Annals of Medicine, 2014; 46: 189–190 © 2014 Informa UK, Ltd. ISSN 0785-3890 print/ISSN 1365-2060 online DOI: 10.3109/07853890.2014.920213
SPECIAL SELECTION: CANCER CLOCKS GUEST EDITORIAL
Circadian clock and cancer therapy: an unexpected journey Roman Kondratov
Ann Med Downloaded from informahealthcare.com by University of Laval on 06/11/14 For personal use only.
Center for Gene Regulation in Health and Diseases and BGES Department, Cleveland State University, Ohio, USA
Chronotherapy of cancer is one of the oldest examples of the clinical application of biological rhythms. Growing understanding of the importance of biological timing in physiology and pathophysiology of many diseases including cancer reforms our views on the role of biological clocks in cancer and cancer treatment. In the present issue the current progress in circadian clockdependent mechanisms of cancer, polymorphism and mutations of clock gene in cancer, cancer-associated clock disruptions, and novel chronotherapeutic approaches are discussed.
The idea to explore biological clocks in order to improve the efficiency of anticancer treatment was proposed a long time ago, but it has not come to be a regular practice in clinic. However, over the last several years, we have seen more and more understanding on the importance of biological rhythms in pathophysiology and treatment of cancer from both clinical and basic research sides. A new era in the clock cancer saga started with the discovery of the clock genes and generation of animal models of clock disruption. Studies by Levi, Hrushevsky, and others (1) have demonstrated that the efficacy of chemotherapy may be dictated by the circadian clocks, and Antoch with colleagues using animal model of clock deficiency have provided evidence that organism sensitivity to anticancer therapy was regulated by the circadian clock proteins (2). Together, these works indicated potential molecular mechanisms and built scientific grounds for chronotherapy of cancer. Fu and Lee with colleagues demonstrated that the circadian clock protein Period 2 is a candidate tumor suppressor gene and thus initiated a chain of studies on the role of the clock in the biology of cancer (3). Lately, circadian disruption has been recognized as a potential independent risk factor for cancer development. In the current issue, several experts in the field review the recent progress on deciphering the reciprocity between circadian clocks and cancer. The present-day research in the field can be subdivided into two major clusters: clock and chronotherapy of cancer, and clock and tumorigenesis. The progress made in cancer chronotherapy is reviewed by Innominato et al. (1). Historically, chronotherapy of cancer was considered as a method to optimize the efficacy of the treatment and to reduce toxicity. Chronomodulated chemotherapy has been efficient in some cases, but did not demonstrate any positive effects in other cases. Multiple possible causes of this discrepancy such as interindividual difference in chronotypes, the gender difference, and different pharmacokinetics and pharmacodynamics of the drugs are discussed
in detail in the review. Authors also examine a novel important direction in chronotherapy—circadian synchronization. Sleep disruption is a common phenomenon among cancer patients, which can be an indication of circadian disruption. Circadian disruption may affect cancer progression and also may contribute to other cancer-associated pathologies such as muscle wasting, fatigue, and sleep loss. Different approaches to restore circadian synchronization such as regulation of the sleep–wake cycle, physical activity, light therapy, and timed meals and pharmacological approaches have been used in different studies across the globe. It is too early now to discuss if the circadian synchronization will prolong survival of cancer patients; however, there is definite evidence that it might improve sleep quality and reduce side effects of treatment. Kettner and colleagues discuss how circadian disruption can affect initiation, development, and progression of tumors (4). Authors made extensive analysis of published data on development of cancer in different animal models of circadian disruption. The general conclusions drawn based on the majority of reports are that the deficiency of core clock genes is a tumor-promoting factor; however, there are several examples when the clock deficit does not result in an increased rate of tumorigenesis, and in some cases has even the opposite effect. A reason for this discrepancy is not clear, but it is quite possible that effects of different clock genes are tissue- and tumor-specific. Authors also review recent data on linkage between clock gene polymorphism and different types of cancer. Additionally, over the last few years different mutations in clock genes have been identified in various tumors. All these data strongly argue for the importance of the clock and clock genes in human cancer. In an attempt to understand the mechanisms linking circadian clock disruption and cancer, virtually all cancer-related cellular pathways have been studied. Initially, significant efforts were directed toward the role of the clock in the genotoxic stress response. The role of the circadian system in the control of oxidative stress, DNA repair, and cell cycle checkpoints have been demonstrated by multiple groups; again there was some discrepancy in interpretation of results, which arose from employing different model systems. Similarly, studies on molecular mechanisms of circadian clocks in cancer were also originally concentrated on the regulation of cell proliferation and genotoxic stress response, reviewed by Sotak et al. (5). Authors have analyzed available data on circadian microarray profiling of different tissues and identified genes with rhythmic expression, which were implicated in the regulation of the cell cycle, checkpoints, apoptosis, and intracellular signal transduction. Recent discoveries suggest some novel directions.
