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Do platelets have a role in cancer?
Hannah Needham
h5p://thrivemdvail.com/prp-‐platelet-‐rich-‐plasma-‐therapy/
Overview
1. What are platelets? 2. Platelet receptors 3. The hallmarks of cancer 4. Metastasis 5. Evasion of the immune system 6. ExtravasaLon
Overview
1. What are platelets? 2. Platelet receptors 3. The hallmarks of cancer 4. Metastasis 5. Evasion of the immune system 6. ExtravasaLon
What are platelets?
• Small, anucleate blood cells
• Small, anucleate blood cells • EssenLal for clot formaLon
What are platelets?
• Small, anucleate blood cells • EssenLal for clot formaLon
• Prevent excessive blood loss following injury
What are platelets?
ResLng platelets Red blood cells
Endothelial cells
Collagen
What are platelets?
What are platelets?
• Vascular damages exposes collagen
AcLvated platelet
• Vascular damages exposes collagen • Platelets bind collagen
What are platelets?
What are platelets?
• Vascular damages exposes collagen • Platelets bind collagen • Promotes platelet acLvaLon & aggregaLon
Overview
1. What are platelets? 2. Platelet receptors 3. The hallmarks of cancer 4. Metastasis 5. Evasion of the immune system 6. ExtravasaLon
collagen
VWF
Platelet Receptors
Platelet
Platelet Receptors
GP1b-‐V-‐IX
VWF
collagen
Platelet Receptors
GP1b-‐V-‐IX GPVI
VWF
collagen
Platelet Receptors
ResLng integrins
GP1b-‐V-‐IX GPVI
VWF
collagen
AcLvaLon
GP1b-‐V-‐IX GPVI
Platelet Receptors
VWF
collagen
Platelet Receptors
Fibrinogen
GP1b-‐V-‐IX GPVI
VWF
collagen
VWF
GP1b-‐V-‐IX GPVI
VWF
collagen
Platelet Receptors
Fibrinogen
ADP
TxA2
VWF
Platelet aggregaLon
Platelet aggregate
Overview
1. What are platelets? 2. Platelet receptors 3. The hallmarks of cancer 4. Metastasis 5. Evasion of the immune system 6. ExtravasaLon
The Hallmarks of Cancer
Hanahan, D. et al., (2011). Hallmarks of Cancer: The Next GeneraLon, Cell. 144(5): 646-‐674
The Hallmarks of Cancer
Genome instability and mutaLon
Hanahan, D. et al., (2011). Hallmarks of Cancer: The Next GeneraLon, Cell. 144(5): 646-‐674
The Hallmarks of Cancer
Genome instability and mutaLon
Evasion of programmed cell death
Hanahan, D. et al., (2011). Hallmarks of Cancer: The Next GeneraLon, Cell. 144(5): 646-‐674
The Hallmarks of Cancer
Genome instability and mutaLon
ReplicaLve immortality
Hanahan, D. et al., (2011). Hallmarks of Cancer: The Next GeneraLon, Cell. 144(5): 646-‐674
Evasion of programmed cell death
The Hallmarks of Cancer
Hanahan, D. et al., (2011). Hallmarks of Cancer: The Next GeneraLon, Cell. 144(5): 646-‐674
Genome instability and mutaLon
ReplicaLve immortality
Ability to metastasise
Evasion of programmed cell death
Overview
1. What are platelets? 2. Platelet receptors 3. The hallmarks of cancer 4. Metastasis 5. Evasion of the immune system 6. ExtravasaLon
Metastasis
Metastasis
Metastasis LymphaLc system
Metastasis LymphaLc system
Metastasis LymphaLc system
Metastasis LymphaLc system
Metastasis
• Cannot predict when this will occur
LymphaLc system
Metastasis LymphaLc system
• Cannot predict when this will occur
• Cannot predict where this will occur
Metastasis LymphaLc system
• Cannot predict when this will occur
• Cannot predict where this will occur
• MulLple tumours possible
The Hallmarks of Cancer
Hanahan, D. et al., (2011). Hallmarks of Cancer: The Next GeneraLon, Cell. 144(5): 646-‐674
Genome instability and mutaLon
ResisLng cell death
ReplicaLve immortality
Ability to metastasize
The Hallmarks of Cancer
Hanahan, D. et al., (2011). Hallmarks of Cancer: The Next GeneraLon, Cell. 144(5): 646-‐674
Genome instability and mutaLon
ResisLng cell death
ReplicaLve immortality
Ability to metastasize
Immune evasion
Overview
1. What are platelets? 2. Platelet receptors 3. The hallmarks of cancer 4. Metastasis 5. Evasion of the immune system 6. ExtravasaLon
Evasion of the Immune System
Evasion of the Immune System
