CYTOSource Current Issues for Cytopathology
New studies linking sleep apnea and other disruptions to cancer add to evidence that poor sleep can be deadly very 2 minutes for 12 hours, the slumbering group was forced to repeat the same sequence: wake up, step over a low bar sweeping across the floor, and go back to sleep. Over and over, an automated bar silently moving back and forth across a cage of laboratory mice mimicked the effects of sleep-disrupting apnea by repeatedly jarring the animals awake, if only for a few seconds. The same 12-hour sequence occurred every day for a week, and after researchers inoculated the sleepy mice with cancer cells, the process continued for another 4 weeks. When it was over, the researchers discovered that tumors implanted in the sleep-fragmented mice were significantly larger and more aggressive than those in mice allowed to sleep normally.1 The
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E
Cancer Cytopathology Cancer Cytopathology
results, recently reported by a team led by David Gozal, MD, chairman of pediatrics and a sleep disorder specialist at the University of Chicago Comer Children’s Hospital, have raised disturbing new questions concerning how sleep apnea and other nighttime disruptions might help promote cancer growth. “What this work has done is just open a door that had not been really open before and indicate that there is certainly a connection between sleep and cancer that we need to explore in much greater detail,” Dr. Gozal says. Estimates suggest that sleep apnea may affect more than 30 million Americans, although it is underdiagnosed. In severe cases, the condition may interrupt sleep as many as 60 to 80 times per hour. “Most people don’t remember it. Your
March March2015 2015
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Fitful Night
brain wakes up for 3 seconds and goes back to sleep,” Dr. Gozal says. The body may not forget as easily. To date, far more work has focused on understanding how nighttime disruptions of our circadian rhythms might impact tumorigenesis and cancer growth. In 2007, the International Agency for Research on Cancer concluded that circadian disruption via shiftwork was “probably carcinogenic to humans.” In women, the majority of the research has involved breast cancer. In men with shifted sleep schedules, such as police officers and airline pilots, studies have shown a similarly heightened risk of prostate cancer. A few years ago, other studies began hinting at a potential link between sleep apnea and a higher cancer incidence or less favorable cancer outcomes. In 2012, researchers at the University of Wisconsin found that people with severe apnea had a nearly 5-fold higher risk of dying of cancer than those with no sleep disruptions.2 Since then, studies in Spain and Australia have reached similar conclusions. Although the data from these relatively small studies are far from definitive, Dr. Gozal says, the “provocative” findings encouraged him to conduct his own research. His laboratory was already studying sleep apnea, long associated with other problems such as cognitive deficits, cardiovascular problems, and metabolic issues. Dr. Gozal and his colleagues had developed a mouse model to help them decipher whether the episodic changes in oxygen levels or the sleep fragmentation itself contributed most to apnea’s complications. His team was stunned by the results suggesting significantly larger and more invasive tumors in the sleep-disrupted mice. Further sleuthing revealed a potential mechanism of action: the sleep fragmentation was associated with the activation of inflammatory pathways and disruption of the immune system, suggesting immune system dysregulation. Since then, Dr. Gozal and his team have discovered an even more startling phenomenon at play involving the immune system’s macrophages charged with gobbling up cancer cells. In sleepfragmented mice, macrophages at the
CYTOSOURCE
The Dark Side of a
By Bryn Nelson, PhD Edited By Terence J. Colgan, MD
CONTINUED from previous page
The Dark Side of a Fitful Night
tumor margins actually acquired a protumor role. Although sleep fragmentation can induce a form of cellular damage known as oxidative stress, the defanged macrophages essentially protected the tumor cells from such damage. The mechanism, he says, is “clearly the milliondollar question,” but one that could help researchers to identify potential targets for anticancer therapy.
Discordant Rhythm and Snooze
CYTOSOURCE
Researchers also are making headway in unraveling other mechanisms by which cancer may take advantage of sleep disruptions. Sarah Markt, ScD, a postdoctoral research fellow in the department of epidemiology at the Harvard School of
land, Ohio, published 2 related studies supporting yet another potential mechanism: that shorter sleep duration might raise the risk of more aggressive cancer. Cheryl Thompson, PhD, a coauthor of both studies and an assistant professor of family medicine, says the first study explored the link between lifestyle factors and breast tumor aggressiveness.4 “We’re doing a really good job of finding breast cancers and for many of them, the prognosis is excellent,” she says. “There’s just some that are very aggressive and result in much more aggressive tumors.” Those types cause the majority of breast cancer mortality, and Dr. Thompson wondered whether a lifestyle analysis would yield any clues.
