Stress-Related Signaling Pathways in Lethal and Nonlethal Prostate Cancer.

TitleStress-Related Signaling Pathways in Lethal and Nonlethal Prostate Cancer.
Publication TypeJournal Article
Year of Publication2016
AuthorsLu D, Sinnott JA, Valdimarsdóttir U, Fang F, Gerke T, Tyekucheva S, Fiorentino M, Lambe M, Sesso HD, Sweeney CJ, Wilson KM, Giovannucci EL, Loda M, Mucci LA, Fall K
JournalClin Cancer Res
Volume22
Issue3
Pagination765-772
Date Published2016 Feb 01
ISSN1557-3265
KeywordsAged, Biomarkers, Tumor, Follow-Up Studies, Gene Expression Regulation, Neoplastic, Glucocorticoids, Humans, Male, Middle Aged, Neoplasm Grading, Neoplasm Staging, Neovascularization, Pathologic, Prostatic Neoplasms, Serotonin, Signal Transduction, Stress, Physiological
Abstract

PURPOSE: Recent data suggest that neuroendocrine signaling may influence progression in some cancers. We aimed to determine whether genes within the five major stress-related signaling pathways are differentially expressed in tumor tissue when comparing prostate cancer patients with lethal and nonlethal disease.

EXPERIMENTAL DESIGN: We measured mRNA expression of 51 selected genes involved in predetermined stress-related signaling pathways (adrenergic, glucocorticoid, dopaminergic, serotoninergic, and muscarinic systems) in tumor tissue and normal prostate tissue collected from prostate cancer patients in the Physicians' Health Study (n = 150; n = 82 with normal) and the Health Professionals Follow-Up Study (n = 254; n = 120 with normal). We assessed differences in pathway expression in relation to prostate cancer lethality as the primary outcome and to biomarkers as secondary outcomes.

RESULTS: Differential mRNA expression of genes within the adrenergic (P = 0.001), glucocorticoid (P < 0.0001), serotoninergic (P = 0.0019), and muscarinic (P = 0.0045) pathways in tumor tissue was associated with the risk of lethality. The adrenergic pathway was also statistically significant (P = 0.001) when comparing against differential expression of genes not involved in the pathways. In adjacent normal prostate tissue, none of the pathways was clearly differentially expressed between lethal and nonlethal prostate cancer. The glucocorticoid and adrenergic pathways were associated with cell proliferation, while the glucocorticoid pathway was additionally associated with angiogenesis and perineural invasion.

CONCLUSIONS: Our study suggests that stress-related signaling pathways, particularly the adrenergic and glucocorticoid, may be dysregulated in the tumors of men whose prostate cancer proves to be lethal, and motivates further investigation of these pathways in functional studies.

DOI10.1158/1078-0432.CCR-15-0101
Alternate JournalClin Cancer Res
PubMed ID26490316
PubMed Central IDPMC4738177
Grant ListCA136578 / CA / NCI NIH HHS / United States
P01CA055075 / CA / NCI NIH HHS / United States
P01 CA055075 / CA / NCI NIH HHS / United States
T32 GM074897 / GM / NIGMS NIH HHS / United States
T32 CA09001 / CA / NCI NIH HHS / United States
R01 CA133891 / CA / NCI NIH HHS / United States
R01 HL026490 / HL / NHLBI NIH HHS / United States
CA090381 / CA / NCI NIH HHS / United States
T32GM074897 / GM / NIGMS NIH HHS / United States
P50 CA090381 / CA / NCI NIH HHS / United States
R35 CA197449 / CA / NCI NIH HHS / United States
CA133891 / CA / NCI NIH HHS / United States
CA141298 / CA / NCI NIH HHS / United States
R01 HL034595 / HL / NHLBI NIH HHS / United States
UL1 TR001427 / TR / NCATS NIH HHS / United States
CA097193 / CA / NCI NIH HHS / United States
T32 CA009001 / CA / NCI NIH HHS / United States
UM1 CA167552 / CA / NCI NIH HHS / United States
R01 CA040360 / CA / NCI NIH HHS / United States
R01 CA136578 / CA / NCI NIH HHS / United States
R01 CA097193 / CA / NCI NIH HHS / United States
CA40360 / CA / NCI NIH HHS / United States
R01 CA034944 / CA / NCI NIH HHS / United States
R01 CA141298 / CA / NCI NIH HHS / United States
Related Faculty: 
Massimo Loda, M.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
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