Disrupted Sleep Awakes Cancer Progression & Invasiveness

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1 Disrupted Sleep Awakes Cancer Progression & Invasiveness Fahed Hakim, MD Pediatric Pulmonary Division, Mayer Children s Hospital Section of Sleep Medicine,The University of Chicago The Brain, Sleep and immunity Laboratory, Tecchnion

2 Why we sleep

3 Sleep cleans brain Xie elt al, Science, 2013 Oct 18;342(6156):373-7

4 Sleep Control Homeostatic and Circadian processes These two processes can interact and at the same time can work separately on controlling our sleep

5 Sleep disruption and deprivation

6 Morbidity of Snoring and OSA Sleepiness Cardiovascular Metabolic Neurobehavioral and Cognitive

7 Cancer

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9 Cancer Biology and Growth Initiation Irreversible DNA damage in critical gene(s) Promotion Expansion of initiated cells Reversible at least initially Repetitive process Progression Vascularization and expansions Phases of cancer growth

10 Cancer and Sleep

11 Hakim & Kim et al, Respir Physiol Neurobiol May 5.

12 Hypoxia in tumor cells

13 Genes induced by Hypoxia To accumulate to the new condition Oxygen transport and iron metabolism Erythropoietin Angiogenesis VEGF Glycolysis and glucose uptake Glut1,3 Growth / cytokines PDGF-B/ IL-8 Cell adhesion and coagulation TF Transcription factors- HIF1α

14 Night shift workers Are exposed to light at night (LAN)on a regular basis experience: Circadian rhythm disruption and phase shift Nocturnal melatonin suppression Sleep disturbances (sleep deprivation or fragmentation)

15 Shift work that involves circadian disruption is probably carcinogenic to humans. (Group 2A) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Painting, firefighting, and shiftwork. Lyon, France: IARC; 2007.

16 Mechanism of cancer in shift work Fritschi et al, Med Hypotheses Jun 30.

17 Nurses Health Study I Night shift work for >30 years is associated with RR of 1.54 for BC Eva S. Schernhammer et al,journal of the National Cancer Institute, Vol. 93, No. 20, 2001

18 Nurses Health Study II A larger cohort showed a higher risk after 20 years of shift work Schernhammer, Eva; et al Epidemiology. 17(1): , January 2006

19 Campos-Rodriguez et al. Am J Respir Crit Care Med, Jan 1, 2012

20 Neito et al. Am J Respir Crit Care Med, 2012 Jul 15

21 Our questions? Does sleep disruption affect solid tumor progression? Does sleep disruption affects metastatic proliferation? If yes, what are the changes in the immune system response to SD,that underlie this tumor progression?

22 Sleep fragmentation Arousal episodes every 2 minutes Sleep deprivation Force wakefulness Sleep Disruption Model (SDM) All paradigm will be applied from 7:00 AM -7:PM Intermittent Hypoxia Cycles of 5.7% and 21% O2 every 3 minutes Sustained Hypoxia Continues 8% O2 and 82% N2 Intermittent Hypercapnia Cycles of 90 sec -5% CO2, 21% O2 and75% N2 followed by 90 sec - 0% CO2, 21% O2 and 79% N2 Intermittent Hypoxia & Hypercapnia Cycles of 90 sec -4% CO2, 5.7% O2 and 90.3% N2 followed by 90 sec - 0% CO2, 21% O2 and 79% N2

23 Cell lines TC-1 ( tumor culture 1 ), cervical cancer model originally from lung epithelial cells, HPV-16 transformed 3LL ( lewis lung carcinoma ) Both can bee used in Solid and Metastatic models (inj SC or IV )

24 Solid Tumor Model

25 Metastatic Tumor Model

26 Experimental Time course

27 Tumor Volume and Weight Hakim et al Cancer Res; 74(5) March 1, 2014

28 More invasive!!!! SF SC SF SC SF SC SF SC

29 Hakim et al Cancer Res; 74(5) March 1, 2014

30 Tumor microenvironment

31 Tumor Associated Macrophages(TAM)

32 Tumor Associated Macrophages Hakim et al Cancer Res; 74(5) March 1, 2014

33 TAM distribution F4/80- TAMs CD45-(TIC) Tumor infiltrating Cells Hoechst-Nuclei Hakim et al Cancer Res; 74(5) March 1, 2014

34 TAM polarity

35 TAM polarity Hakim et al Cancer Res; 74(5) March 1, 2014

36 Toll Like Receptors

37 Toll like receptor 4

38 TLR4 KO mice SF SC WT TLR4 KO Hakim et al Cancer Res; 74(5) March 1, 2014

39 TLR4/MYD88/TRIF Hakim et al Cancer Res; 74(5) March 1, 2014

40 What we have shown Chronic SF induces accelerated tumor growth, expansion and invasiveness in a solid tumor model. The increased numbers and differential tumor location of TAM and associated MMP-9 expression suggest that SF-mediated effects on TAM polarity and function may underlie the increased invasive and aggressive tumorigenesis in SF. Moreover, the significant reductions in tumor growth and TAM numbers in the SF-TLR4 -/-, SF-MYD88-/- and SF-TRIF-/- mice further indicate that TLR4 signaling pathways operate as major contributors to the SF-mediated effects on tumor progression, TAM polarity and function.

41 Acknowledgments Lea s Team

42 Acknowledgments Gozal s Lab Supported by National Institutes of Health grants HL and HL

43 Acknowledgments Rolls s Lab