• Only 0.1% of tumour cells survive in the circulaLon
Evasion of the Immune System
• Only 0.1% of tumour cells survive in the circulaLon
• Platelets protect tumour cells from the immune system
Tumour cell
Podoplanin ligand
Evasion of the Immune System
AcLvated platelet
Podoplanin ligand
CLEC-‐2
Evasion of the Immune System
Tissue factor
Thrombin
Podoplanin ligand
CLEC-‐2
Evasion of the Immune System
Tissue factor
Thrombin
Podoplanin ligand
CLEC-‐2
G-‐protein coupled receptor
Evasion of the Immune System
Tissue factor
Thrombin
Podoplanin ligand
CLEC-‐2
G-‐protein coupled receptor P-‐SelecLn P-‐SelecLn receptor (PGSL-‐1)
Evasion of the Immune System
Tissue factor
Thrombin
Podoplanin ligand
CLEC-‐2
G-‐protein coupled receptor P-‐SelecLn P-‐SelecLn receptor (PGSL-‐1)
Evasion of the Immune System
Tissue factor
Thrombin
ADP
ADP
ADP
ADP
Platelet acLvaLon Platelet acLvaLon
Platelet acLvaLon
Tissue factor
Thrombin
ADP
ADP
ADP
ADP
Down-‐regulate expression of NK cell receptors
Natural Killer cell
Significance of Podoplanin / CLEC -‐2
Podoplanin ligand
CLEC-‐2
Significance of Podoplanin / CLEC -‐2
Podoplanin ligand
CLEC-‐2
MS-‐1 AnLbody
Significance of Podoplanin / CLEC -‐2
• AnL-‐podoplanin anLbody
Takagi, S., Sato, S., Oh-‐hara, T., et al., (2013) Platelets promote tumor growth and metastasis via direct interacLon between Aggrus/podoplanin and CLEC-‐2, PLos One. 8(8): 73609
Significance of Podoplanin / CLEC -‐2
• AnL-‐podoplanin anLbody
Takagi, S., Sato, S., Oh-‐hara, T., et al., (2013) Platelets promote tumor growth and metastasis via direct interacLon between Aggrus/podoplanin and CLEC-‐2, PLos One. 8(8): 73609
Significance of Podoplanin / CLEC -‐2
• AnL-‐podoplanin anLbody
• Reduces experimental metastasis
Takagi, S., Sato, S., Oh-‐hara, T., et al., (2013) Platelets promote tumor growth and metastasis via direct interacLon between Aggrus/podoplanin and CLEC-‐2, PLos One. 8(8): 73609
Significance of Podoplanin / CLEC -‐2
• AnL-‐podoplanin anLbody
• Reduces experimental metastasis and spontaneous metastasis
Takagi, S., Sato, S., Oh-‐hara, T., et al., (2013) Platelets promote tumor growth and metastasis via direct interacLon between Aggrus/podoplanin and CLEC-‐2, PLos One. 8(8): 73609
• AnL-‐podoplanin anLbody
• Reduces experimental metastasis and spontaneous metastasis
• May not impair hemostasis and clofng
Significance of Podoplanin / CLEC -‐2
Takagi, S., Sato, S., Oh-‐hara, T., et al., (2013) Platelets promote tumor growth and metastasis via direct interacLon between Aggrus/podoplanin and CLEC-‐2, PLos One. 8(8): 73609
Overview
1. What are platelets? 2. Platelet receptors 3. The hallmarks of cancer 4. Metastasis 5. Evasion of the immune system 6. ExtravasaLon
ExtravasaLon
Integrins P-‐SelecLn
ExtravasaLon
Integrins P-‐SelecLn
ExtravasaLon
• Platelets sLmulate endothelial cells
Integrins P-‐SelecLn
Growth factors
ExtravasaLon
Integrins P-‐SelecLn
• Platelets sLmulate endothelial cells • Vascular permeability increased
ExtravasaLon
Integrins P-‐SelecLn
• Platelets sLmulate endothelial cells • Vascular permeability increased • Tumour cells proliferate
ExtravasaLon
Integrins P-‐SelecLn
Blood vessel formaLon • Platelets sLmulate endothelial cells • Vascular permeability increased • Tumour cells proliferate
VEGF
ExtravasaLon
• Platelets sLmulate endothelial cells • Vascular permeability increased • Tumour cells proliferate
References • Stegner, D., Düfng, S. and Nieswandt, B., (2014) MechanisLc explanaLon
for platelet contribuLon to cancer metastasis, Thrombosis Research. 133(2): 149-‐157
• Erpenbeck, L. & Schön, M.P., (2010) Deadly allies: the fatal interplay
between platelets and metastasizing cancer cells, Blood. 115 (17): 3427-‐3436
• Takagi, S., Sato, S., Oh-‐hara, T., et al., (2013) Platelets promote tumor growth and metastasis via direct interacLon between Aggrus/podoplanin and CLEC-‐2, PLos One. 8(8): 73609