© DIMEDROL68 / FOTOLIA.COM
‘I was able to show that people who had grade-3 tumors, or the fastest growing, actually had fewer hours of sleep compared to the other [people].’ —Cheryl Thompson, PhD Public Health in Boston, Massachusetts, recently found some potentially telling clues in an analysis of 928 older Icelandic men drawn from a long-term study called the Age, Gene/Environment Susceptibility (AGES)-Reykjavik study. “In the Icelandic study, we found that men who had more disrupted sleep—those who reported more problems falling asleep and staying asleep—had lower melatonin levels than those who reported no sleep problems,” Dr. Markt says.3 Other research has suggested that melatonin, a hormone linked to the body’s circadian rhythms, holds important anticancer properties. Whereas darkness signals the brain’s pineal gland to produce melatonin, light hitting the eye’s retina triggers a halt in its production. Among the men in the AGES-Reykjavik study, lower levels of melatonin correlated with a higher overall risk of prostate cancer and a higher risk of more advanced forms of the disease. Although Dr. Markt is careful to note that the study does not establish causation, she is hoping to replicate her findings in a US-based cohort. She also wants to expand her research to take into account the growing focus on sleep apnea. In 2012 and 2013, researchers at Case Western Reserve University in Cleve-
Her questionnaire contained only one question regarding sleep, but the results were striking. Patients who reported sleeping fewer hours per night in the 2 years before their diagnosis tended to have a significantly higher breast cancer recurrence score, which is a measure of the cancer’s likelihood of recurrence. For a follow-up study, the researchers broadened the patient pool and examined the link between sleep duration and the widely used 3-point tumor grade scale.5 “I was able to show that people who had grade 3 tumors, or the fastest growing, actually had fewer hours of sleep compared to the other [people],” Dr. Thompson says. Her underlying hypothesis is that shorter sleep duration is one among many ways to undermine the body’s circadian rhythms, leading to disruptions in critical metabolic processes such as DNA and cellular repair. Several researchers point out that multiple, interrelated pathways may be influencing the observed links between sleep disruptions and cancer, complicating the effort to untangle them. Nevertheless, the field is forging ahead. Dr. Thompson has modified her patient questionnaire to include more sleeprelated questions, and she hopes to focus
more closely on sleep quality. Among her ongoing work, she is also conducting gene expression profiles of the breast tumors in women who get less sleep than their peers to learn whether certain genes might be driving the cancer’s aggressiveness. She also hopes to conduct a long-term sleep intervention study among women at higher risk of breast cancer. “I got asked a long time ago if I would recommend sleeping longer for breast cancer prevention,” Dr. Thompson says. Her answer? No, she recommends it to help prevent a multiplicity of conditions. “Sleep is so good for so many things.” References 1. Hakim F, Wang Y, Zhang SX, et al. Fragmented sleep accelerates tumor growth and progression through recruitment of tumor-associated macrophages and TLR4 signaling. Cancer Res. 2014;74:1329-1337. 2. Nieto FJ, Peppard PE, Young T, Finn L, Hla KM, Farre R. Sleep-disordered breathing and cancer mortality: results from the Wisconsin Sleep Cohort Study. Am J Respir Crit Care Med. 2012;186:190-194. 3. Sigurdardottir LG, Markt SC, Rider JR, et al. Urinary melatonin levels, sleep disruption, and risk of prostate cancer in elderly men [published online ahead of print August 5, 2014]. Eur Urol. pii: S03022838(14)00648-4. 4. Thompson CL, Li L. Association of sleep duration and breast cancer OncotypeDX recurrence score. Breast Cancer Res Treat. 2012;134:1291-1295. 5. Khawaja A, Rao S, Li L, Thompson CL. Sleep duration and breast cancer phenotype. J Cancer Epidemiol. 2013;2013:467927. DOI: 10.1002/cncy.21538
Content in this section does not reflect any official policy or medical opinion of the American Cancer Society or of the publisher unless otherwise noted. © American Cancer Society, 2015.