Ann Med Downloaded from informahealthcare.com by University of Laval on 06/11/14 For personal use only.
190
R. Kondratov
Endoplasmic reticulum (ER) stress and unfolded protein response signaling have been implicated in cancer. Pluquet and colleagues propose and discuss in detail the reciprocal interaction between the circadian clocks and the ER stress machinery (6). Several important regulators of unfolded protein response signaling are under direct clock transcriptional and post-transcriptional control, and their expression demonstrates rhythms in different tissues in vivo. In turn, ER stress-activated factors control the expression of clock genes. Therefore, circadian disruption may result in ER stress which further affects the clock and thus contributes to cancer. I also want to draw attention to a few other important physiological systems which are major contributors to cancer. Circadian clock-dependent control of inflammation, genome stability, senescence, and aging has been recently established. As discussed by Kettner et al., chronic inflammation and senescence can change the local environment and stimulate production of secreted factors that create a microenvironment favoring tumor growth (4). Circadian disruption will promote both chronic inflammation and senescence, thus stimulating tumor development. There are many important questions that have been raised by recent studies and these reviews. Here are a few that I consider the most interesting: 1. Is the role of the clock and clock proteins tissue- and tumor-specific? In other words, can some clock proteins act as tumor-promoting or tumor-suppressing factors depending on the context? 2. Do cancer-specific mutations in circadian clock genes affect the function of corresponding proteins and/or the clock? Are these mutations tumor-promoting? 3. Can clock proteins be considered as potential biomarkers of cancer progression? 4. If we consider the clock as a potential target for pharmacological intervention, what must be a goal for pharmacological modulations: resetting clock in tumor or in normal tissues? Suppression or activation of some clock proteins? In conclusion I would like to make several additional remarks. At the beginning of any journey many things look oversimple or over-complicated; with the progress of the journey, this
original ‘naïve’ view is usually significantly transformed based on unexpected difficulties and discoveries encountered along the way. With development of chronobiology of cancer, we understand now that it is not so simple and straightforward as was expected at the beginning. Data interpretations must be made with caution, and multiple parameters must be taken into consideration before applying potential approaches to medical treatment. It is also important to keep in mind that cancer is not a single disease but rather a multitude of different diseases that may require different treatments. Therefore, it would be naïve to expect that circadian clock disruption will be observed in every tumor, or that clock disruption will contribute to all tumors. While application of the chronotherapy approach in the clinic is still slow, in the modern era of personalized medicine the knowledge of the individual chronotype may be critical for treatment and, probably, will have to be included as an important component of diagnostic procedures. Both clinical and basic research data are promising and warrant further studies in the stirring field of the circadian clock biology of cancer. Declaration of interest: The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.
References 1. Innominato PF, Roche VP, Palesh OG, Ulusakarya A, Spiegel D, Lévi FA. The circadian timing system in clinical oncology. Ann Med. 2014 (this issue). 2. Gorbacheva VY, Kondratov RV, Zhang R, Cherukuri S, Gudkov AV, Takahashi JS, et al. Circadian sensitivity to the chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK/ BMAL1 transactivation complex. Proc Natl Acad Sci U S A. 2005;102: 3407–12. 3. Fu L, Pelicano H, Liu J, Huang P, Lee CC. The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell. 2002;111:41–50. 4. Kettner NM, Katchy CA, Fu L. Circadian gene variants in cancer. Ann Med. 2014 (this issue). 5. Soták M, Sumová A, Pácha J. Crosstalk between the circadian clock and the cell cycle in cancer. Ann Med. 2014 (this issue). 6. Pluquet O, Dejeans N, Chevet E. Watching the clock: endoplasmic reticulum-mediated control of circadian rhythms in cancer. Ann Med. 2014 (this issue).
