Skewing Towards Neuroendocrine Phenotype in High Grade or High Stage Androgen-Responsive Primary Prostate Cancer

Puccetti, Luca; Supuran, Claudiu T.; Fasolo, Pier Paolo; Conti, Enrico; Sebastiani, Giancarlo; Lacquaniti, Sergio; Mandras, R.; Milazzo, Maria G.; Dogliani, Natalia; Giuli, Paolo De; Fasolis, Giuseppe

doi:10.1016/j.eururo.2005.03.018

Cited by 32 publications

(19 citation statements)

References 40 publications

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“…Although immunoperoxidase histochemistry is an imprecise method of protein quantification, it is the only technique currently available for assessing protein levels in small tissue samples and localizing expression to specific cell types. We focused on two pathways known to be associated with prostate cancer behavior: neuroendocrine effectors and apoptosis (28,(29)(30)(31). Of the 80 genes in the grade classifier with known biological functions, 5 are reported to modulate neuropeptide or amine metabolism: monoamine oxidase A (MAOA), YWHAZ͞ 14-3-3-, OAZ2, CPE, and SLC22A3.…”

Section: Immunohistochemical (Ihc) Analysis Of Gleason Grade-associatedmentioning

confidence: 99%

A molecular correlate to the Gleason grading system for prostate adenocarcinoma

True

Coleman²,

Hawley

et al. 2006

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

259

225

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Adenocarcinomas of the prostate can be categorized into tumor grades based on the extent to which the cancers histologically resemble normal prostate glands. Because grades are surrogates of intrinsic tumor behavior, characterizing the molecular phenotype of grade is of potential clinical importance. To identify molecular alterations underlying prostate cancer grades, we used microdissection to obtain specific cohorts of cancer cells corresponding to the most common Gleason patterns (patterns 3, 4, and 5) from 29 radical prostatectomy samples. We paired each cancer sample with matched benign lumenal prostate epithelial cells and profiled transcript abundance levels by microarray analysis. We identified an 86-gene model capable of distinguishing low-grade (pattern 3) from high-grade (patterns 4 and 5) cancers. This model performed with 76% accuracy when applied to an independent set of 30 primary prostate carcinomas. Using tissue microarrays comprising >800 prostate samples, we confirmed a significant association between high levels of monoamine oxidase A expression and poorly differentiated cancers by immunohistochemistry. We also confirmed grade-associated levels of defender against death (DAD1) protein and HSD17␤4 transcripts by immunohistochemistry and quantitative RT-PCR, respectively. The altered expression of these genes provides functional insights into grade-associated features of therapy resistance and tissue invasion. Furthermore, in identifying a profile of 86 genes that distinguish high-from low-grade carcinomas, we have generated a set of potential targets for modulating the development and progression of the lethal prostate cancer phenotype.carcinoma ͉ monoamine oxidase A ͉ microarray ͉ expression profile

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Section: Immunohistochemical (Ihc) Analysis Of Gleason Grade-associatedmentioning

confidence: 99%

A molecular correlate to the Gleason grading system for prostate adenocarcinoma

True

Coleman²,

Hawley

et al. 2006

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

259

225

View full text Add to dashboard Cite

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“…As NEPC cells are independent of androgens for their growth, ADT might provide them with a selective survival advantage (9). In fact, the percentage of neuroendocrine cells sharply increases in high-grade and advanced stage prostate tumors upon establishment of ADT (10,11). More importantly, cancer cells lacking AR and/or PSA expression are frequently detected in bone metastatic lesions among ARþ and PSAþ malignant phenotypes (12).…”

Section: Introductionmentioning

confidence: 99%

Interleukin-1β Promotes Skeletal Colonization and Progression of Metastatic Prostate Cancer Cells with Neuroendocrine Features

