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


METHODS
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.
Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Donghao
D
Lu
Department of Statistics, Ohio State University, Columbus, OH.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.
Jennifer A
JA
Sinnott
Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.|Faculty of Medicine, Center of Public Health Sciences, School of Health Sciences, University of Iceland, Reykjavík, Iceland (UV).
Unnur
U
Valdimarsdóttir
Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Fang
F
Fang
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.|Department of Epidemiology, College of Medicine and College of Public Health and Health Professions, University of Florida, Gainesville, FL.
Travis
T
Gerke
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA.
Svitlana
S
Tyekucheva
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.|Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA.|Pathology Unit, Addarii Institute, S. Orsola-Malpighi Hospital, Bologna, Italy.
Michelangelo
M
Fiorentino
Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Regional Cancer Center, Uppsala University Hospital, Uppsala, Sweden.
Mats
M
Lambe
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.|Divisions of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.|Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Howard D
HD
Sesso
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Christopher J
CJ
Sweeney
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.|Faculty of Medicine, Center of Public Health Sciences, School of Health Sciences, University of Iceland, Reykjavík, Iceland (UV).
Kathryn M
KM
Wilson
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.|Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Edward L
EL
Giovannucci
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.|Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA.
Massimo
M
Loda
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.|Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Lorelei A
LA
Mucci
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.|Clinical Epidemiology and Biostatistics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
Katja
K
Fall
D000368:Aged; D014408:Biomarkers, Tumor; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological / Q000235:genetics
D014408:Biomarkers, Tumor; D005938:Glucocorticoids; D012701:Serotonin