טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentNa'ara Shorook
SubjectThe Role of L1 Cell Adhesion Molecule in Neural Invasion of
Pancreatic Cancer
DepartmentDepartment of Medicine
Supervisor Professor Ziv Gil
Full Thesis textFull thesis text - English Version


Abstract

Cancerous neural invasion (CNI) is the process of neoplastic invasion of nerves. While it's a known route of tumor dissemination, CNI is also related to poor outcomes.  Pancreatic ductal adenocarcinoma (PDAC) cells have this tendency to invade along nerves with prevalence of 80-100%. 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. However, the exact mechanism that drives cancer cells to disseminate along nerves is unknown.

L1 cell adhesion molecule (L1CAM) is a 200-220kDa transmembrane glycoprotein of the immunoglobulin superfamily. In many human cancers, L1CAM is constitutively over-expressed, and its expression is generally associated with poor prognosis and metastases formation. Immunohistochemical analysis of human pancreatic ductal adenocarcinoma (PDAC) specimens showed overexpression of L1CAM in cancer cells in the perineural niche as well as in adjacent Schwann cells (SC). The expression level was significantly higher in the invaded nerves compared to non-invaded nerves. By modeling the neural microenvironment, we found that L1CAM secreted from SCs acts as a strong chemoattractant to cancer cells, through activation of MAP kinase signaling. L1CAM also upregulated expression of metalloproteinase-2 (MMP-2) and MMP-9 by PDAC cells, through STAT3 activation. Using a transgenic Pdx-1-Cre/KrasG12D /p53R172H (KPC) mouse model, we show that treatment with anti-L1CAM Ab significantly reduces CNI in vivo.