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Time Matters: Importance of Circadian Rhythms, Disruption, and Chronotherapy in Urologic Malignancies

  • Sierra T. Pence
    Affiliations
    Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, Bethesda, MD, 20817, USA.
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  • Gregory T. Chesnut
    Affiliations
    Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, Bethesda, MD, 20817, USA.

    Urology Service, Department of Surgery, Walter Reed National Military Medical Center, Bethesda, Maryland, 20814, USA.
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  • Ayesha A. Shafi
    Correspondence
    Correspondence: 240-694-2703
    Affiliations
    Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, Bethesda, MD, 20817, USA.

    The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, 20817, USA.
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Open AccessPublished:January 21, 2023DOI:https://doi.org/10.1016/j.urology.2023.01.009

      ABSTRACT

      The human body was evolutionarily programmed to run on cycles, termed circadian rhythms, which integrate human behavior and bodily function with the environment. Disruption to these rhythms via desynchronization have been deemed a probable carcinogen by the WHO. Subsequent research has identified alterations in multiple core clock genes when comparing tumor and benign tissues. This review will discuss core clock genes associated with urogenital malignancies and highlight impactful research regarding circadian biology use in treatment. Chronotherapy, treatment alignment with an individual's biological rhythm, remains a relatively untouched field within urology that should be explored to possibly enhance therapeutic outcomes.

