1. TGF-β Receptor I/ ALK-5 and Pancreatic and Biliary Cancer
Charles Queen

2. Activin Receptor-Like Kinase 5
Most common TGF-β type I receptor
Receptor Serine/Threonine Kinase
Recruited and Activated by TGF-β RII
Phosphorylated in GS domain

3. TGF-β Pathway

4. Normal Pathway Function
Tumor suppressor
Inhibit proliferation
G1 arrest by p15
Induce apoptosis
Promote differentiation

5. ALK-5 Knockout Mice Model
Die at midgestation
Severe defects in vascular development of the yolk sac and placenta
Absence of circulating red blood cells
Severe growth retardation

6. Role in Cancer Progression
Tumors increase TGF-β (ligand) production
TGF-β can induce epithelial-mesenchymal transition
Endothelial cells respond to TGF-β signal by upregulating angiogenesis
TGF-β suppresses proliferation and differentiation of lymphocytes

7. Somatic Loss of Heterozygosity in Pancreatic and Biliary Cancer
LOH occurs in ~1% of pancreatic tumors
LOH occurs in ~8% of biliary cancer tumors

8. Pancreatic Cancer -Silent Killer -Nearly twice as common in men
-Resistant to chemotherapy agents

9. Biliary Cancer Often only diagnosed in advanced stages
As tumor grows, it may disrupt bile flow
Surgery is the main treatment

10. Summary Serine/threonine kinase Tumor suppressor
Important in vascular development especially branching of blood vessels
ALK-5 LOH can cause pancreatic and biliary cancer
Pancreatic and biliary cancers often go detected until they reach advanced, metastatic stages of cancer