Jim Burch, MS, PhD, Jim Burch, MS, PhD, Assistant Professor Assistant Professor Department of Epidemiology and Biostatistics Department of Epidemiology and Biostatistics Cancer Prevention and Control Program Cancer Prevention and Control Program Center for Colorectal Cancer Research Center for Colorectal Cancer Research University of South Carolina University of South Carolina Dorn VA Medical Center Dorn VA Medical Center Columbia, SC Columbia, SC E-mail : [email protected]Phone : 803 734-4459 Circadian Disruption & Circadian Disruption & Cancer Cancer
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Jim Burch, MS, PhD, Assistant Professor Department of Epidemiology and Biostatistics Cancer Prevention and Control Program Center for Colorectal Cancer.
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Jim Burch, MS, PhD, Jim Burch, MS, PhD, Assistant ProfessorAssistant Professor
Department of Epidemiology and BiostatisticsDepartment of Epidemiology and BiostatisticsCancer Prevention and Control ProgramCancer Prevention and Control ProgramCenter for Colorectal Cancer ResearchCenter for Colorectal Cancer Research
University of South Carolina University of South Carolina Dorn VA Medical CenterDorn VA Medical Center
Circadian Disruption & CancerCircadian Disruption & Cancer
ObjectivesObjectives
Provide an overview of human circadian systems Provide an overview of human circadian systems Summarize the effects of shift work on circadian systemssSummarize the effects of shift work on circadian systemss Describe how circadian biology relates to carcinogenesisDescribe how circadian biology relates to carcinogenesis
“Timing is everything...”
The Endogenous ClockThe Endogenous Clock
• SCN neurons have an endogenous rhythm
• Ambient light sets/resets the SCN, providing Ambient light sets/resets the SCN, providing timing cues to peripheral oscillators timing cues to peripheral oscillators (heart, liver, kidneys)(heart, liver, kidneys)
• Timing cues are neural or hormonalTiming cues are neural or hormonal
• In response to these signals, the organism In response to these signals, the organism displays circadian (~24-hour) rhythms in displays circadian (~24-hour) rhythms in physiology & behaviorphysiology & behavior
• Cellular metabolism & proliferation also Cellular metabolism & proliferation also show circadian coordination w/in tissuesshow circadian coordination w/in tissues
Canaple, L. et al. Cancer Res 2003;63:7545-7552
• Bmal1 & ClockBmal1 & Clock expressed in ~24-hour cycles expressed in ~24-hour cycles
• Form a heterodimer that regulates other clock gene Form a heterodimer that regulates other clock gene expression, maintains endogenous circadian rhythmsexpression, maintains endogenous circadian rhythms
• PeriodPeriod ( (perper) and ) and CryptochromeCryptochrome ( (CryCry) genes are ) genes are transcribed & translated in response to Bmal1 & transcribed & translated in response to Bmal1 & ClockClock
• Per & Cry form a negative feedback loop by Per & Cry form a negative feedback loop by inhibiting Bmal1 & Clock transcriptional activation, inhibiting Bmal1 & Clock transcriptional activation, thus lowering their own expressionthus lowering their own expression
• Per and Cry also increase Bmal1 & Clock gene Per and Cry also increase Bmal1 & Clock gene transcription, initiating next phase of the cycletranscription, initiating next phase of the cycle
• This cycle runs autonomously in the cell, but can be This cycle runs autonomously in the cell, but can be regulated (entrained) by ambient lightregulated (entrained) by ambient light
United States at NightKusanagi et al. Neurosci Lett. 365:124–7. 2004
Adapted from: Wilson BW. Biol. Effects of EMFs Vol. I. Academic Press, NY. 1994.