      Keywords

      Introduction

      Prior to the invention of light, the human body internalized the temporal rhythm of Earth's rotation to better survive. This evolutionary time keeping machinery consists of circadian rhythms which run continuously to carry out essential functions that integrate behavior, physiology, and metabolism to maintain homeostasis
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      . Disruption to these cycles, caused by exposure to light during night hours or other forms of desynchronization, has been linked to negative effects in the human body. In this review, we will discuss circadian function, disruption, effect on tumorigenesis, and possible treatment adjuncts that involve circadian rhythmicity.
      The body's central clock, within the hypothalamus, produces melatonin which induces transcriptional factors that affect gene expression across the body
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      A database of tissue-specific rhythmically expressed human genes has potential applications in circadian medicine.
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      Circadian rhythms, sleep, and metabolism.
      . Modern lifestyles with artificial lighting and sleep deprivation, have introduced challenges to the body's endogenous rhythm. Desynchronization with the external environment leads to circadian disruption, which has been linked to adverse health outcomes including sleep disorders, metabolic disorder, mood disorders, neurocognitive decline, cardiovascular disease, and malignancy
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      Shift work, which involves circadian disruption, has been recognized by the World Health Organization's (WHO) International Agency for Research on Cancer as a probable human carcinogen (Group 2A) since 2007
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      Carcinogenicity of shift-work, painting, and fire-fighting.
      . Historically clinical studies of circadian rhythm dysfunction focused on shift workers, given their routinely experienced abnormal eating times, jet lag, sleep deprivation, and light-dark dysrhythmia. This study population has been identified to potentially have a higher incidence of malignancies, such as breast or prostate cancer (PCa)
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      . However, a pooled analysis including 8.5 million participants found no association between ever-exposure of night shift work and breast, prostate, ovarian, pancreatic, or colorectal cancer
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      Association Between Night-Shift Work and Cancer Risk: Updated Systematic Review and Meta-Analysis.
      . Further epidemiology studies focused on specific disease types are necessary to discern the correlation of circadian disruption and cancer progression.
      Given the link to tumorigenesis, research in the area expanded greatly. In those efforts, genome sequencing identified the core components of the circadian clock. At the molecular level, the circadian system is controlled by a network of feedback loops regulated by transcriptional factors. The core proteins, circadian locomotor output cycles kaput (CLOCK) and brain and muscle arnt-like protein (BMALI1, also termed ARNTL) dimerize and increase expression of period (PER1, PER2, PER3) and cryptochrome (CRY1, CRY2). With increased levels of CRY1 and CRY2 accumulating during the day, they eventually dimerize with PERs and provide negative feedback to the system
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      Transcriptional architecture and chromatin landscape of the core circadian clock in mammals.
      ,
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      Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions.
      . BMAL1 is controlled by additional factors including RORa, Rev-erba, and Rev-erbb. RORa stimulates BMAL1 expression, while Rev-erba, and b suppress BMAL1 expression. NPAS2 plays a similar role to that of CLOCK in the forebrain and the brain's central clock
      • DeBruyne JP
      • Weaver DR
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      CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock.
      . Several secondary and tertiary components of the circadian system have been identified, with the core clock genes (CCGs) molecular mechanism of action(s) summarized in Figure 1
      • Takahashi JS.
      Transcriptional architecture of the mammalian circadian clock.
      .
      Figure 1:
      Figure 1Model of core circadian clock machinery. The core clock machinery consists of positive (CLOCK and BMAL1) and negative (Cryptochrome (CRY) and Period (PER)) components. These regulators function together to maintain daily rhythmicity throughout an organism, impacting metabolic regulation, cell cycle control, and DNA repair among other key processes. CLOCK/BMAL1 heterodimers bind to E-box sites to regulate expression of core clock genes (CCGs), including CRY1, CRY2, PER1, PER2, and PER3. CLOCK/BMAL1 also regulates expression of additional clock-controlled genes, such as RORa and Rev-erb(a/b), which, in turn, regulate expression of BMAL1 through binding to ROR response elements (RORE). Thus, this autoregulatory network consisting of positive and negative transcription-translation feedback loops confer daily rhythmicity for homeostatic maintenance.
      Animal studies have identified processes regulated by these CCGs that impact key pathways of growth and regulation including cell cycle control, apoptosis, DNA repair, and metabolic regulation
      • Shafi AA
      • Knudsen KE.
      Cancer and the Circadian Clock.
      . Importantly, rodent data has established a causative link of disruption to light-dark cycles with cancer
      • Walker 2nd, WH
      • Bumgarner JR
      • Walton JC
      • et al.
      Light Pollution and Cancer.
      . Jochle (1964) first found this positive relationship after exposing rodents to constant light and identifying an increased occurrence of spontaneous mammary tumors
      • Joechle W.
      Trends in Photophysiologic Concepts.
      . Subsequent studies demonstrated increased spontaneous tumor formation (lung adenocarcinoma, leukemias, hepatocarcinomas), shortened life span, and tumor microenvironment changes including increased macrophage recruitment, upregulation in genes involved in lipogenesis, and hypervascularization
      • Anisimov VN
      • Baturin DA
      • Popovich IG
      • et al.
      Effect of exposure to light-at-night on life span and spontaneous carcinogenesis in female CBA mice.
      • Guerrero-Vargas NN
      • Navarro-Espindola R
      • Guzman-Ruiz MA
      • et al.
      Circadian disruption promotes tumor growth by anabolic host metabolism; experimental evidence in a rat model.
      • Yasuniwa Y
      • Izumi H
      • Wang KY
      • et al.
      Circadian disruption accelerates tumor growth and angio/stromagenesis through a Wnt signaling pathway.
      . Together, these studies demonstrate that constant light exposure had a profound impact on tumorigenesis, tumor growth, and increased mortality.
      In humans, specific variations in CCGs are associated with developing breast, prostate, and lung carcinoma
      • Mocellin S
      • Tropea S
      • Benna C
      • Rossi CR.
      Circadian pathway genetic variation and cancer risk: evidence from genome-wide association studies.
      . These same CCGs also secondarily affect the absorption, distribution, metabolism, and elimination of medications providing multiple avenues of control of treatment plans. Moreover, circadian rhythms have been identified in many aspects of the immune system, with increased immune activity identified in certain parts of the day
      • Shivshankar P
      • Fekry B
      • Eckel-Mahan K
      • Wetsel RA.
      Circadian Clock and Complement Immune System-Complementary Control of Physiology and Pathology?.
      ,
      • Scheiermann C
      • Kunisaki Y
      • Frenette PS.
      Circadian control of the immune system.
      .This unexplored relationship could enhance the effectiveness of immunotherapies given administration timing during or directly prior to peak immune system activity, especially within hormone related malignancies with known timed secretion of hormones
      • Nobis CC
      • Cuesta M
      • Daudelin JF
      • et al.
      The Assessment of Circadian Rhythms Within the Immune System.
      ,
      • Sen A
      • Hoffmann HM.
      Role of core circadian clock genes in hormone release and target tissue sensitivity in the reproductive axis.
      .
      Chronotherapy considers these relationships and is defined as the alignment of disease treatment with an individual's biological rhythm. Cell models simulating early stages of colon cancer illustrated a variability in chemotherapy response based off administration timing. Chemotherapy administered between 4 a.m. and 8 a.m. cured mutant cells in 100% compared to only 18% cured when administered between 8 p.m. and 12 a.m.
      • Axelrod DE.
      Chronotherapy of Early Colon Cancer: Advantage of Morning Dose Schedules.
      . Clinically, chronotherapy has been effective in the administration of medications for asthma, cardiovascular disease, and hypertension, but remains relatively unexplored in urologic malignancies
      • Song JU
      • Park HK
      • Lee J.
      Impact of dosage timing of once-daily inhaled corticosteroids in asthma: A systematic review and meta-analysis.
      • Hermida RC
      • Hermida-Ayala RG
      • Smolensky MH
      • et al.
      Does Timing of Antihypertensive Medication Dosing Matter?.
      • Awad K
      • Banach M.
      The optimal time of day for statin administration: a review of current evidence.
      . With regards to radiation, a review of therapies found differences in local control, survival time, and toxicity that varied based on the time of radiation delivery
      • Chan S
      • Rowbottom L
      • McDonald R
      • et al.
      Does the Time of Radiotherapy Affect Treatment Outcomes? A Review of the Literature.
      . In this review, we will summarize epidemiologic studies investigating the connection of circadian disruption and cancer incidence, identify genome specific associations, and explore the current research available regarding chronotherapy.

