Tracking clonal diversity in metastatic prostate cancer progression.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 193-193
Author(s):  
Christopher Hovens ◽  
Matthew Hong ◽  
Geoff Macintyre ◽  
David Wedge ◽  
Peter Van Loo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Large Scale ◽  
Metastatic Prostate Cancer ◽  
Genetic Relationships ◽  
Metastatic Potential ◽  
Response To Therapy ◽  
Tumor Evolution ◽  
End Stage ◽  
Lethal Prostate Cancer

193 Background: Genomic heterogeneity has been observed in a number of tumor types including prostate cancer. However, how subclonal tumor diversity changes during metastasis and progression to lethality remains unexplored. Large scale genomic analyses have reported the most prevalent somatic aberrations associated with the dominant clone of the tumor without permitting an analysis of subclonal complexity or how this complexity impinges on metastatic potential or resistance to treatment. Methods: To understand and track the evolution of lethal prostate cancer from initial therapy to end stage metastases, we performed longitudinal and multiregional sampling of tumors from 7 patients with lethal prostate cancer. We performed whole-genome sequencing, RNA sequencing, and SNP profiling. Computational approaches were used to reconstruct the genetic relationships and evolution of the tumors. These evolutionary tree reconstructions allowed us to observe the dynamics of chromoplexy and mutational processes along specific branches of tumor evolution. To refine the genetic landscape and spatial connections between subclones, we employed deep, targeted re-sequencing of variant loci in the original sequenced samples, in additional FFPE sites sampled from the organ confined tumors, and from blood. Results: We show that while all primary and metastatic prostate tumors share a single ancestral clone, metastases arise from subclones present at minor frequencies in the primary tumor. We reveal that individual metastases comprise mixtures of subclones indicative of intra-metastatic heterogeneity. We provide evidence for cross-metastatic site seeding and dynamic remolding of subclonal mixtures in response to therapy suggesting a distinct metastatic hierarchy. Ultra-deep sequencing of end-stage blood reveals the presence of diverse subclones with metastatic potential derived from various stages in the evolution of the tumor. Conclusions: Our results demonstrate unexpected complexity in the origins of both primary and metastatic prostate cancer, with distinct implications for treatment of advanced disease.

scholarly journals USP44 Promoter Methylation in Plasma Cell-Free DNA in Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4607
Author(s):  
Dora Londra ◽  
Sophia Mastoraki ◽  
Evangelos Bournakis ◽  
Martha Zavridou ◽  
Anastasios Thanos ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Real Time ◽  
Plasma Cell ◽  
Promoter Methylation ◽  
Metastatic Prostate Cancer ◽  
Response To Therapy ◽  
Tumor Evolution ◽  
Cell Free Dna ◽  
Free Dna ◽  
First Time

Liquid biopsy provides real-time monitoring of tumor evolution and response to therapy through analysis of circulating tumor cells (CTCs) and plasma-circulating tumor DNA (ctDNA). USP44 is a critical gene which plays an important role in cell proliferation; however, its accurate role in other cellular networks is under research. USP44 promoter methylation has been so far reported in colorectal neoplasia and metastatic breast cancer. In this study, we examined for the first time USP44 promoter methylation in plasma cell-free DNA (cfDNA) of patients with prostate cancer (early stage n = 32, metastatic n = 39) and 10 healthy donors (HD). USP44 promoter methylation was detected in plasma cell-free DNA by a newly developed highly specific and sensitive real-time MSP method. Our findings indicate that USP44 promoter is methylated in plasma cell-free DNA of metastatic prostate cancer patients and that detection of USP44 promoter methylation is significantly associated with overall survival (OS) (p = 0.008). We report for the first time that detection of USP44 promoter methylation in plasma cell free DNA provides significant prognostic information in metastatic prostate cancer.

scholarly journals TMEFF2: A Transmembrane Proteoglycan with Multifaceted Actions in Cancer and Disease

