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Brain Derived
Neurotrophic Factor
A Sound mind and a Sound body
How BDNF works to prevent Cancer
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
Regulation of BDNF Expression
 High BDNF

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

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

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Environmental Enrichment
Voluntary Exercise
Social Support
Antidepressants
Nurturing
Mental Stimulation
Estrogen
Calorie
Restriction/Decreased Food
Intake
 Increased Insulin Sensitivity
 Low BDNF


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
Depression
Dementia
Social Isolation
Chronic Stress
Cognitive Impairment
 Alzheimers
 Poor learning and
memory
 Obesity
 Type 2 diabetes
 Cardiovascular Disease
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 Febbraio Nat. Rev. Endocrinol. (2012) 8: 457-465
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
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
The BDNF Paradox
 Does BDNF promote cancer or prevent it?
Local Effects of BDNF
 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
TrkB
BDNF
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?
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…
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 depressionlike behaviour
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 neurotrophic factor (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 downregulated leptin
production in adipocytes via sympathoneural b-adrenergic signaling. These results suggest that genetic or
environmental activation of this BDNF/leptin axis may have therapeutic significance for cancer.
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!
43% at 3
weeks,
77 % at 6
weeks
decrease
in tumor
size with
EE
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
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
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
Systemic Effects of BDNF
Controversy
 Authors claim mice housed with exercise wheel
demonstrated no effect on tumor size
 Exercise physiologists have shown otherwise with
numerous other cancers
Spectrum of Stress?
Eustress
(tumor inhibitory)
EE
Distress
(tumor promoting)
Group Housing
Social isolation
With wheel
Social isolation
No wheel
Myokine vs Adipokine
BDNF
Leptin
Pedersen and Febbraio
Nat. Rev. Endocrinol. (2012) 8: 457-465
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
Questions?