      Prostate Cancer

      Epidemiology and Cancer Incidence

      PCa, the second most common cause of cancer death in American men, has repeatedly been linked to circadian disruption
      • Siegel RL
      • Miller KD
      • Fuchs HE
      • Jemal A.
      Cancer statistics, 2022.
      . Erren at al. reported a 40% relative risk increase in PCa after analyzing thirty studies of flight personnel and shift workers
      • Erren TC
      • Pape HG
      • Reiter RJ
      • Piekarski C.
      Chronodisruption and cancer.
      . A population-based case-control study also reported an association of core circadian genes with PCa in night shift workers, especially those who worked longer hours
      • Wendeu-Foyet MG
      • Koudou Y
      • Cenee S
      • et al.
      Circadian genes and risk of prostate cancer: Findings from the EPICAP study.
      . Rotating night shifts is also correlated with a 73% increased risk of PCa
      • Lozano-Lorca M
      • Olmedo-Requena R
      • Vega-Galindo MV
      • et al.
      Night Shift Work, Chronotype, Sleep Duration, and Prostate Cancer Risk: CAPLIFE Study.
      . Interestingly, the magnitude of PCa risk in Lozano-Lorca's case-control study was three times higher in individuals who self-identified as an evening chronotype, often described as a ‘night owl’, compared to those with a morning chronotype
      • Lozano-Lorca M
      • Olmedo-Requena R
      • Vega-Galindo MV
      • et al.
      Night Shift Work, Chronotype, Sleep Duration, and Prostate Cancer Risk: CAPLIFE Study.
      . This alteration of magnitude suggests the possibility of an additional genetic variation that modulates circadian response to interruption. Outside of shift work, circadian disruption is also seen in individuals with standard work weeks. For example, Hu (2020) identified a 52% increased risk of PCa in those with greater than one hour of social jetlag, defined by the difference in waking time between weekday and weekend days
      • Hu L
      • Harper A
      • Heer E
      • et al.
      Social Jetlag and Prostate Cancer Incidence in Alberta's Tomorrow Project: A Prospective Cohort Study.
      . Similarly, men with lower levels of morning melatonin, linked to subjective reports of difficulty sleeping, had a fourfold increased risk of PCa
      • Sigurdardottir LG
      • Markt SC
      • Rider JR
      • et al.
      Urinary melatonin levels, sleep disruption, and risk of prostate cancer in elderly men.
      . Although inconclusive, several epidemiological studies have identified the correlation of circadian dysfunction and increased PCa
      • Erren TC
      • Pape HG
      • Reiter RJ
      • Piekarski C.
      Chronodisruption and cancer.
      ,
      • Siegel RL
      • Miller KD
      • Fuchs HE
      • Jemal A.
      Cancer statistics, 2022.
      • Wendeu-Foyet MG
      • Koudou Y
      • Cenee S
      • et al.
      Circadian genes and risk of prostate cancer: Findings from the EPICAP study.
      • Lozano-Lorca M
      • Olmedo-Requena R
      • Vega-Galindo MV
      • et al.
      Night Shift Work, Chronotype, Sleep Duration, and Prostate Cancer Risk: CAPLIFE Study.
      • Hu L
      • Harper A
      • Heer E
      • et al.
      Social Jetlag and Prostate Cancer Incidence in Alberta's Tomorrow Project: A Prospective Cohort Study.
      . Additional studies are needed to determine the specific lifestyle choices associated with this increased risk.

