טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentAmit Moran
SubjectThe Influence of Tumor-Associated Macrophages on Pancreatic
Adenocarcinoma Neural Invasion
DepartmentDepartment of Medicine
Supervisor Professor Ziv Gil
Full Thesis textFull thesis text - English Version


Abstract

Tumor spread along nerves, a phenomenon known as perineural invasion, occurs in almost all cases of pancreatic ductal adenocarcinoma (PDAC). Cancer nerve invasion is also common in head and neck, prostate, breast, and gastrointestinal carcinomas. Intra and extra pancreatic nerves serve as conduits for tumor spread, and at the time of PDAC diagnosis most patients are inoperable due to the involvement of extra-pancreatic structures surrounded by these nerves. Perineural spread also induces intractable pain, which contributes to significant morbidity and deteriorated quality of life. Although neural invasion is associated with poor outcome, the mechanism that triggers this phenomenon is unknown.

RET is a well-recognized oncogene, but its role in the development and progression of PDAC is unclear. We provide studies of human specimens and in vivo genetic evidence demonstrating the activation of RET by perineural macrophages in PDAC carcinogenesis, and define its role as a mediator of cancer perineural invasion.

Endoneurial F4/80 macrophages expressing the RET ligand- GDNF are recruited from the bone marrow and infiltrates nerves invaded by cancer. Deletion of GDNF in bone marrow derived endoneurial macrophages or inhibition of their recruitment with GW2580 to the tumor microenvironment reduces perineural invasion. Deletion of RET in PDAC or its pharmacological inhibition reduces perineural invasion. Studies of human specimens shows RET over expression in premalignant and cancerous tissue of PDAC. Development of a new transgenic model consistent with hyper functional RET, demonstrate that RET activation mutation induces PDAC and neural invasion in the background of P53 inactivation.

Taken together, our findings show that the RET oncogene and its ligand GDNF are key regulators of cancer perineural invasion. The infiltration of bone marrow derived endoneurial macrophages and the secretion of GDNF are essential event in PDAC nerve invasion. These findings identify GDNF/RET pathway as a target for TK inhibitors, which may be used in combination with conventional modalities or as a single agent to reduce the morbidity associated with cancer neural spread.