The Melatonin HypothesisThe Melatonin Hypothesis
Shift Work & Circadian DesynchronizationShift Work & Circadian Desynchronization
20% of U.S. work force performs shift 20% of U.S. work force performs shift work (~15 MM); ~20-30% attrition rate work (~15 MM); ~20-30% attrition rate w/in 2-3 yearsw/in 2-3 years
Critical work sectorsCritical work sectors: medical care : medical care providers, emergency response teams providers, emergency response teams (police, fire, rescue), military personnel, (police, fire, rescue), military personnel, public utilities, transportationpublic utilities, transportation
Personal MonitoringPersonal Monitoring: : Rest/activity & urine samples,Rest/activity & urine samples, 24-hr period, 3rd day of work week24-hr period, 3rd day of work week
SymptomsSymptoms: Questions regarding sleep disturbances, fatigue,: Questions regarding sleep disturbances, fatigue, mental state from mental state from Standard Shift Work IndexStandard Shift Work Index
Sleep AnalysisSleep Analysis: Total sleep time, sleep efficiency sleep latency, : Total sleep time, sleep efficiency sleep latency, sleep fragmentation, ambient light exposure via wrist actigraphysleep fragmentation, ambient light exposure via wrist actigraphy
BiomarkersBiomarkers:: Post-Work and Post-Sleep urinary Post-Work and Post-Sleep urinary melatoninmelatonin metabolitemetabolite (6-OHMS) levels; cr-adjusted & total sleep time (6-OHMS) levels; cr-adjusted & total sleep time excretion; 73 questionnaire items screenedexcretion; 73 questionnaire items screened
Circadian DesynchronizationCircadian Desynchronization: Sleep: Sleep::Work 6-OHMS RatioWork 6-OHMS Ratio Note: if ratio Note: if ratio << 1 => disrupted melatonin rhythm1 => disrupted melatonin rhythm
Melatonin, Sleep, & Shift Work AdaptationMelatonin, Sleep, & Shift Work Adaptation(Burch et al. J Occ Environ Med. 47:893-901. 2005)(Burch et al. J Occ Environ Med. 47:893-901. 2005)
Symptoms among Shift Workers with Symptoms among Shift Workers with Disrupted Circadian Melatonin ProductionDisrupted Circadian Melatonin Production
High Interdaily Stability (IS)High Interdaily Stability (IS)ID: 1151
0
200
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9:4
7
12:1
1
14:3
6
17:0
1
19:2
6
21:5
0
0:1
5
2:4
0
5:0
5
7:2
9
9:5
4
12:1
9
14:4
4
17:0
8
19:3
3
21:5
8
0:2
3
2:4
7
5:1
2
7:3
7
10:0
2
12:2
6
14:5
1
17:1
6
19:4
1
22:0
5
0:3
0
2:5
5
5:2
0
7:4
4
10:0
9
12:3
4
time
ac
tiv
ity
ID: 1009
-50
50
150
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650
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15
:50
17
:51
19
:52
21
:53
23
:54
1:5
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3:5
6
5:5
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7:5
8
9:5
9
12
:00
14
:01
16
:02
18
:03
20
:04
22
:05
0:0
6
2:0
7
4:0
8
6:0
9
8:1
0
10
:11
12
:12
14
:13
16
:14
18
:15
20
:16
22
:17
0:1
8
2:1
9
4:2
0
time
activ
ity
ID:1182
-100
400
900
1400
12:5
4
15:1
7
17:4
0
20:0
3
22:2
7
0:5
0
3:1
3
5:3
6
8:0
0
10:2
3
12:4
6
15:0
9
17:3
3
19:5
6
22:1
9
0:4
2
3:0
6
5:2
9
7:5
2
10:1
5
12:3
9
15:0
2
17:2
5
19:4
8
22:1
2
0:3
5
2:5
8
5:2
1
7:4
5
10:0
8
12:3
1
14:5
4
17:1
8
time
acti
vit
y
ID: 1241
0
100
200
300
400
500
8:2
7
10:4
2
12:5
7
15:1
2
17:2
8
19:4
3
21:5
8
0:1
3
2:2
9
4:4
4
6:5
9
9:1
4
11:3
0
13:4
5
16:0
0
18:1
5
20:3
1
22:4
6
1:0
1
3:1
6
5:3
2
7:4
7
10:0
2
12:1
7
14:3
3
16:4
8
19:0
3
21:1
8
23:3
4
1:4
9
4:0
4
6:1
9
8:3
5
10:5
0
time
acti
vit
y
Low Interdaily Stability (IS)
High Relative Amplitude (RA)ID:1071
0
200
400
600
800
1000
1200
12:4
1
14:5
4
17:0
8
19:2
2
21:3
6
23:4
9
2:0
3
4:1
7
6:3
1
8:4
4
10:5
8
13:1
2
15:2
6
17:3
9
19:5
3
22:0
7
0:2
1
2:3
4
4:4
8
7:0
2
9:1
6
11:2
9
13:4
3
15:5
7
18:1
1
20:2
4
22:3
8
0:5
2
3:0
6
5:1
9
7:3
3
9:4
7
time
acti
vit
y
ID:1094
0100200300400500600700800
10:3
9
12:4
4
14:5
0
16:5
6
19:0
2
21:0
7
23:1
3
1:1
9
3:2
5
5:3
0
7:3
6
9:4
2
11:4
8
13:5
3
15:5
9
18:0
5
20:1
1
22:1
6
0:2
2
2:2
8
4:3
4
6:3
9
8:4
5
10:5
1
12:5
7
15:0
2
17:0
8
19:1
4
21:2
0
23:2
5
1:3
1
3:3
7
5:4
3
7:4
8
9:5
4
12:0
0
time
acti
vit
y
ID:1256
0
500
1000
1500
2000
11:3
6
13:5
0
16:0
5
18:2
0
20:3
5
22:4
9
1:04
3:19
5:34
7:48
10:0
3
12:1
8
14:3
3
16:4
7
19:0
2
21:1
7
23:3
2
1:46
4:01
6:16
8:31
10:4
5
13:0
0
15:1
5
17:3
0
19:4
4
21:5
9
0:14
2:29
4:43
6:58
9:13
11:2
8
13:4
2
time
acti
vity
ID:1187
-100
100
300
500
700
9:31
11:5
4
14:1
8
16:4
1
19:0
5
21:2
8
23:5
2
2:15
4:39
7:02
9:26
11:4
9
14:1
3
16:3
6
19:0
0
21:2
3
23:4
7
2:10
4:34
6:57
9:21
11:4
4
14:0
8
16:3
1
18:5
5
21:1
8
23:4
2
2:05
4:29
6:52
9:16
11:3
9
14:0
3
timeac
tivi
ty
Low Relative Amplitude (RA)
Characterizing Circadian Rest/Activity Rythms
Melatonin & Circadian Rest/Activity Rythms
Shift Work & Melatonin: SummaryShift Work & Melatonin: Summary