Russell²,

et al. 2013

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Despite the progress made in the early detection and treatment of prostate adenocarcinoma, the metastatic lesions from this tumor are incurable. We used genome-wide expression analysis of human prostate cancer cells with different metastatic behavior in animal models to reveal that bone-tropic phenotypes upregulate three genes encoding for the cytokine interleukin-1b (IL-1b), the chemokine CXCL6 (GCP-2), and the protease inhibitor elafin (PI3). The Oncomine database revealed that these three genes are significantly upregulated in human prostate cancer versus normal tissue and correlate with Gleason scores !7. This correlation was further validated for IL-1b by immunodetection in prostate tissue arrays. Our study also shows that the exogenous overexpression of IL-1b in nonmetastatic cancer cells promotes their growth into large skeletal lesions in mice, whereas its knockdown significantly impairs the bone progression of highly metastatic cells. In addition, IL-1b secreted by metastatic cells induced the overexpression of COX-2 (PTGS2) in human bone mesenchymal cells treated with conditioned media from bone metastatic prostate cancer cells. Finally, we inspected human tissue specimens from skeletal metastases and detected prostate cancer cells positive for both IL-1b and synaptophysin while concurrently lacking prostate-specific antigen (PSA, KLK3) expression. Collectively, these findings indicate that IL-1b supports the skeletal colonization and metastatic progression of prostate cancer cells with an acquired neuroendocrine phenotype. Cancer Res; 73(11); 3297-305. Ó2013 AACR.

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“…[5][6][7] Two recent studies in patients with hormone-refractory disease have demonstrated an independent poor prognostic role of elevated levels of circulating chromogranin A, a marker of neuroendocrine differentiation, 8,9 although in patients with hormone naive disease a significant relationship between amount of neuroendocrine cells and disease stage and grade but not with disease-free survival and overall survival has been unequivocally proven. [10][11][12] Neuroendocrine differentiation regulatory mechanisms might play a role in the transition from an androgen-dependent to an androgen-resistant phenotype in prostate cancer, and in vivo studies, both in animals 13 and humans, 14 have shown that the neuroendocrine prostate cancer compartment increases after androgen deprivation.…”

mentioning

confidence: 99%

Human ASH1 expression in prostate cancer with neuroendocrine differentiation

et al. 2008

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Neuroendocrine differentiation in prostate cancer correlates with overall prognosis and disease progression after androgen-deprivation therapy, although its specific mechanisms are currently poorly understood. A role of Notch pathway has been reported in determining neuroendocrine phenotype of normal and neoplastic tissues. The aim of this study was to analyze whether this pathway might affect neuroendocrine differentiation in prostate cancer. Human achaete-scute homolog 1 (hASH1), a pivotal member of the Notch pathway, was investigated in 80 prostate cancers selected and grouped according to chromogranin A immunohistochemistry, as follows: prostate cancers without neuroendocrine differentiation, untreated (25 cases); prostate cancers with neuroendocrine differentiation, untreated (40 cases); prostate cancers with previous androgen-deprivation therapy, all having neuroendocrine differentiation (15 cases). Human ASH1 protein was analyzed by immunohistochemistry, whereas the presence of hASH1 mRNA transcripts was investigated on paraffin material by real-time PCR. By immunohistochemistry, hASH1 was colocalized with chromogranin A in neuroendocrine cells of normal prostatic gland. It was absent in all but one prostate cancers without neuroendocrine differentiation, whereas it was positive in 25% of prostate cancers with neuroendocrine differentiation/ untreated, with a significant correlation with the extent of neuroendocrine features (P ¼ 0.02). Moreover, comparing untreated and treated prostate cancers with neuroendocrine differentiation, a positive association with androgen-deprivation therapy was observed (P ¼ 0.01). In prostate cancers with neuroendocrine differentiation, RNA analysis confirmed the association of higher transcript levels in androgen deprivationtreated compared with untreated patients (P ¼ 0.01). In addition, hASH1 mRNA analysis in microdissected chromogranin A-positive and chromogranin A-negative areas within the same tumor demonstrated a two-to sevenfold increase of hASH1 mRNA expression in chromogranin A-positive tumor cell populations.

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Skewing Towards Neuroendocrine Phenotype in High Grade or High Stage Androgen-Responsive Primary Prostate Cancer

Cited by 32 publications

References 40 publications

A molecular correlate to the Gleason grading system for prostate adenocarcinoma

A molecular correlate to the Gleason grading system for prostate adenocarcinoma

Interleukin-1β Promotes Skeletal Colonization and Progression of Metastatic Prostate Cancer Cells with Neuroendocrine Features

Human ASH1 expression in prostate cancer with neuroendocrine differentiation

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