      Gene Studies

      The largest prostatic genome study to date illustrated a significant statistical association between circadian pathway genetic variation and the risk of PCa
      • Mocellin S
      • Tropea S
      • Benna C
      • Rossi CR.
      Circadian pathway genetic variation and cancer risk: evidence from genome-wide association studies.
      . The specific CCGs associated with a significant increased risk of PCa are summarized in Table 1, Table 2
      • Mocellin S
      • Tropea S
      • Benna C
      • Rossi CR.
      Circadian pathway genetic variation and cancer risk: evidence from genome-wide association studies.
      ,
      • Wendeu-Foyet MG
      • Koudou Y
      • Cenee S
      • et al.
      Circadian genes and risk of prostate cancer: Findings from the EPICAP study.
      ,
      • Zhu Y
      • Stevens RG
      • Hoffman AE
      • et al.
      Testing the circadian gene hypothesis in prostate cancer: a population-based case-control study.
      • Gu F
      • Zhang H
      • Hyland PL
      • et al.
      Inherited variation in circadian rhythm genes and risks of prostate cancer and three other cancer sites in combined cancer consortia.
      • Chu LW
      • Till C
      • Yang B
      • et al.
      Circadian genes and risk of prostate cancer in the prostate cancer prevention trial.
      • Chu LW
      • Zhu Y
      • Yu K
      • et al.
      Variants in circadian genes and prostate cancer risk: a population-based study in China.
      • Markt SC
      • Valdimarsdottir UA
      • Shui IM
      • et al.
      Circadian clock genes and risk of fatal prostate cancer.
      • Yu CC
      • Chen LC
      • Chiou CY
      • et al.
      Genetic variants in the circadian rhythm pathway as indicators of prostate cancer progression.
      . Interestingly, genetic variations are correlated with other factors outside of cancer risk. Across three cohort studies, CRY1 variation was found to be associated with fatal prostate cancer
      • Markt SC
      • Valdimarsdottir UA
      • Shui IM
      • et al.
      Circadian clock genes and risk of fatal prostate cancer.
      . Downregulation of NPAS2 expression was associated with aggressive PCa and worse biochemical recurrence free survival
      • Yu CC
      • Chen LC
      • Chiou CY
      • et al.
      Genetic variants in the circadian rhythm pathway as indicators of prostate cancer progression.
      . Lower expressions of PER1, PER2, and CRY2 and higher expression of CSNK1E, were also associated with disease progression
      • Feng D
      • Xiong Q
      • Zhang F
      • et al.
      Identification of a Novel Nomogram to Predict Progression Based on the Circadian Clock and Insights Into the Tumor Immune Microenvironment in Prostate Cancer.
      . Future studies are ongoing to determine the molecular mechanisms underpinning CCGs function in PCa.
      Table 1CCGs associated with a significant increased risk of GU cancer
      GENEPVALUEAUTHORTYPE
      ARNTL<0.001Mocellin, S., et al. (2018)PCa
      <0.05Zhu, Y., et al. (2009)PCa
      <0.001Zhou, L., et al. (2020)RCC
      CLOCK0.02Gu, F., et al. (2017)PCa
      0.01Mocellin, S., et al. (2018)PCa
      CRY2<0.05Chu, L., et al. (2008)PCa
      <0.05Gu, F., et al. (2017)PCa
      CSNK1E<0.05Chu, L., et al. (2008)PCa
      0.02Wendeu-Foyet, M., et al. (2019)PCa
      <0.05Zhu, Y., et al. (2009)PCa
      NPAS2<0.05Chu, L., et al. (2008)PCa
      <0.0001Chu, L., et al. (2018)PCa
      0.006Gu, F., et al. (2017)PCa
      0.002Mocellin, S., et al. (2018)PCa
      0.003Wendeu-Foyet, M., et al. (2019)PCa
      <0.05Zhu, Y., et al. (2009)PCa
      NR1D10.005Mocellin, S., et al. (2018)PCa
      <0.001Zhou, L., et al. (2020)RCC
      PER1<0.05Chu, L., et al. (2008)PCa
      0.004Wendeu-Foyet, M., et al. (2019)PCa
      <0.001Zhou, L., et al. (2020)RCC
      <0.05Litlekalsoy, J., et al. (2016)UCa
      Urothelial Cancer (UCa) is used interchangeable with bladder cancer
      PER2<0.001Zhou, L., et al. (2020)RCC
      <0.01Mazzoccoli G., et al. (2012)RCC
      <0.05Litlekalsoy, J., et al. (2016)UCa
      Urothelial Cancer (UCa) is used interchangeable with bladder cancer
      PER3<0.05Chu, L., et al. (2008)PCa
      0.009Mocellin, S., et al. (2018)PCa
      RORA<0.001Mocellin, S., et al. (2018)PCa
      <0.001Zhou, L., et al. (2020)RCC
      low asterisk Urothelial Cancer (UCa) is used interchangeable with bladder cancer
      Table 2CCGs associated with other variables of GU cancer
      GENEASSOCIATIONPVALUEAUTHOR
      CLOCKImproved Overall Survival, RCC0.009Zhou, L., et al. (2020)
      CRY1Fatal PCa0.01Markt, S., et al (2015)
      multi-cohort study
      0.01Markt, S., et al (2015)
      multi-cohort study
      0.05Markt, S., et al (2015)
      multi-cohort study
      PCa Prognosis0.029Shafi, A., et al (2021)
      Gleason Score ≥70.027Wendeu-Foyet, M., et al. (2019)
      Improved Overall Survival, RCC0.00076Zhou, L., et al. (2020)
      CRY 2Improved Overall Survival, RCC<0.0001Zhou, L., et al. (2020)
      NPAS2Biochemical Recurrence0.039Yu, C., et al. (2019)
      Progression of Localized PCa0.032Yu, C., et al. (2019)
      low asterisk multi-cohort study