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3862
Author(s):  
Motasim Masood ◽  
Stefan Grimm ◽  
Mona El-Bahrawy ◽  
Ernesto Yagüe
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Transmembrane Protein ◽  
Intracellular Localization ◽  
Amyloid Β ◽  
Inverse Correlation ◽  
Response To Therapy ◽  
Endocrine Function ◽  
Type I ◽  
Amyloid Β Protein

Transmembrane protein with an EGF-like and two Follistatin-like domains 2 (TMEFF2) is a 374-residue long type-I transmembrane proteoglycan which is proteolytically shed from the cell surface. The protein is involved in a range of functions including metabolism, neuroprotection, apoptosis, embryonic development, onco-suppression and endocrine function. TMEFF2 is methylated in numerous cancers, and an inverse correlation with the stage, response to therapy and survival outcome has been observed. Moreover, TMEFF2 methylation increases with breast, colon and gastric cancer progression. TMEFF2 is methylated early during oncogenesis in breast and colorectal cancer, and the detection of methylated free-circulating TMEFF2 DNA has been suggested as a potential diagnostic tool. The TMEFF2 downregulation signature equals and sometimes outperforms the Gleason and pathological scores in prostate cancer. TMEFF2 is downregulated in glioma and cotricotropinomas, and it impairs the production of adrenocorticotropic hormone in glioma cells. Interestingly, through binding the amyloid β protein, its precursor and derivatives, TMEFF2 provides neuroprotection in Alzheimer’s disease. Despite undergoing extensive investigation over the last two decades, the primary literature regarding TMEFF2 is incoherent and offers conflicting information, in particular, the oncogenic vs. onco-suppressive role of TMEFF2 in prostate cancer. For the first time, we have compiled, contextualised and critically analysed the vast body of TMEFF2-related literature and answered the apparent discrepancies regarding its function, tissue expression, intracellular localization and oncogenic vs. onco-suppressive role.

Intratibial implantation of tumor cells  v1

2021 ◽  
Author(s):  
Shubhangi Agarwal ◽  
donna.peehl not provided ◽  
Renuka Sriram
Keyword(s):  
Prostate Cancer ◽  
Cancer Patient ◽  
Metastatic Prostate Cancer ◽  
Prostate Cancer Patient ◽  
Tumor Cell Line ◽  
Small Cell ◽  
Response To Therapy ◽  
Tumor Characteristics ◽  
Patient Derived Xenograft ◽  
Neuroendocrine Prostate Cancer

This protocol describes the steps required for the successful implantation of small cell neuroendocrine prostate cancer patient-derived xenograft (PDX) cells in the bone. Bone is one of the most common sites for the development of metastatic prostate cancer and its study is important for evaluating the tumor characteristics and response to therapy. This protocol can be used for the implantation of any tumor cell line in the bone.

scholarly journals 4284 Development of a Survey Instrument to Predict Uptake of and Adherence to Active Surveillance among Men with Low-Risk Prostate Cancer

2020 ◽  
Vol 4 (s1) ◽  
pp. 128-129
Author(s):  
Aaron T Seaman ◽  
Kathryn L. Taylor ◽  
Kimberly Davis ◽  
Kenneth G. Nepple ◽  
Michelle A. Mengeling ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Active Surveillance ◽  
Cancer Progression ◽  
Large Scale ◽  
Survey Instrument ◽  
Low Risk ◽  
Cognitive Interviews ◽  
Risk Prostate Cancer ◽  
Low Risk Prostate Cancer ◽  
Single Instrument