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New studies linking sleep apnea and other disruptions to cancer add to evidence that poor sleep can be deadly very 2 minutes for 12 hours, the slumbering group was forced to repeat the same sequence: wake up, step over a low bar sweeping across the floor, and go back to sleep. Over and over, an automated bar silently moving back and forth across a cage of laboratory mice mimicked the effects of sleep-disrupting apnea by repeatedly jarring the animals awake, if only for a few seconds. The same 12-hour sequence occurred every day for a week, and after researchers inoculated the sleepy mice with cancer cells, the process continued for another 4 weeks. When it was over, the researchers discovered that tumors implanted in the sleep-fragmented mice were significantly larger and more aggressive than those in mice allowed to sleep normally.1 The
© FOCUS POCUS LTD / FOTOLIA.COM
E
Cancer Cytopathology Cancer Cytopathology
results, recently reported by a team led by David Gozal, MD, chairman of pediatrics and a sleep disorder specialist at the University of Chicago Comer Children’s Hospital, have raised disturbing new questions concerning how sleep apnea and other nighttime disruptions might help promote cancer growth. “What this work has done is just open a door that had not been really open before and indicate that there is certainly a connection between sleep and cancer that we need to explore in much greater detail,” Dr. Gozal says. Estimates suggest that sleep apnea may affect more than 30 million Americans, although it is underdiagnosed. In severe cases, the condition may interrupt sleep as many as 60 to 80 times per hour. “Most people don’t remember it. Your
March March2015 2015
137 2
The Dark Side of a Fitful Night
Fitful Night
brain wakes up for 3 seconds and goes back to sleep,” Dr. Gozal says. The body may not forget as easily. To date, far more work has focused on understanding how nighttime disruptions of our circadian rhythms might impact tumorigenesis and cancer growth. In 2007, the International Agency for Research on Cancer concluded that circadian disruption via shiftwork was “probably carcinogenic to humans.” In women, the majority of the research has involved breast cancer. In men with shifted sleep schedules, such as police officers and airline pilots, studies have shown a similarly heightened risk of prostate cancer. A few years ago, other studies began hinting at a potential link between sleep apnea and a higher cancer incidence or less favorable cancer outcomes. In 2012, researchers at the University of Wisconsin found that people with severe apnea had a nearly 5-fold higher risk of dying of cancer than those with no sleep disruptions.2 Since then, studies in Spain and Australia have reached similar conclusions. Although the data from these relatively small studies are far from definitive, Dr. Gozal says, the “provocative” findings encouraged him to conduct his own research. His laboratory was already studying sleep apnea, long associated with other problems such as cognitive deficits, cardiovascular problems, and metabolic issues. Dr. Gozal and his colleagues had developed a mouse model to help them decipher whether the episodic changes in oxygen levels or the sleep fragmentation itself contributed most to apnea’s complications. His team was stunned by the results suggesting significantly larger and more invasive tumors in the sleep-disrupted mice. Further sleuthing revealed a potential mechanism of action: the sleep fragmentation was associated with the activation of inflammatory pathways and disruption of the immune system, suggesting immune system dysregulation. Since then, Dr. Gozal and his team have discovered an even more startling phenomenon at play involving the immune system’s macrophages charged with gobbling up cancer cells. In sleepfragmented mice, macrophages at the
CYTOSOURCE
The Dark Side of a
By Bryn Nelson, PhD Edited By Terence J. Colgan, MD
CONTINUED from previous page
The Dark Side of a Fitful Night
tumor margins actually acquired a protumor role. Although sleep fragmentation can induce a form of cellular damage known as oxidative stress, the defanged macrophages essentially protected the tumor cells from such damage. The mechanism, he says, is “clearly the milliondollar question,” but one that could help researchers to identify potential targets for anticancer therapy.
Discordant Rhythm and Snooze
CYTOSOURCE
Researchers also are making headway in unraveling other mechanisms by which cancer may take advantage of sleep disruptions. Sarah Markt, ScD, a postdoctoral research fellow in the department of epidemiology at the Harvard School of
land, Ohio, published 2 related studies supporting yet another potential mechanism: that shorter sleep duration might raise the risk of more aggressive cancer. Cheryl Thompson, PhD, a coauthor of both studies and an assistant professor of family medicine, says the first study explored the link between lifestyle factors and breast tumor aggressiveness.4 “We’re doing a really good job of finding breast cancers and for many of them, the prognosis is excellent,” she says. “There’s just some that are very aggressive and result in much more aggressive tumors.” Those types cause the majority of breast cancer mortality, and Dr. Thompson wondered whether a lifestyle analysis would yield any clues.