      Chronotherapy

      Although the mortality rate for men with PCa is low, approximately one-third of patients suffer from recurrence after localized treatment with some progressing to castration-resistant PCa (CRPC)
      • Bansal D
      • Reimers MA
      • Knoche EM
      • Pachynski RK.
      Immunotherapy and Immunotherapy Combinations in Metastatic Castration-Resistant Prostate Cancer.
      . Given the aggressiveness of CRPC, enhancement of treatment via chronomodulation should be further explored. A small study of men with CRPC identified no objective difference or change in metastatic disease with circadian infused floxuridine. Dosing was 0.15 mg/kg/day with 70% of the drug administered between 3 and 9 p.m. with the remaining being administered between 9 and 3 p.m. While this phase II study without a control group failed to show improved oncologic outcomes with circadian-informed dosing, it did show such dosing to be feasible and tolerable
      • Rajagopalan K
      • Peereboom D
      • Budd GT
      • et al.
      Phase II trial of circadian infusion floxuridine (FUDR) in hormone refractory metastatic prostate cancer.
      . Going forward, it is important to design and perform prospective studies to discern the effectiveness of chronotherapy in PCa patients given the possible effects of circadian hormonal release on androgen deprivation therapy response.
      A retrospective study of patients with localized PCa that received high dose radiotherapy (HDRT), median of 78 Gy, identified differences among side effects and treatment response dependent on treatment time. The study found a significant correlation between treatment after 5 p.m. and increased prevalence of both acute gastrointestinal and GU side effects. In patients with advanced disease, T2b or greater, evening treatment was also associated with a significantly worse biochemical failure recurrence survival 6-year rate (69% vs 81%, P = 0.04) compared to those treated before 5 p.m. The association remained significant after accounting for age, stage, Gleason score, initial prostate-specific antigen level and androgen deprivation therapy
      • Hsu FM
      • Hou WH
      • Huang CY
      • et al.
      Differences in toxicity and outcome associated with circadian variations between patients undergoing daytime and evening radiotherapy for prostate adenocarcinoma.
      . Negoro et al. analyzed lower urinary tract symptoms (LUTS) in men receiving proton beam therapy (PBT) for localized PCa by quantifying via the international prostate symptom score (IPSS) questionnaire prior to PBT and again during the last three sessions of treatment. Following PBT, the average IPSS total score increased significantly from 8 to 14.9 with the quality-of-life score increasing significantly from 2 to 4 on average. Morning radiation, between 8:30 and 10:30 a.m., significantly reduced post therapy LUTS compared with radiation performed after noon. Time of day was the only significant determinant in score when considering risk classification, concurrent therapies, PBT dose, prior IPSS score, LUTS medications, and diabetes
      • Negoro H
      • Iizumi T
      • Mori Y
      • et al.
      Chronoradiation Therapy for Prostate Cancer: Morning Proton Beam Therapy Ameliorates Worsening Lower Urinary Tract Symptoms.
      . Notably, provider fatigue was not analyzed and should be considered a potential confounding variable in future chronotherapy research, which can be used to lessen side effects and toxicities to improve quality of life for PCa patients.
      Another treatment consideration within chronotherapy is circadian resynchronization. In recent years, melatonin had been explored as a potential adjunct to cancer therapy with research identifying potential mechanisms and use as an anticancer agent
      • Reiter RJ
      • Rosales-Corral SA
      • Tan DX
      • et al.
      Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis.
      . Levels of melatonin, a core controller of circadian rhythm, have been found to be inversely related to the progression of PCa
      • Srinivasan V
      • Spence DW
      • Pandi-Perumal SR
      • Trakht I
      • Cardinali DP.
      Therapeutic actions of melatonin in cancer: possible mechanisms.
      . Research in urology is limited, but in a variety of proliferative cell lines including benign prostate hyperplasia (BPH), high-grade intraepithelial neoplasia (HGPIN), localized PCa, and aggressive PCa with metastasis, melatonin treatment resulted in resynchronization of some CCG circadian levels
      • Jung-Hynes B
      • Huang W
      • Reiter RJ
      • Ahmad N.
      Melatonin resynchronizes dysregulated circadian rhythm circuitry in human prostate cancer cells.
      . These findings suggest the use of melatonin has a potential reversal agent of circadian disruption.

