancer entered the study. Plasma CgA levels and other biochemical parameters, such as serum prostate specific antigen, serum alkaline phosphatase, serum lactate dehydrogenase, serum albumin and hemoglobin concentration, were measured at baseline (i.e. when hormone refractoriness occurred) and their prognostic role was evaluated together with patient performance status, Gleason score (at diagnosis of prostate cancer) and the presence of visceral metastases. Furthermore, plasma CgA was prospectively evaluated in 50 patients undergoing chemotherapy.At baseline, 45 patients (43.3%) showed elevated CgA values. Plasma CgA negatively correlated with survival, either in univariate analysis (P=0.008) or in multivariate analysis, after adjusting for previously mentioned prognostic parameters (P<0.05). In the patient subset undergoing chemotherapy, median CgA (range) values were 13.3 (3.0-141.0) U/l at baseline, 19.1 (3.0-486.0) U/l after 3 months, 20.8 (3.0-702.0) U/l after 6 months and 39.4 (3.0-414.0) U/l after 9 months (P<0.01). The corresponding supranormal rates were 17/50 (34%), 23/50 (46%), 26/50 (52%) and 34/50 (68%) respectively (P<0.005).Elevated plasma CgA levels are frequently observed in prostate cancer patients with hormonerefractory disease and correlate with poor prognosis. NE differentiation in hormone-refractory patients is a time-dependent phenomenon and is not influenced by conventional antineoplastic treatments.

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Section: Introductionmentioning

confidence: 99%

Independent prognostic role of circulating chromogranin A in prostate cancer patients with hormone-refractory disease

Berruti

Mosca²,

Tucci³

et al. 2005

Endocr Relat Cancer

118

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“…The reported frequency of NED in CaP ranges from 30% to 100% depending on the study design and the biomarker panel used to define the phenotype (4)(5)(6). Recent findings indicate that NED correlates with poor prognosis and androgen-independent growth (7)(8)(9).…”

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confidence: 99%

RNA interference of achaete–scute homolog 1 in mouse prostate neuroendocrine cells reveals its gene targets and DNA binding sites

Wang²,

Stormo³

et al. 2004

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

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We have previously characterized a transgenic mouse model (CR2-TAg) of metastatic prostate cancer arising in the neuroendocrine (NE) cell lineage. Biomarkers of NE differentiation in this model are expressed in conventional adenocarcinoma of the prostate with NE features. To further characterize the pathways that control NE proliferation, differentiation, and survival, we established prostate NE cancer (PNEC) cell lines from CR2-TAg prostate tumors and metastases. GeneChip analyses of cell lines harvested at different passages, and as xenografted tumors, indicated that PNECs express consistent features ex vivo and in vivo and share a remarkable degree of similarity with primary CR2-TAg prostate NE tumors. PNECs express mAsh1, a basic helix-loop-helix (bHLH) transcription factor essential for NE cell differentiation in other tissues. RNA interference knockdown of mAsh1, GeneChip comparisons of treated and control cell populations, and a computational analysis of down-regulated genes identified 12 transcriptional motifs enriched in the gene set. Affected genes, including Adcy9, Hes6, Iapp1, Ndrg4, c-Myb, and Mesdc2, are enriched for a palindromic E-box motif, CAGCTG, indicating that it is a physiologically relevant mAsh1 binding site. The enrichment of a c-Myb binding site and the finding that c-Myb is down-regulated by mAsh1 RNA interference suggest that mAsh1 and c-Myb are in the same signaling pathway. Our data indicate that mAsh1 negatively regulates the cell cycle (e.g., via enhanced Cdkn2d, Bub1 expression), promotes differentiation (e.g., through effects on cAMP), and enhances survival by inhibiting apoptosis. PNEC cell lines should be generally useful for genetic and͞or pharmacologic studies of the regulation of NE cell proliferation, differentiation, and tumorigenesis.neuroendocrine cell biology ͉ mouse prostate neuroendocrine cancer cell lines ͉ mAsh1 ͉ functional genomics ͉ phylogenetic footprinting T he prostate is a tubuloaveolar gland lined with a slowly renewing epithelium composed of three cell lineages. Secretory luminal cells predominate. Lineage progenitors appear to reside in a basal cell layer underlying luminal cells. A small population of scattered neuroendocrine (NE) cells produce dendrite-like processes that extend over several cell diameters to contact members of the other two epithelial lineages. Although they export a number of neuropeptides (1-3), the precise role played by NE cells in normal prostate physiology remains unclear.Pure NE tumors of the prostate are rare but, like most NE cell cancers, are very aggressive. Conventional adenocarcinoma of the human prostate (CaP) can display features of focal NE differentiation (NED) even when initiation does not occur in NE cells. The reported frequency of NED in CaP ranges from 30% to 100% depending on the study design and the biomarker panel used to define the phenotype (4-6). Recent findings indicate that NED correlates with poor prognosis and androgen-independent growth (7-9).The mechanisms governing development of NED in CaP are obscur...

