Molecular alterations associated with prostate cancer

Androgen-deprivation therapy (ADT) is the standard treatment for metastatic prostate cancer. One factor that has been implicated in the metastatic process is the cell adhesion molecule N-cadherin. In this study, we investigated if the expression of N-cadherin was influenced by androgen deprivation and was associated with metastasis in prostate cancer. The effect of androgen deprivation on N-cadherin expression was initially studied in androgen-dependent (AD) LNCaP and androgen-independent (AI) LNCaP-19 and PC-3 prostate cancer cell lines. Expression of N-cadherin increased in the absence of androgens in AI LNCaP-19 primary tumors and metastases and also in vitro, but not in AI PC-3 tumors, indicating a possible involvement of the androgen receptor in the regulation of N-cadherin. N-cadherin was absent in AD LNCaP tumors. No clear associations between N-cadherin and factors related with epithelial–mesenchymal transition or neuroendocrine differentiation could be established. In addition, N-cadherin was evaluated by immunohistochemistry in human prostate tumors. Expression of N-cadherin was more frequently found in tumors from patients treated with ADT than in tumors from patients with no prior hormonal treatment. N-cadherin expression was also associated with metastasis and Gleason score. Furthermore, increased N-cadherin was detected in prostate cancer biopsies already 3 months after initiation of ADT when tumors were in a regressed state. In summary the results indicate that androgen deprivation induces N-cadherin in prostate tumors. Moreover, N-cadherin was increased in castration-resistant tumors in patients with established metastases. This might indicate that castration induces molecular alterations in the tumor cells, resulting in a more invasive and metastatic phenotype.

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MP17-12 MOLECULAR ALTERATIONS IN PROSTATE CANCER AND ASSOCIATION WITH MRI FEATURES

The Journal of Urology ◽

10.1016/j.juro.2015.02.854 ◽

2015 ◽

Vol 193 (4S) ◽

Author(s):

Daniel Lee ◽

Jacqueline Fontugne ◽

Naveen Gumpeni ◽

Kyung Park ◽

Theresa MacDonald ◽

...

Keyword(s):

Prostate Cancer ◽

Molecular Alterations ◽

Mri Features

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Molecular Alterations in Prostate Cancer as Diagnostic, Prognostic, and Therapeutic Targets

Advances in Anatomic Pathology ◽

10.1097/pap.0b013e31818a5c19 ◽

2008 ◽

Vol 15 (6) ◽

pp. 319-331 ◽

Cited By ~ 39

Author(s):

Bora Gurel ◽

Tsuyoshi Iwata ◽

Cheryl M. Koh ◽

Srinivasan Yegnasubramanian ◽

William G. Nelson ◽

...

Keyword(s):

Prostate Cancer ◽

Therapeutic Targets ◽

Molecular Alterations

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An Emerging Landscape for Canonical and Actionable Molecular Alterations in Primary and Metastatic Prostate Cancer

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-19-0531 ◽

2020 ◽

Vol 19 (6) ◽

pp. 1373-1382 ◽

Cited By ~ 3

Author(s):

Nancy A. Dawson ◽

Matthew Zibelman ◽

Timothy Lindsay ◽

Rebecca A. Feldman ◽

Michelle Saul ◽

...

Keyword(s):

Prostate Cancer ◽

Metastatic Prostate Cancer ◽

Molecular Alterations

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Evidence for a field effect in early prostate cancer (PCa): Gene expression profiles in normal-appearing prostate tissue (NT) adjacent to tumor (T) as predictors of clinical outcome.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.5029 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 5029-5029 ◽

Cited By ~ 1

Author(s):

Eric A. Klein ◽

Sara Moscovita Falzarano ◽

Nan Zhang ◽

Dejan Knezevic ◽

Tara Maddala ◽

...

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Field Effect ◽

Proportional Hazards ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Cox Proportional Hazards ◽

