1. Neural Plasticity in Pancreatic Cancer and Pancreatitis
Eduardo Henrique Pirolla, MD, PhD, FIAMBS
Collaborative Professor/Research/Spaulding/MGH Laboratory/HMS
Collaborative Mentor and Supervisor of Fellows of Spaulding/ MGH Laboratory/HMS
Collaborator- Optional Lectures - PPCR – Harvard Public Health School
Clinical Research PPCR Alumni Graduate Harvard Medical School
Doctor by the University of Sao Paulo Medical School
MBA in Economy’s Health of School of Public Health of USP
Harvard Medical School Postgraduate Member
Staff Chief of Team Surgeon at Sirio Libanes Hospital and Albert Einstein Hospital
F. Fregni, MD, PhD, MPH
Associate Professor and Director of Lab Spaulding/ and Massachusetts General Hospital – Harvard Medical School
Director of Principle and Practice of Clinical Research, Harvard School of Public Health

2. Neural Plasticity in Pancreatic Cancer and Pancreatitis
Definition
“Plastic” - ability to react and reshape system as response physical stimullation
Cronic diseases → adaptive - reactic
CNS / PNS
Morphological / Functional alteration of nerves
“Neural Plasticity”

3. Neural Plasticity in Pancreatic Cancer and Pancreatitis
Intra-pancreatics nerves
Increase size
Increase density
Alterations
Pancreatitis
Pancreatic cancer
Switched autonomic and sensory fibers
Infiltrated perineural (neuritis)
Invaded cancer cells
Neuropathic pain

4. Neural Plasticity in Pancreatic Cancer and Pancreatitis
Synergizes
Enhanced excitability sensory neurons
Pancreatic neural plasticity
Schwann cell toward
Cancer
CNS alterations
Maintain
Bidirectional interation
Nerves  Non-neural
pancreatic cells
Damage
Neurophatic pain
Neutrons - mediators
↑ Cancer growth
↑ Inflamation

5. Neural Plasticity in Pancreatic Cancer and Pancreatitis
“Extreme Examples”
Interactions between nervous system and gastrointestinal tract → e.g. → Acute pancreatitis
Pancreas
Central Nerve System
E.H. Pirolla et al, Spinal Cord (2014) 1-4. doi: /sc
I.E. Demir et al, Nature (2015) doi: /nrgastro

6. Neural Plasticity in Pancreatic Cancer and Pancreatitis
Anatomic / Physiologic studies
Digestive hormone
Pancreatic inervation
Exocrine section
Enteropancreatic reflex
Neuroplastic in all Pancreatic disorders
E.H. Pirolla et al, Spinal Cord (2014) 1-4. doi: /sc
I.E. Demir et al, Nature (2015) doi: /nrgastro

7. Neural Plasticity in Pancreatic Cancer and Pancreatitis
Distribution of the patient’s ASIA Classification according to
serum pancreatic enzyme level and acute pancreatitis
Pirolla EH et al. Nature G. Spinal Cord 2014

8. Neural Plasticity in Pancreatic Cancer and Pancreatitis
Distribution of the patient’s level of spinal cord injury
according to serum pancreatic enzyme level and acute pancreatitis
Pirolla EH et al. Nature G. Spinal Cord 2014

9. Neural Plasticity in Pancreatic Cancer and Pancreatitis
Distribution of the presence of adynamic ileum according to
serum pancreatic enzyme level and acute pancreatitis
Pirolla EH et al. Nature G. Spinal Cord 2014

10. Neural Plasticity in Pancreatic Cancer and Pancreatitis
Distribution of the associated fracture according to serum
pancreatic enzyme level and acute pancreatitis
Pirolla EH et al. Nature G. Spinal Cord 2014

11. Neural Plasticity in Pancreatic Cancer and Pancreatitis
Anatomy of pancreatic innervation

12. Neural Plasticity in Pancreatic Cancer and Pancreatitis
Sympathetic and parasympathetic nerves
Spinal Cord (Th6-Th9)
Right vagal trunks
(+)
Right and left splancnic nerves
(–)

13. Neural Plasticity in Pancreatic Cancer and Pancreatitis
The cell bodies of the sensory fibres lie in the dorsal root ganglia