Workers on permanent night shifts had a disrupted Workers on permanent night shifts had a disrupted 24-hour melatonin rhythm24-hour melatonin rhythm
Desynchronized circadian melatonin rhythm associated Desynchronized circadian melatonin rhythm associated with sleep disruption, fatigue, and mental symptiomswith sleep disruption, fatigue, and mental symptioms
Disrupted melatonin rhythms may be associated withDisrupted melatonin rhythms may be associated with poor performance and increased accident/injury riskpoor performance and increased accident/injury risk
Methods implemented in this study can be applied toMethods implemented in this study can be applied to health studies (shift workers, cancer patients)health studies (shift workers, cancer patients)
Shift Work & Cancer RiskShift Work & Cancer RiskOccupations linked with Occupations linked with breast cancerbreast cancer
risk include: Flight Attendants, Nursing risk include: Flight Attendants, Nursing & Health Care& Health Care
Recent more carefully controlled studies Recent more carefully controlled studies support previous results support previous results (e.g., Nurses Health Study cohort)(e.g., Nurses Health Study cohort)
More recent studies link shift work w/ More recent studies link shift work w/ colorectalcolorectal & & prostateprostate cancer risks cancer risks
Source: Antoni MH, et al. Nat Rev Cancer. 2006 Mar;6(3):240-8
Stress & Cancer
• Many inflammatory diseases linked with stress • Local stress effects may be pro-inflammatory• Stress, negative emotions associated w/ pro-neoplastic cytokines: IL-1, TNF-alpha, gamma interferon, IL-6, VEGF
Source: Sephton et al. JNCI. 92:994-1000. 2000.
Disrupted Cortisol Rhythm & Breast Cancer SurvivalBreast Cancer Survival
Rich et al. Clin Cancer Res. 11:1757-64. 2005. Mormont et al. Clin Cancer Res. 6: 3038-45. 2000
Right. Kaplan-Meier estimates of survival as a function of the 24-h rhythm parameters, r24 (a) and I<O (b), assigned to quartiles: 1 - very high; 2 -high; 3 - low; 4 - very low. Survival curves compared with log-rank test (r24 p=10-4; I<O p=10-4). Left. Cytokine serum levels for TNF-a, TGF-a, and IL-6 in patientswith ‘‘good’’ (>0.47) or ‘‘dampened’’ (<0.35) activity rhythm measured by the autocorrelation coefficient r24.
Circadian Disruption
& Metastatic Colorectal
Cancer
Inhibits breast cancer cell Inhibits breast cancer cell growth growth in vitro in vitro (MCF-7) (MCF-7)
Stimulates the immune Stimulates the immune system (T, NK cells)system (T, NK cells)
Melatonin & Breast CancerMelatonin & Breast Cancer
Inhibits chemically induced mammary tumors Inhibits chemically induced mammary tumors in vivoin vivo Melatonin concentrates human breast tumors; levels decrease with Melatonin concentrates human breast tumors; levels decrease with increasing tumor size, stage & gradeincreasing tumor size, stage & grade Reduced nocturnal production linked with increased breast cancer risks, Reduced nocturnal production linked with increased breast cancer risks, clinical trials underwayclinical trials underway
Melatonin & Colon CancerMelatonin & Colon Cancer Melatonin & its receptors Melatonin & its receptors
are present in human colon are present in human colon and GI tissueand GI tissue
MelatoninMelatonin exerts exerts antiproliferative effects on antiproliferative effects on normal colonic epithelial as normal colonic epithelial as well as colon cancer cells well as colon cancer cells in in vitrovitro
Melatonin may have local Melatonin may have local anti-inflammatory anti-inflammatory properties (decr. COX-2)properties (decr. COX-2)
Melatonin & its receptors Melatonin & its receptors are present in human colon are present in human colon and GI tissueand GI tissue
MelatoninMelatonin exerts exerts antiproliferative effects on antiproliferative effects on normal colonic epithelial as normal colonic epithelial as well as colon cancer cells well as colon cancer cells in in vitrovitro
Melatonin may have local Melatonin may have local anti-inflammatory anti-inflammatory properties (decr. COX-2)properties (decr. COX-2)
Melatonin administration effective in animal models for treatment of colitis & Melatonin administration effective in animal models for treatment of colitis & colon cancercolon cancer Clinical trials using melatonin increase 1-yr survival (colorectal & other cancer Clinical trials using melatonin increase 1-yr survival (colorectal & other cancer patients)patients)
Circadian Tumor Circadian Tumor GrowthGrowth
Tumors exhibit Tumors exhibit rhythmic growth rhythmic growth patterns that are patterns that are in phase with in phase with clock gene clock gene expression expression (therapeutic (therapeutic application?)application?)