© DIMEDROL68 / FOTOLIA.COM
‘I was able to show that people who had grade-3 tumors, or the fastest growing, actually had fewer hours of sleep compared to the other [people].’ —Cheryl Thompson, PhD Public Health in Boston, Massachusetts, recently found some potentially telling clues in an analysis of 928 older Icelandic men drawn from a long-term study called the Age, Gene/Environment Susceptibility (AGES)-Reykjavik study. “In the Icelandic study, we found that men who had more disrupted sleep—those who reported more problems falling asleep and staying asleep—had lower melatonin levels than those who reported no sleep problems,” Dr. Markt says.3 Other research has suggested that melatonin, a hormone linked to the body’s circadian rhythms, holds important anticancer properties. Whereas darkness signals the brain’s pineal gland to produce melatonin, light hitting the eye’s retina triggers a halt in its production. Among the men in the AGES-Reykjavik study, lower levels of melatonin correlated with a higher overall risk of prostate cancer and a higher risk of more advanced forms of the disease. Although Dr. Markt is careful to note that the study does not establish causation, she is hoping to replicate her findings in a US-based cohort. She also wants to expand her research to take into account the growing focus on sleep apnea. In 2012 and 2013, researchers at Case Western Reserve University in Cleve-
Her questionnaire contained only one question regarding sleep, but the results were striking. Patients who reported sleeping fewer hours per night in the 2 years before their diagnosis tended to have a significantly higher breast cancer recurrence score, which is a measure of the cancer’s likelihood of recurrence. For a follow-up study, the researchers broadened the patient pool and examined the link between sleep duration and the widely used 3-point tumor grade scale.5 “I was able to show that people who had grade 3 tumors, or the fastest growing, actually had fewer hours of sleep compared to the other [people],” Dr. Thompson says. Her underlying hypothesis is that shorter sleep duration is one among many ways to undermine the body’s circadian rhythms, leading to disruptions in critical metabolic processes such as DNA and cellular repair. Several researchers point out that multiple, interrelated pathways may be influencing the observed links between sleep disruptions and cancer, complicating the effort to untangle them. Nevertheless, the field is forging ahead. Dr. Thompson has modified her patient questionnaire to include more sleeprelated questions, and she hopes to focus
more closely on sleep quality. Among her ongoing work, she is also conducting gene expression profiles of the breast tumors in women who get less sleep than their peers to learn whether certain genes might be driving the cancer’s aggressiveness. She also hopes to conduct a long-term sleep intervention study among women at higher risk of breast cancer. “I got asked a long time ago if I would recommend sleeping longer for breast cancer prevention,” Dr. Thompson says. Her answer? No, she recommends it to help prevent a multiplicity of conditions. “Sleep is so good for so many things.” References 1. Hakim F, Wang Y, Zhang SX, et al. Fragmented sleep accelerates tumor growth and progression through recruitment of tumor-associated macrophages and TLR4 signaling. Cancer Res. 2014;74:1329-1337. 2. Nieto FJ, Peppard PE, Young T, Finn L, Hla KM, Farre R. Sleep-disordered breathing and cancer mortality: results from the Wisconsin Sleep Cohort Study. Am J Respir Crit Care Med. 2012;186:190-194. 3. Sigurdardottir LG, Markt SC, Rider JR, et al. Urinary melatonin levels, sleep disruption, and risk of prostate cancer in elderly men [published online ahead of print August 5, 2014]. Eur Urol. pii: S03022838(14)00648-4. 4. Thompson CL, Li L. Association of sleep duration and breast cancer OncotypeDX recurrence score. Breast Cancer Res Treat. 2012;134:1291-1295. 5. Khawaja A, Rao S, Li L, Thompson CL. Sleep duration and breast cancer phenotype. J Cancer Epidemiol. 2013;2013:467927. DOI: 10.1002/cncy.21538
Content in this section does not reflect any official policy or medical opinion of the American Cancer Society or of the publisher unless otherwise noted. © American Cancer Society, 2015.
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