Brain Derived Neurotrophic Factor

1. Brain Derived Neurotrophic Factor A Sound mind and a Sound body How BDNF works to prevent Cancer

2. What is BDNF? • Neurotrophin • Same family of proteins as NGF • Secreted growth factor • Pro and mature forms • 37 kDa, on Chr 11p13 • Originally characterized in the brain • Survival, Growth and Maintenance of Neurons • Important Role in Learning and Memory • Synaptic Plasticity

3. Regulation of BDNF Expression • High BDNF • Environmental Enrichment • Voluntary Exercise • Social Support • Antidepressants • Nurturing • Mental Stimulation • Estrogen • Calorie Restriction/Decreased Food Intake • Increased Insulin Sensitivity • Low BDNF • Depression • Dementia • Social Isolation • Chronic Stress • Cognitive Impairment • Alzheimers • Poor learning and memory • Obesity • Type 2 diabetes • Cardiovascular Disease

4. BDNF is also a Myokine • BDNF produced by a variety of cell types including skeletal muscle (myokine) • Factors secreted by contracting muscle = myokines • Muscle represents the largest endocrine organ Pedersen and FebbraioNat. Rev. Endocrinol. (2012) 8: 457-465

5. Buff and Brainy • Exercise promotes neurogenesis, protects against neurodegeneration • Prevents/delays/treats Alzheimer's & Parkinsons disease • Alleviates Depression • Regain mobility following paralysis • Effects mediated by BDNF

6. BDNF Signaling Pathways • Pro-BDNF interacts with p75NTR (low affinity receptor) and is associated with cell death • mBDNF dimer is a growth factor for Neurons

7. The BDNF Paradox • Does BDNF promote cancer or prevent it?

8. Local Effects of BDNF TrkB • If tumors express both BDNF and the BDNF receptor, TrkB…can BDNF promote tumor growth? • Yes – in tissue culture • Yes – in specific subsets of tumors BDNF

9. The BDNF Paradox • If BDNF promotes tumor growth, why doesn’t exercise, environmental enrichment, yoga, social support, etc. promote tumor growth? • Is our Department of Integrative Medicine doomed?

10. Local vs Systemic Effects of BDNF • Low BDNF • Depression • Dementia • Social Isolation • Chronic Stress • Cognitive Impairment • Alzheimers • Poor learning and memory • Obesity • Type 2 diabetes • Cardiovascular Disease BDNF affects more than just neurons…

11. BDNF KO Mouse • Homozygote (-/-) • survive 10-14 days after birth • death due to nervous system and sensory defects, impacting breathing and balance • Heterozygote (+/-) • Aggressive (males) • Locomotor hyperactivity • Overeaters (34% heavier than wt) • Brain serotonergic abnormalities, normalized by FLX • Conditional KO’s (deleted in forebrain) • males- hyperactive with normal anxiety related behaviours • females- normal locomotion, but striking increase in depression-like behaviour

12. SUMMARY Cancer is influenced by its microenvironment, yet broader, environmental effects also play a role but remain poorly defined. We report here that mice living in an enriched housing environment show reduced tumor growth and increased remission. We found this effect in melanoma and colon cancer models, and that it was not caused by physical activity alone. Serum from animals held in an enriched environment (EE) inhibited cancer proliferation in vitro and was markedly lower in leptin. Hypothalamic brain-derived neurotrophicfactor (BDNF) was selectively upregulated by EE, and its genetic overexpression reduced tumor burden, whereas BDNF knockdown blocked the effect of EE. Mechanistically, we show that hypothalamic BDNF downregulatedleptinproduction in adipocytes via sympathoneuralb-adrenergic signaling. These results suggest that genetic or environmental activation of this BDNF/leptin axis may have therapeutic significance for cancer.

13. Environmental Enrichment and Cancer Progression • Examined the influence of complex physical and social environments on biologic function and health • Expt animals live in gym with 20-30 animals • Control animals live in regular cage in groups of 5 • Mouse models of melanoma (syngraft) and colon cancer (Apc min) The mouse gym!

14. 43% at 3 weeks, 77 % at 6 weeks decrease in tumor size with EE

15. EE Induces Systemic Changes in Metabolism • Mice weighed 6% less than control mice • Significant decrease in serum IGF1 • Adiponectin (tumor suppressor) increased • Leptin levels decreased to 13% of controls • Leptin conveys metabolic info to the brain • Is a mitogen, metabolic regulator, survival and/or angiogenic factor • Sera from EE mice inhibited melanoma growth in vitro • Pre treatment of EE sera with leptin neutralizing antibody reversed this effect

16. Other EE associated changes • Immunocompetence Increased • Spleen enlarged • Lymphocytes from EE mice proliferate in response to Con A • NK cell activity increased • Altered Hypothalamic-Pituitary-Adrenal axis • Critical for energy balance • Neuroendocrine immune interaction • Changes distinct from voluntary running alone • In both conditions, cortisol increased

17. Hypothalamic BDNF decreases circulating leptin levels • EE mice had elevated hypothalamic BDNF • Used a viral vector to increase hypothalamic BDNF expression in mice • Mimicked the effects of EE • Blocked BDNF using RNAi • EE effect eliminated • BDNF sends signal to fat cells via sympathetic nervous system to produce less leptin • Effect requires presence of cortisol

18. Systemic Effects of BDNF

19. Controversy • Authors claim mice housed with exercise wheel demonstrated no effect on tumor size • Exercise physiologists have shown otherwise with numerous other cancers

20. Spectrum of Stress? Distress (tumor promoting) Eustress (tumor inhibitory) Group Housing EE Social isolation With wheel Social isolation No wheel

21. Myokinevs Adipokine BDNF Leptin Pedersen and Febbraio Nat. Rev. Endocrinol. (2012) 8: 457-465

22. Conclusions • BDNF expressed by muscle and brain inhibit tumor growth • Produces effects which counteract inflammation produced by adipokines (produced by adipose tissue) • EE and exercise effects may be distinct • Explains in part why patients who exercise and/or have good social support demonstrate improved survival following a cancer diagnosis

23. Questions?