טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentAlishekevitz Dror
SubjectThe Impact of Blocking VEGF Pathways on Tumor Re-growth and
Metastasis Following Chemotherapy
DepartmentDepartment of Medicine
Supervisor Professor Yuval Shaked
Full Thesis textFull thesis text - English Version


Abstract

Chemotherapy is one of the main treatment modalities for cancer. While it has been shown that it effectively eradicate tumor cells, tumor re-growth or spread at distant sites is eventually observed. It has been demonstrated that tumor cells acquired resistance to the therapy and that could explain the re-growth of tumors. However, growing body of evidence revealed that the host in response to therapy generated pro-tumorigenic and pro-metastatic effects which in turn could promote tumor relapse and aggressiveness. In this thesis we studied two aspects of host response to therapy on tumor growth with the focus on VEGF and VEGF receptor pathways. We asked whether such host response effects can be blocked by disrupting any of these pathways. Here we show that a combined treatment with anti-VEGF-A and folinic acid/5-fluorouracil/oxaliplatin (FOLFOX) but not with anti-VEGF-A and gemcitabine/cisplatinum (Gem/CDDP) enhances the treatment outcome partly due to reduced angiogenesis, in both primary tumors and in experimental lung metastases models. However, neither treatment group exhibited an improved treatment outcome in the spontaneous lung metastases model nor were changes in endothelial cell numbers found at metastatic sites. Since chemotherapy has recently been shown to induce tumor cell invasion, we tested the invasion properties of tumor cells when exposed to plasma from FOLFOX-treated mice or cancer patients. While plasma from FOLFOX-treated mice or patients induced invasion properties of tumor cells, the combination of anti-VEGF-A and FOLFOX abrogated these effects, despite the reduced plasma VEGF-A levels detected in FOLFOX-treated mice. Over all our results show that therapeutic benefit of VEGF-A blockade has strong correlation with the tumor stage and model.

Additional growth factor investigated in this study is the pro-lymphangiogenic growth factor, VEGF-C, which was highly expressed in plasma of PTX-treated mice. Plasma from PTX-treated mice induced migration, invasion, and tube formation of lymphatic endothelial cells when compared to plasma from control mice. In both 4T1 breast and Lewis lung carcinomas an increased number of lymphatic vessels positioned at the center of tumors were found in PTX-treated mice when compared to tumors from control mice, in which the lymphatic vessels positioned only at the tumor periphery. Since VEGFR3 is a major receptor for VEGF-C-induced lymphangiogenesis, we evaluated the therapeutic effect of anti-VEGFR3 blocking antibody (31C1) in combination with PTX. 4T1 bearing mice treated with PTX? exhibited a decline in primary tumor growth and inhibition of metastases when compared to mice treated with PTX monotherapy.