OBJECTIVES/GOALS: Active surveillance (AS) is a recognized strategy to manage low-risk prostate cancer (PCa) in the absence of cancer progression. Little prospective data exists on the decisional factors associated with selecting and adhering to AS in the absence of cancer progression. We developed a survey instrument to predict AS uptake and adherence. METHODS/STUDY POPULATION: We utilized a three-step process to develop and refine a survey instrument designed to predict AS uptake and adherence among men with low-risk PCa: 1) We identified relevant conceptual domains based on prior research and a literature review. 2) We conducted 21 semi-structured concept elicitation interviews to identify patient-perceived barriers and facilitators to AS uptake and adherence among men with a low-risk PCa who had been on AS for ≥1 year. The identified concepts became the basis of our draft survey instrument. 3) We conducted two rounds of cognitive interviews with men with low-risk PCa (n = 12; n = 6) to refine and initially validate the instrument. RESULTS/ANTICIPATED RESULTS: Relevant concepts identified from the initial interviews included the importance of patient: knowledge of their PCa risk, value in delaying treatment, trust in urologist and the AS surveillance protocol, and perceived social support. Initially, the survey was drafted as a single instrument to be administered after a patient had selected AS comprising sections on patient health, AS selection, and AS adherence. Based on the first round of cognitive interviews, we revised the single instrument into two surveys to track shifts in patient preference and experience. The first, administered at diagnosis, focuses on selection, and the second, a 6-month follow up, focuses on adherence. Following revisions, participants indicated the revised 2-part instrument was clear and not burdensome to complete. DISCUSSION/SIGNIFICANCE OF IMPACT: The instrument’s content validity was evaluated through cognitive interviews, which supported that the survey items’ intended and understood meanings were isomorphic. In the next phase, we plan to conduct a large-scale prospective cohort study to evaluate the predictive validity, after which it will be available for public research use.

scholarly journals Neutrophils are mediators of metastatic prostate cancer progression in bone

2020 ◽  
Vol 69 (6) ◽  
pp. 1113-1130 ◽  
Author(s):  
Diane L. Costanzo-Garvey ◽  
Tyler Keeley ◽  
Adam J. Case ◽  
Gabrielle F. Watson ◽  
Massar Alsamraae ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Metastatic Prostate Cancer ◽  
Prostate Cancer Progression

LONGITUDINAL COHORT ANALYSIS OF LETHAL PROSTATE CANCER PROGRESSION IN TRANSGENIC MICE

1998 ◽  
pp. 1500-1505 ◽  
Author(s):  
CHUN X. HSU ◽  
BRIAN D. ROSS ◽  
CLARENCE E. CHRISP ◽  
SOLOMON Z. DERROW ◽  
LINDA G. CHARLES ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Transgenic Mice ◽  
Cancer Progression ◽  
Cohort Analysis ◽  
Prostate Cancer Progression ◽  
Longitudinal Cohort ◽  
Lethal Prostate Cancer

scholarly journals Role of Heparan Sulfate 2-O-Sulfotransferase in Prostate Cancer Cell Proliferation, Invasion, and Growth Factor Signaling

2011 ◽  
Vol 2011 ◽  
pp. 1-14 ◽  
Author(s):  
Brent W. Ferguson ◽  
Sumana Datta
Keyword(s):  
Prostate Cancer ◽  
Growth Factor ◽  
Heparan Sulfate ◽  
Cancer Progression ◽  
Metastatic Potential ◽  
Growth Factor Signaling ◽  
Cancer Cell Proliferation ◽  
Determining Factors ◽  
Proliferation And Invasion

Heparan-sulfate proteoglycans (HSPGs) are required for maximal growth factor signaling in prostate cancer progression. The degree of sulfate modification on the covalently attached heparan sulfate (HS) chains is one of the determining factors of growth factor-HSPG interactions. Sulfate groups are transferred to HS chains via a series of O-sulfotransferases. In the present study, we demonstrate that Heparan sulfate 2-O-sulfotransferase (2OST) is essential for maximal proliferation and invasion of prostate cancer cells in the LNCaP-C4-2B model. We also show that a decrease in invasion due to 2OST siRNA is associated with an increase in actin and E-cadherin accumulation at the cell surface. 2OST expression correlates with increasing metastatic potential in this model. We demonstrate that 2OST expression is upregulated by the stress-inducible transcription factors HIF1α, ATF2, and NFκB. Chromatin immunoprecipitation analysis suggests that HIF1αand ATF2 act directly on the 2OST promoter, while NFκB acts indirectly.

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