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
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.