SPECIAL SELECTION: CANCER CLOCKS GUEST EDITORIAL
Circadian clock and cancer therapy: an unexpected journey Roman Kondratov
Ann Med Downloaded from informahealthcare.com by University of Laval on 06/11/14 For personal use only.
Center for Gene Regulation in Health and Diseases and BGES Department, Cleveland State University, Ohio, USA
Chronotherapy of cancer is one of the oldest examples of the clinical application of biological rhythms. Growing understanding of the importance of biological timing in physiology and pathophysiology of many diseases including cancer reforms our views on the role of biological clocks in cancer and cancer treatment. In the present issue the current progress in circadian clockdependent mechanisms of cancer, polymorphism and mutations of clock gene in cancer, cancer-associated clock disruptions, and novel chronotherapeutic approaches are discussed.
The idea to explore biological clocks in order to improve the efficiency of anticancer treatment was proposed a long time ago, but it has not come to be a regular practice in clinic. However, over the last several years, we have seen more and more understanding on the importance of biological rhythms in pathophysiology and treatment of cancer from both clinical and basic research sides. A new era in the clock cancer saga started with the discovery of the clock genes and generation of animal models of clock disruption. Studies by Levi, Hrushevsky, and others (1) have demonstrated that the efficacy of chemotherapy may be dictated by the circadian clocks, and Antoch with colleagues using animal model of clock deficiency have provided evidence that organism sensitivity to anticancer therapy was regulated by the circadian clock proteins (2). Together, these works indicated potential molecular mechanisms and built scientific grounds for chronotherapy of cancer. Fu and Lee with colleagues demonstrated that the circadian clock protein Period 2 is a candidate tumor suppressor gene and thus initiated a chain of studies on the role of the clock in the biology of cancer (3). Lately, circadian disruption has been recognized as a potential independent risk factor for cancer development. In the current issue, several experts in the field review the recent progress on deciphering the reciprocity between circadian clocks and cancer. The present-day research in the field can be subdivided into two major clusters: clock and chronotherapy of cancer, and clock and tumorigenesis. The progress made in cancer chronotherapy is reviewed by Innominato et al. (1). Historically, chronotherapy of cancer was considered as a method to optimize the efficacy of the treatment and to reduce toxicity. Chronomodulated chemotherapy has been efficient in some cases, but did not demonstrate any positive effects in other cases. Multiple possible causes of this discrepancy such as interindividual difference in chronotypes, the gender difference, and different pharmacokinetics and pharmacodynamics of the drugs are discussed
in detail in the review. Authors also examine a novel important direction in chronotherapy—circadian synchronization. Sleep disruption is a common phenomenon among cancer patients, which can be an indication of circadian disruption. Circadian disruption may affect cancer progression and also may contribute to other cancer-associated pathologies such as muscle wasting, fatigue, and sleep loss. Different approaches to restore circadian synchronization such as regulation of the sleep–wake cycle, physical activity, light therapy, and timed meals and pharmacological approaches have been used in different studies across the globe. It is too early now to discuss if the circadian synchronization will prolong survival of cancer patients; however, there is definite evidence that it might improve sleep quality and reduce side effects of treatment. Kettner and colleagues discuss how circadian disruption can affect initiation, development, and progression of tumors (4). Authors made extensive analysis of published data on development of cancer in different animal models of circadian disruption. The general conclusions drawn based on the majority of reports are that the deficiency of core clock genes is a tumor-promoting factor; however, there are several examples when the clock deficit does not result in an increased rate of tumorigenesis, and in some cases has even the opposite effect. A reason for this discrepancy is not clear, but it is quite possible that effects of different clock genes are tissue- and tumor-specific. Authors also review recent data on linkage between clock gene polymorphism and different types of cancer. Additionally, over the last few years different mutations in clock genes have been identified in various tumors. All these data strongly argue for the importance of the clock and clock genes in human cancer. In an attempt to understand the mechanisms linking circadian clock disruption and cancer, virtually all cancer-related cellular pathways have been studied. Initially, significant efforts were directed toward the role of the clock in the genotoxic stress response. The role of the circadian system in the control of oxidative stress, DNA repair, and cell cycle checkpoints have been demonstrated by multiple groups; again there was some discrepancy in interpretation of results, which arose from employing different model systems. Similarly, studies on molecular mechanisms of circadian clocks in cancer were also originally concentrated on the regulation of cell proliferation and genotoxic stress response, reviewed by Sotak et al. (5). Authors have analyzed available data on circadian microarray profiling of different tissues and identified genes with rhythmic expression, which were implicated in the regulation of the cell cycle, checkpoints, apoptosis, and intracellular signal transduction. Recent discoveries suggest some novel directions.