      Renal Cancer

      Epidemiology and Cancer Incidence

      Renal cancer is a major global disease with more than 400,000 new cases diagnosed yearly. No research has correlated circadian disruption with renal cancer, however, one small randomized controlled trial found night shift workers had improved blood pressure control with timed light therapy treatments, illustrating a role of circadian regulation on the kidney
      • Hannemann J
      • Laing A
      • Middleton B
      • et al.
      Light therapy improves diurnal blood pressure control in night shift workers via reduction of catecholamines: the EuRhythDia study.
      .

      Gene Studies

      Primary tumor samples of kidney renal cell carcinoma (RCC), the most common subtype, have demonstrated downregulation of CCGs compared to normal renal tissue
      • Zhou L
      • Luo Z
      • Li Z
      • et al.
      Circadian clock is associated with tumor microenvironment in kidney renal clear cell carcinoma.
      ,
      • Mazzoccoli G
      • Piepoli A
      • Carella M
      • et al.
      Altered expression of the clock gene machinery in kidney cancer patients.
      . Mouse models illustrated suppression of CLOCK in RCC samples compared to normal tissue
      • Ohashi M
      • Umemura Y
      • Koike N
      • et al.
      Disruption of circadian clockwork in in vivo reprogramming-induced mouse kidney tumors.
      . A similar lack of CLOCK expression was seen in human Wilms tumor samples
      • Ohashi M
      • Umemura Y
      • Koike N
      • et al.
      Disruption of circadian clockwork in in vivo reprogramming-induced mouse kidney tumors.
      . Zhou et al. (2020) identified downregulation of CLOCK, CRY1, and CRY2, while downregulation of PER2 was found in a different sample
      • Zhou L
      • Luo Z
      • Li Z
      • et al.
      Circadian clock is associated with tumor microenvironment in kidney renal clear cell carcinoma.
      ,
      • Mazzoccoli G
      • Piepoli A
      • Carella M
      • et al.
      Altered expression of the clock gene machinery in kidney cancer patients.
      . These CCGs have also been linked to RCC tumorigenesis, further underscoring the need to elucidate the mechanisms of action underpinning CCG function in cancer progression
      • Zhou L
      • Luo Z
      • Li Z
      • et al.
      Circadian clock is associated with tumor microenvironment in kidney renal clear cell carcinoma.
      .
      Regarding prognosis, individual upregulation of CLOCK, CRY1, CRY2, PER2 and PER3 in RCC patients was associated with a statistically significant improved overall survival rate of 33-56% depending on which CCG was upregulated
      • Zhou L
      • Luo Z
      • Li Z
      • et al.
      Circadian clock is associated with tumor microenvironment in kidney renal clear cell carcinoma.
      . In a large genomic study of multiple cancers, downregulation of CLOCK, CRY2, PER1, PER2, and PER3 resulted in significantly higher mortality rate in kidney cancers while a high expression of ARNTL2 and NR1D1 was linked to poorer survival outcomes
      • Chang WH
      • Lai AG.
      Timing gone awry: distinct tumour suppressive and oncogenic roles of the circadian clock and crosstalk with hypoxia signalling in diverse malignancies.
      . Moreover, expression of CLOCK was positively associated with an abundance of infiltrating immune cells which are often used as therapeutic targets. Interestingly, outside of CRY1, the copy number alteration of CCG mutations affected the presence of immune infiltrates suggesting a possible correlation of difficult to treat RCC with certain forms of CCG dysregulation
      • Zhou L
      • Luo Z
      • Li Z
      • et al.
      Circadian clock is associated with tumor microenvironment in kidney renal clear cell carcinoma.
      .

