טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentRachman Chen
SubjectHost Response to Tumor Resection and its Impact on
Metastasis
DepartmentDepartment of Medicine
Supervisors Professor Peleg Hasson
Professor Yuval Shaked
Full Thesis textFull thesis text - English Version


Abstract


Metastasis remains the cause of over 90% of cancer-related deaths; which makes it a major obstacle in cancer treatment. The formation of pre-metastatic niches in secondary organs adds complexity to the challenge of curing metastatic disease. Surgery is still one of the main treatment modalities of cancer. It is sometimes complementary to chemotherapy, radiation and/or new targeted anti-cancer drugs. In this study we evaluated the host reaction to surgery and its impact on metastasis and angiogenesis. Our results show that plasma from mice undergo surgery promotes cancer aggressiveness by means of an induction in angiogenesis, tumor cell invasion, migration, epithelial to mesenchymal transition (EMT) and an upregulation of MMP9 when compared to plasma from control mice. In-vivo, assessment of metastasis spread by using an experimental lung metastasis assay via tail vein injection, revealed that mice undergo surgery and subsequently injected with tumor cells succumb to extensive metastasis in the lungs when compared to control mice injected with tumor cells. Similar results were observed when the mice did not undergo surgery but were ‘preconditioned’ with plasma from mice undergo surgery when compared to plasma from control mice. Ex-vivo analysis of the pre-metastatic lungs indicated that extra cellular matrix (ECM) remodeling occurs in the lungs following surgery. Since Lysyl Oxidase (LOX) is an extracellular enzyme that catalyzes cross-linking of collagen and elastin, it contributes to ECM remodeling. Lungs from mice undergo surgery exhibited overexpression of LOX and LOXl2 enzymes when compared to control mice. Using a LOX activity assay revealed that a day after surgery, increased LOX activity was found in the lungs in such mice when compared to control mice. The inhibition of LOX family by β-aminopropionitrile (BAPN) or by neutralizing antibodies against LOX or LOXl2 hindered the pro-metastatic effects of surgery and blocked the seeding of metastatic tumor cells in the lungs. Furthermore, utilizing a clinically oriented model of breast cancer in order to test the impact of surgery on metastasis spread was performed. We found that at the time of primary tumor resection the mice treated with BAPN survived longer than mice treated with PBS. These results indicate that targeting LOX concomitantly with surgery may improve treatment outcomes. Taken together our results emphasize the critical role of LOX in the reactive host following surgery, and support the notion that LOX is an appropriate molecule to target in patients that undergoes tumor resection.