14. Neural Plasticity in Pancreatic Cancer and Pancreatitis
Comparison of human and mouse pancreatic neuroplasticity in chronic pancreatitis and pancreatic cancer

15. Neural Plasticity in Pancreatic Cancer and Pancreatitis
Neurophatic-neuroplastic alterations in human and experimental chronic pancreatitis

16. Neural Plasticity in Pancreatic Cancer and Pancreatitis
Interactions between neurons, glial cells and cancer cells

17. Neural Plasticity in Pancreatic Cancer and Pancreatitis
Characteristics features
“Normal” human
Chronic P/P Cancer
Neural density
Normal
Increased
Neural size
Hypertrophy
Neural distribution
Small nerve trunks (intralolular stroma septae)
More and large-size nerves (> than pancreatic tissue)
Pancreatic
Neuroplasticity

18. Neural Plasticity in Pancreatic Cancer and Pancreatitis
Neurothrophic Attributis of Pancreatic Cancer
Paracrine mediators
Pancreatic cancer
NGF
Artemin / Neurlurin
Growth-associate protein - 43
Pancreatic
Neuropathy
(Normal/cancer tissue)
Pancreatic
Pain

19. Neural Plasticity in Pancreatic Cancer and Pancreatitis
“Scoring System”
Immune Inflammatory Cells “ATTACK”
Severity I (perineuritis):
Immune cells around perineurium, not between nerve fiber bundles.
Severity II (endoneuritis):
Inflammatory cells between nerves fibers and trunk.
Immune
cells
Degree of neural
density
Degree of
pain
CD8+ cytotoxis
Macrophages T cells
Mast cells > MT type (several GI disorders)
Neuroimmune
interaction
Regulate IL-8 intracellular expression
Neurogenic
inflammation
(substance P)

20. Neural Plasticity in Pancreatic Cancer and Pancreatitis
Key Mechanism of Pain
Histamine
5-hydroxytryptamine
Cytokines
Prostaglandins
↑ Mast cells
MT type
Mediators
(hypersensitivity)
Neuropathic
pain
G.I. disorders
e.g. – ulcerative colites, IBS
Pancreatic Cancer include – Neural invasion strong affinity P.C. cells and neurons

21. Neural Plasticity in Pancreatic Cancer and Pancreatitis
Pancreatic Cancer and Neural Invasion
Kinesin-Like protein KIF14
Rho GDP – dissociation inhibitor 2
Neural invasion → affect CNS spinal astroglial activity

22. Neural Plasticity in Pancreatic Cancer and Pancreatitis
Nerves as Modulators of Disease Progression
Research rate models of prostate cancer
Adrenergic fiber depletion with
6-hydroxydopamine
Surgical denervation of prostate via hypogastric nerves
Decrease tumor and distant metastases

23. Neural Plasticity in Pancreatic Cancer and Pancreatitis
Anatomy and Evolution Chronic Pancreatitis to Cancer
Pirolla EH et al. Nature G. Spinal Cord 2014

24. Neural Plasticity in Pancreatic Cancer and Pancreatitis
Conclusions
Neural plasticity is an inherent feature of chronic pancreatitis and pancreatic cancer, and involves neuronal activation at the peripheral, spinal and supraspinal level.
Neural plasticity, pancreatic neuritis, neural invasion and altered distribution of sympathetic and sensory nerve fibres constitute the pancreatic neuropathy in these diseases and correlate with the severity of neuropatic pain sensation
Pain and neural invasion are prognostic in pancreatic cancer and so understanding the underlying mechanismsholds major translational relevance
Patients with chronic pancreatitis exhibit central hyperalgesia and alterations in brain resting activity and brain resting activity and brain microstructure
Current animal models of chronic pancreatitis and genetically engineered mouse models of pancreatic cancer largely fail to recapitulate the intrapancreatic neuropathy and plasticity of nerve trunks in the pancreas
Schwann cells of peripheral nerves are activated in the preneoplastic stage of cancer, possess strong affinity to cancer cells and initiate nerve-cancer cell interactions
Neural modulation for treatment of nerves (CNS/PNS/Splancnic nerves system)
Nature, November 2015
Pirolla EH et al. 2016

25. Neural Plasticity in Pancreatic Cancer and Pancreatitis