Clock gene Clock gene disruption (disruption (perper) ) linked with linked with circadian circadian disturbances & disturbances & increased cancer increased cancer susceptibility susceptibility
Wood et al. Mol Cancer Ther. 5:2023-33. 2006.
Phenotypic Characteristics of SNPs in Circadian Genes
There are ~2-3 million SNPs in the human genome, some result in slightly different protein isoforms. www.bioteach.ubc.ca/Bioinformatics/DeCODE
Zhu et al. Cancer Epidemiol Biomarkers Prev. 14: 268–70. 2005.
Clock Genes & Breast CancerClock Genes & Breast Cancer
Dorn VA Hospital Colonoscopy Patients(N≈ 4,000/year; ~50% with polyps)
Case-Control Study (n=600 Men)Controls: Patients without polyps or colon cancer (n=200)Cases: Patients with colorectal polyps (n=200) or colon cancer (n=200)
Source: Levi F. Cancer Causes & Control.17:611–621. 2006.
Role of Circadian Disruption in Polyp Formation and RecurrenceRole of Circadian Disruption in Polyp Formation and Recurrence Phase 1: Case-Control Study Phase 2: Randomized Clinical Trial
Base Population
Outcomes
Dorn VA Hospital Colonoscopy Patients(N=~4,000/yr, ~25% w/polyps)
N=300 Men (50% AA, 50% EA):Controls: Patients w/o Polyps (n=150)
Central Nervous System• Depression• Fatigue, Insomnia• Overeating• Type A behavior
Salivary
cortisol levels of 104 patients with
metastatic breast cancer were assessed
at study entry at 0800, 1200, 1700, and
2100 hours on each of 3 consecutive
days, and the slope of diurnal cortisol
variation was calculated using a regression
of log-transformed cortisol concentrations
on sample collection time.
NK cell numbers were measured by
flow cytometry, and NK cell activity
was measured by the chromium release
assay. The survival analysis was conducted
by the Cox proportional hazards
regression model with two-sided
statistical testing. Results: Cortisol
slope predicted subsequent survival up
to 7 years later. Source: Sephton et al. JNCI. 92:994-1000. 2000.
Interdaily Stability (IS) and Relative Amplitude (RA)
• Both are nonparametric variables dedicated for actigraphy analyses.
• The IS, which is the strength of coupling of the rhythm to supposedly stable environmental zeitgebers, quantifies the invariability between the days. The IS is the 24h value from the chi-square periodogram, normalized for the number of data.
• The RA, a measure to describe the signal-to-noise ratio, is an alternative to the cosinor amplitude. The RA can be calculated from the most active 10h period and the least active 5h period in the average 24h pattern.
AcknowledgmentsAcknowledgments
SupportSupport: Veteran’s Administration Research Career Development Award: Veteran’s Administration Research Career Development Award
William Hrushesky, MD William Hrushesky, MD WJB Dorn VA Medical Center, COBREWJB Dorn VA Medical Center, COBRE Patricia Wood, MD, PhDPatricia Wood, MD, PhD WJB Dorn VA Medical Center, COBREWJB Dorn VA Medical Center, COBRE Wael Youssef, MDWael Youssef, MD WJB Dorn VA Medical CenterWJB Dorn VA Medical Center
COBRECOBRE Frank Berger, PhDFrank Berger, PhD USC Center for Colon Cancer ResearchUSC Center for Colon Cancer Research Shawn Youngstedt, PhDShawn Youngstedt, PhD USC Department of Exercise Science USC Department of Exercise Science Dawen Xie, MD, PhDDawen Xie, MD, PhD USC Dept Epidemiology & Biostatistics, USC Dept Epidemiology & Biostatistics,
South Carolina Cancer Center South Carolina Cancer Center Kisito Ogoussan, MS, MDKisito Ogoussan, MS, MD USC Dept Epidemiology & BiostatisticsUSC Dept Epidemiology & Biostatistics