      Chronotherapy

      The involvement of circadian regulation in RCC and the body's immune reaction provide opportunities for immunotherapy therapy enhancement. The relationship is likely complicated involving circadian rhythms, their effect on hormones, absorption, and the immune system, and the cascading effects on immunotherapies. Iacobelli (1995) used continuously infused circadian adjusted doses, with maximum delivery between 6 p.m. and 3 a.m., to analyze tolerability and toxicity of interferon-a (INF-a) treatment in metastatic RCC. Given the continuous infusion, higher doses were administered, with an objective response found in 2 of 16 patients who had previously failed therapies
      • Iacobelli S
      • Garufi C
      • Irtelli L
      • et al.
      A phase I study of recombinant interferon-alpha administered as a seven-day continuous venous infusion at circadian-rhythm modulated rate in patients with cancer.
      . One patient showed >75% reduction of the renal mass as well as the disappearance of all abdominal, mediastinal, and pulmonary lymph node enlargement. It is unknown if the circadian based infusion led to a response or if it was simply the higher dosage, given there were no controls in the study. Additionally, 16 of 18 patients were able to tolerate higher daily doses than standard treatment without serious toxicity. Further research is required to identify if circadian infusions allow for increased dose tolerability. More recently, Re et al. (2020) analyzed metastatic RCC response to recombinant human interleukin -2 (IL-2) treatment across three chronotherapy schedules (5 a.m. to 1 p.m., 1 to 9 p.m., and 9 p.m. to 5 a.m.)
      • Re GL
      • Santeufemia DA
      • Re FL
      • et al.
      Interleukin-2 chronotherapy for metastatic renal cell carcinoma: Results of a phase I-II study.
      . Each schedule was an eight-hour IL-2 infusion with a Gaussian distribution of drug concentration peaking after four hours. Stability of disease occurred in 11 cases with an overall disease control rate of 53%. Patients who received treatment from 1 to 9 p.m. had a shorter medial overall survival compared to the other study arms, however the difference was not significant (p=0.090). Further analysis of chronomodulated immunotherapies is warranted for further determination of chronotherapy in RCC.

      Bladder Cancer

      Epidemiology and Cancer Incidence

      Bladder cancer (BCa) is one of the leading causes of human death worldwide with a historically high morbidity and mortality often due to a late presentation
      • Patel VG
      • Oh WK
      • Galsky MD.
      Treatment of muscle-invasive and advanced bladder cancer in 2020.
      . With regards to circadian disruption, a population-based case-control study identified a 70% increase in bladder cancer within men who had been shift works. The increase climbed to nearly 100% if the men at worked in shift work for more than 10 years
      • Parent ME
      • El-Zein M
      • Rousseau MC
      • Pintos J
      • Siemiatycki J.
      Night work and the risk of cancer among men.
      . Within another review, three small studies showed that night-shift work increased the risk of urinary cancer by nearly 10% without clarification of bladder cancer specifically
      • Dun A
      • Zhao X
      • Jin X
      • et al.
      Association Between Night-Shift Work and Cancer Risk: Updated Systematic Review and Meta-Analysis.
      .

      Gene Studies

      CCG expression in muscle invasive bladder cancer (MIBC) is intricate, with multiple genes illustrating various effects. In tissue samples from patients with MIBC, downregulation of PER2 and PER3 were seen in tumor cells compared to neighboring mucosa
      • Litlekalsoy J
      • Rostad K
      • Kalland KH
      • Hostmark JG
      • Laerum OD.
      Expression of circadian clock genes and proteins in urothelial cancer is related to cancer-associated genes.
      . Similar to RCC, Chang et al. (2019) found downregulation of CLOCK, CRY2, PER1, PER2, and PER3 resulted in a significantly higher mortality rate
      • Chang WH
      • Lai AG.
      Timing gone awry: distinct tumour suppressive and oncogenic roles of the circadian clock and crosstalk with hypoxia signalling in diverse malignancies.
      . Zhou et al. (2021) created a circadian rhythm-related score (CRRS) based on the presence of certain CCGs that accurately predicted five-year survival rates. A high CRRS was correlated with both an unfavorable prognosis, a higher benefit from immunotherapy, and a low half inhibitory concentration of cisplatin. This suggests the score could possibly be used as a screen for cisplatin efficacy
      • Zhou R
      • Chen X
      • Liang J
      • et al.
      A circadian rhythm-related gene signature associated with tumor immunity, cisplatin efficacy, and prognosis in bladder cancer.
      . The CRRS was also significantly associated with sensitivity of chemotherapeutic agents, such as cisplatin, doxorubicin, gemcitabine, methotrexate, and vinblastine. In total, these genomic studies, summarized in Table 1, link the importance of CCGs alterations and bladder cancer incidence.