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“…The presence of extensive multifocal NE features in tumors is an indication of increased aggressiveness and androgen independence (11)(12)(13). While the prognostic value of tumor NE status remains controversial, a strong link between NE status and long term, disease-specific survival has been reported (14). Tumor cell populations become enriched for NE cells following long term anti-androgen therapy (15), and although the NE cells appear to be nonmitotic, the carcinoma cells adjacent to these NE foci have been noted to exhibit increased proliferative activity (16,17).…”

mentioning

confidence: 99%

Activated 3′,5′-Cyclic AMP-dependent Protein Kinase Is Sufficient to Induce Neuroendocrine-like Differentiation of the LNCaP Prostate Tumor Cell Line

Cox¹,

Deeble²,

Bissonette³

et al. 2000

Journal of Biological Chemistry

112

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Neuroendocrine (NE) differentiation within prostate tumors is proposed to be a contributing factor in disease progression. However, the cellular origin and molecular mechanism controlling differentiation of prostatic NE cells are unresolved. The prostate tumor cell line, LNCaP, can reversibly acquire many NE characteristics in response to treatment with ␤-adrenergic receptor agonists and activators of adenylate cyclase. In this study, we demonstrate that these treatments induce protein kinase A (PKA) activation in LNCaP cells and that ectopic expression of a constitutively activated form of the PKA catalytic subunit, CI␣, results in acquisition of NE characteristics, including the extension of neuritic processes, cessation of mitotic activity, and production of neuron-specific enolase. Forskolin-, epinephrine-, and isoproterenol-dependent NE differentiation of LNCaP cells was significantly inhibited by expressing a dominant negative mutant of the PKA regulatory subunit, RI␣. These results demonstrate that prostatic NE differentiation in response to these agents depends on PKA activation, and this signaling pathway may provide a therapeutic target for treating advanced forms of prostate cancer.Efforts to develop novel therapeutic strategies for treating advanced prostate cancer have resulted in a considerable interest in the potential role of prostatic neuroendocrine (NE) 1 cells in disease progression (reviewed in Refs. 1 and 2). It has become evident that NE cells are a normal component of both the developing and mature prostatic epithelium and are postulated to be derived from stem cells common to both the exocrine and basal cell populations (3, 4). NE cells produce a variety of neurosecretory products that exhibit growth-promoting activities, including parathyroid hormone-related peptides, neurotensin, serotonin, calcitonin, and bombesin-related peptides (5-9), suggesting that these cells function through endocrine/paracrine mechanisms to regulate the normal development and secretory activity of the prostate.Virtually all prostatic adenocarcinomas contain foci of cells with NE characteristics (10). The presence of extensive multifocal NE features in tumors is an indication of increased aggressiveness and androgen independence (11-13). While the prognostic value of tumor NE status remains controversial, a strong link between NE status and long term, disease-specific survival has been reported (14). Tumor cell populations become enriched for NE cells following long term anti-androgen therapy (15), and although the NE cells appear to be nonmitotic, the carcinoma cells adjacent to these NE foci have been noted to exhibit increased proliferative activity (16, 17). These studies suggest that NE cells that develop within prostate tumors may produce neurosecretory factors that contribute to increased malignancy and decreased responsiveness to androgen ablation therapy.The androgen-responsive prostate tumor cell line, LNCaP, has emerged as a useful model for testing the development of a NE phenotype in adenocarcinoma ...

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Cathepsin D and chromogranin A as predictors of long term disease specific survival after radical prostatectomy for localized carcinoma of the prostate

Cited by 112 publications

References 36 publications

Independent prognostic role of circulating chromogranin A in prostate cancer patients with hormone-refractory disease

Independent prognostic role of circulating chromogranin A in prostate cancer patients with hormone-refractory disease

RNA interference of achaete–scute homolog 1 in mouse prostate neuroendocrine cells reveals its gene targets and DNA binding sites

Activated 3′,5′-Cyclic AMP-dependent Protein Kinase Is Sufficient to Induce Neuroendocrine-like Differentiation of the LNCaP Prostate Tumor Cell Line

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