Clinical Recurrence ◽

Molecular Alterations ◽

Cox Proportional Hazards Models

5029 Background: We previously identified genes whose expression predicts aggressive PCa (clinical recurrence (cR), prostate cancer death (PCD), adverse pathology) when assessed in histologically heterogeneous tumor foci and in biopsies (Klein ASCO 2012). These results enabled the definition of a multi-gene Genomic Prostate Score (GPS), which has been clinically validated (Cooperberg AUA 2013). There is interest regarding a possible field effect in PCa, i.e. molecular alterations throughout the gland that may influence PCa development. We conducted exploratory analyses to evaluate gene expression, including GPS, in adjacent normal-appearing tissue (NT) for prediction of cR and PCD. Methods: Cohort sampling was used to select 127 patients with and 374 without cR from 2,641 patients treated with RP for T1/T2 PCa. Expression of 732 genes was measured by qRT-PCR separately in T and NT (defined as > 3 mm from T) specimens. GPS (0-100 units) was determined using the genes and algorithm from the validation study. Analysis used Cox proportional hazards models and Storey’s false discovery rate (FDR) control. Results: 410 evaluable patients had paired T and NT. Of the 405 genes which were predictive of outcome in T (FDR < 20%), 289 (71%) showed similar but weaker effects in NT. 47 genes were associated with cR in NT (FDR < 20%), of which 34 also concordantly predicted cR in T (FDR < 20%). GPS assessed in NT significantly predicted time to cR (HR/20 units = 1.8; 95% CI: 1.3-2.4; p< 0.001) and PCD (HR/20 units = 1.9; 95% CI: 1.2-3.0; p = 0.005) but was less predictive than GPS in T (HR/20 units = 4.8 for cR; 95% CI: 3.7-6.2; p < 0.001 and HR/20 units = 6.9 for PCD; 95% CI: 4.4-10.7; p < 0.001). The strongest components of GPS in predicting cR and PCD in NT were stromal response and androgen signaling genes (p < 0.05); proliferation and cellular organization genes did not consistently provide a significant contribution in NT. Conclusions: These data indicate that gene expression profiles, including GPS, can predict outcome in NT, albeit more weakly than in tumor. These findings suggest that there is an underlying field effect associated with the development of aggressive PCa.

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Molecular Alterations during Progression of Prostate Cancer to Androgen Independence

Clinical Chemistry ◽

10.1373/clinchem.2011.165977 ◽

2011 ◽

Vol 57 (10) ◽

pp. 1366-1375 ◽

Cited By ~ 77

Author(s):

Punit Saraon ◽

Keith Jarvi ◽

Eleftherios P Diamandis

Keyword(s):

Prostate Cancer ◽

Molecular Mechanisms ◽

Therapeutic Strategies ◽

Androgen Independence ◽

Molecular Alterations ◽

Signaling Mechanisms ◽

Hormonal Therapies ◽

Epigenetic Signatures ◽

Key Pathways ◽

Androgen Independent

BACKGROUND Prostate cancer is the most commonly diagnosed cancer among men in North America and is a leading cause of death. Standard treatments include androgen deprivation therapy, which leads to improved clinical outcomes. However, over time, most tumors become androgen independent and no longer respond to hormonal therapies. Several mechanisms have been implicated in the progression of prostate cancer to androgen independence. CONTENT Most tumors that have become androgen independent still rely on androgen receptor (AR) signaling. Mechanisms that enhance AR signaling in androgen-depleted conditions include: AR gene amplification, AR mutations, changes in the balance of AR cofactors, increases in steroidogenic precursors, and activation via “outlaw” pathways. Along with AR signaling, various other AR-independent “bypass” pathways have been shown to operate aberrantly during androgen independence. Changes in the epigenetic signatures and microRNA concentrations have also been implicated in the development of androgen-independent prostate cancer. SUMMARY Understanding of the molecular mechanisms that lead to the development of androgen-independent prostate cancer will allow for improved therapeutic strategies that target key pathways and molecules that are essential for these cells to survive.

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Molecular alterations in prostate cancer

Cancer Letters ◽

10.1016/j.canlet.2008.04.047 ◽

2008 ◽

Vol 271 (1) ◽

pp. 13-24 ◽

Cited By ~ 22

Author(s):

Mark A. Reynolds

Keyword(s):

Prostate Cancer ◽

Molecular Alterations

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Single-Cell Proteomics Defines the Cellular Heterogeneity of Localized Prostate Cancer

10.1101/2021.01.25.428046 ◽

2021 ◽

Author(s):

Laura De Vargas Roditi ◽

Andrea Jacobs ◽

Jan H. Rueschoff ◽

Pete Bankhead ◽

Stephane Chevrier ◽

...

Keyword(s):

Prostate Cancer ◽

Single Cell ◽

Immune Cell ◽

Cell Mass ◽

Prognostic Biomarkers ◽

Cellular Heterogeneity ◽

Localized Prostate Cancer ◽

Tissue Samples ◽

Molecular Alterations ◽

Cell To Cell Variability

ABSTRACTLocalized prostate cancer exhibits multiple genomic alterations and heterogeneity at the proteomic level. Single-cell technologies capture important cell-to-cell variability responsible for heterogeneity in biomarker expression that may be overlooked when molecular alterations are based on bulk tissue samples. The aim of this study was to identify novel prognostic biomarkers and describe the heterogeneity of prostate cancer and the associated immune cell infiltrates by simultaneously quantifying 36 proteins using single-cell mass cytometry analysis of over 1,6 million cells from 58 men with localized prostate cancer. To perform this task, we proposed a novel computational pipeline, Franken, which showed unprecedented combination of performance, sensitivity and scalability for high dimensional clustering compared to state of the art methods. We were able to describe subpopulations of immune, stromal, and prostate cells, including unique changes occurring in tumor tissues and high grade disease providing insights into the coordinated progression of prostate cancer. Our results further indicated that men with localized disease already harbor rare subpopulations that typically occur in castration-resistant and metastatic disease, which were confirmed through imaging. Our methodology could be used to discover novel prognostic biomarkers to personalize treatment and improve outcomes.

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