      Chronotherapy

      There is limited data on chronomodulated treatments of BCa. A trial completed in 1985 involved twelve patients with >T3 urothelial cancer that were administered monthly circadian-timed doxorubicin and cisplatin chemotherapy immediately after radical cystectomy. 77% had no recurrence at 3.5 years. No other details were given regarding the circadian timing of the dosing
      • Hrushesky WJ
      • Roemeling RV
      • Wood PA
      • Langevin TR
      • Lange P
      • Fraley E.
      High-dose intensity, circadian-timed doxorubicin and cisplatin adjuvant chemotherapy for bladder cancer.
      . Further retrospective studies are warranted to identify a possible association of CCGs with BCa, enhance patient quality of life, and improve efficacy of treatment.
      Multiple studies have correlated CCG effects on cisplatin, a mainstay of treatment for MIBC. As mentioned previously, a CCG based algorithm predicted cisplatin efficacy in BCa
      • Zhou R
      • Chen X
      • Liang J
      • et al.
      A circadian rhythm-related gene signature associated with tumor immunity, cisplatin efficacy, and prognosis in bladder cancer.
      . It is proposed that CCGs have these effects because of their close correlation with DNA repair and affect cisplatin's role in blocking cell division
      • Kang TH
      • Sancar A.
      Circadian regulation of DNA excision repair: implications for chrono-chemotherapy.
      . Furthermore, CRY1 was found to accumulate in some samples of cisplatin resistant cells and prevented paclitaxel induced cell death
      • Jia M
      • Su B
      • Mo L
      • et al.
      Circadian clock protein CRY1 prevents paclitaxelinduced senescence of bladder cancer cells by promoting p53 degradation.
      . These effects on cisplatin and other therapies require further investigation. Lastly, Wu et al. (2021) identified a potential space for melatonin therapy in BCa with tumor growth rate and weight lower in melatonin-treated mice group
      • Wu J
      • Tan Z
      • Li H
      • et al.
      Melatonin reduces proliferation and promotes apoptosis of bladder cancer cells by suppressing O-GlcNAcylation of cyclin-dependent-like kinase 5.
      . Given the limited screening markers for BCa combined with the expense and invasiveness of surveillance, more research is needed to further clarify the circadian effects seen in BCa to discover ways for CCGs to serve as adjuncts to diagnostic, prognostic, and therapeutic measures.

      Conclusion

      The human body and its multitude of systems are regulated by circadian rhythm. In this review, we have highlighted and reported studies that identified the impact CCGs on cell regulation and have also linked CCG alteration with malignancies throughout the GU system. Further research is warranted to determine whether specific subgroups of the population are more likely to be affected by disruption and to identify any environmental factors or lifestyle choices that impact CCG alterations. Research is especially important for underprivileged populations, who are more likely to engage in night shift work. Given the continued racial disparities in healthcare, identification of CCGs alternations in different disease stages of specific populations is warranted to identify further means of diagnosis and treatment in those populations.
      Further understanding of CCG impact also provides an avenue of exploration for potential new biomarkers and therapeutics. Given the system wide circadian effects on hormones, digestion, absorption, renal function, and immune cells; the potential impact of chronomodulation is unknown. The limited studies of chronotherapy reviewed in this article illustrate a possible mechanism of increased dosages without toxicity, however, further research is warranted. Additional research on the use of melatonin and its ability to correct circadian disruption is also necessary.
      Although this evidence is exciting, there are many limitations to the presented studies. Much of the human circadian research is observational with few control groups or randomized studies. Additionally, much of the reported data is from small sample sizes. The future of chronotherapy also requires genetic testing and buy-in from healthcare providers to possibly treat outside of modern work hours, creating a resource heavy treatment enhancement. Even still, chronotherapy has remained relatively unexplored in urologic malignancies and has the potential to impact many patients as a therapeutic enhancement. For that reason alone, future research is warranted to distinguish at-risk populations, potential screening tools, and the effect of chronotherapy on cancer treatments.
      Model of core circadian clock machinery. The core clock machinery consists of positive (CLOCK and BMAL1) and negative (Cryptochrome (CRY) and Period (PER)) components. These regulators function together to maintain daily rhythmicity throughout an organism, impacting metabolic regulation, cell cycle control, and DNA repair among other key processes. CLOCK/BMAL1 heterodimers bind to E-box sites to regulate expression of core clock genes (CCGs), including CRY1, CRY2, PER1, PER2, and PER3. CLOCK/BMAL1 also regulates expression of additional clock-controlled genes, such as RORa and Rev-erb(a/b), which, in turn, regulate expression of BMAL1 through binding to ROR response elements (RORE). Thus, this autoregulatory network consisting of positive and negative transcription-translation feedback loops confer daily rhythmicity for homeostatic maintenance.

      Author Contributions

      Conceptualization, A.A.S.; Resources, S.T.P. and A.A.S.; Writing – Original Draft, S.T.P. and A.A.S.; Writing – Review & Editing, S.T.P., G.T.C., and A.A.S.; A.A.S.; Funding Acquisition, A.A.S.

      Acknowledgements

      This work was supported by a Young Investigator Award from the Prostate Cancer Foundation (AAS). We are grateful for each individual support and input. The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views, opinions, or policies opinions of the Uniformed Services University of the Health Sciences (USUHS), the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF), the Department of Defense (DoD) or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government.

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