Ann Med Downloaded from informahealthcare.com by University of Laval on 06/11/14 For personal use only.
190
R. Kondratov
Endoplasmic reticulum (ER) stress and unfolded protein response signaling have been implicated in cancer. Pluquet and colleagues propose and discuss in detail the reciprocal interaction between the circadian clocks and the ER stress machinery (6). Several important regulators of unfolded protein response signaling are under direct clock transcriptional and post-transcriptional control, and their expression demonstrates rhythms in different tissues in vivo. In turn, ER stress-activated factors control the expression of clock genes. Therefore, circadian disruption may result in ER stress which further affects the clock and thus contributes to cancer. I also want to draw attention to a few other important physiological systems which are major contributors to cancer. Circadian clock-dependent control of inflammation, genome stability, senescence, and aging has been recently established. As discussed by Kettner et al., chronic inflammation and senescence can change the local environment and stimulate production of secreted factors that create a microenvironment favoring tumor growth (4). Circadian disruption will promote both chronic inflammation and senescence, thus stimulating tumor development. There are many important questions that have been raised by recent studies and these reviews. Here are a few that I consider the most interesting: 1. Is the role of the clock and clock proteins tissue- and tumor-specific? In other words, can some clock proteins act as tumor-promoting or tumor-suppressing factors depending on the context? 2. Do cancer-specific mutations in circadian clock genes affect the function of corresponding proteins and/or the clock? Are these mutations tumor-promoting? 3. Can clock proteins be considered as potential biomarkers of cancer progression? 4. If we consider the clock as a potential target for pharmacological intervention, what must be a goal for pharmacological modulations: resetting clock in tumor or in normal tissues? Suppression or activation of some clock proteins? In conclusion I would like to make several additional remarks. At the beginning of any journey many things look oversimple or over-complicated; with the progress of the journey, this
original ‘naïve’ view is usually significantly transformed based on unexpected difficulties and discoveries encountered along the way. With development of chronobiology of cancer, we understand now that it is not so simple and straightforward as was expected at the beginning. Data interpretations must be made with caution, and multiple parameters must be taken into consideration before applying potential approaches to medical treatment. It is also important to keep in mind that cancer is not a single disease but rather a multitude of different diseases that may require different treatments. Therefore, it would be naïve to expect that circadian clock disruption will be observed in every tumor, or that clock disruption will contribute to all tumors. While application of the chronotherapy approach in the clinic is still slow, in the modern era of personalized medicine the knowledge of the individual chronotype may be critical for treatment and, probably, will have to be included as an important component of diagnostic procedures. Both clinical and basic research data are promising and warrant further studies in the stirring field of the circadian clock biology of cancer. Declaration of interest: The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.
References 1. Innominato PF, Roche VP, Palesh OG, Ulusakarya A, Spiegel D, Lévi FA. The circadian timing system in clinical oncology. Ann Med. 2014 (this issue). 2. Gorbacheva VY, Kondratov RV, Zhang R, Cherukuri S, Gudkov AV, Takahashi JS, et al. Circadian sensitivity to the chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK/ BMAL1 transactivation complex. Proc Natl Acad Sci U S A. 2005;102: 3407–12. 3. Fu L, Pelicano H, Liu J, Huang P, Lee CC. The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell. 2002;111:41–50. 4. Kettner NM, Katchy CA, Fu L. Circadian gene variants in cancer. Ann Med. 2014 (this issue). 5. Soták M, Sumová A, Pácha J. Crosstalk between the circadian clock and the cell cycle in cancer. Ann Med. 2014 (this issue). 6. Pluquet O, Dejeans N, Chevet E. Watching the clock: endoplasmic reticulum-mediated control of circadian rhythms in cancer. Ann Med. 2014 (this issue).
