טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentVoloshin-Sela Tali
SubjectAnalysis of Host Molecular Responses to Cancer Therapy as
Possible Contributors to Tumor Angiogenesis and
Metastases Growth
DepartmentDepartment of Medicine
Supervisor Professor Yuval Shaked
Full Thesis textFull thesis text - English Version


Abstract

One of the major obstacles in clinical oncology is that tumors may eventually relapse and metastasize. While most of the studies focus on the mechanisms by which tumor resistance to therapy is acquired by malignant cells, in our studies, we searched for possible mechanisms originate in the host, which contribute to tumor relapse and metastatic spread. We found that several cytokines and growth factors known to promote angiogenesis and cell proliferation are significantly over-expressed in the plasma of mice treated with paclitaxel (PTX) chemotherapy; among those are G-CSF and IL-1β. Focusing on G-CSF as a factor known to minimize the myelosuppressive effects of chemotherapy, we shown that exogenous administration of G-CSF to mice bearing either Lewis lung or EMT-6 breast carcinoma following treatment with PTX, resulted in inferior therapy efficacy, due in part to induction in systemic angiogenesis mediated by various types of bone marrow derived cells (BMDCs). We identified an alternative agent to that of G-CSF which, on one hand, mobilizes BMDCs and therefore reduces the myelosuppressive effects of PTX, and on the other hand, lack the pro-angiogenic activity found in G-CSF-treated tumors. Using AMD-3100 (MozobilÒ)- a small molecule drug antagonist of CXCR4 which like G-CSF can be used to mobilize hematopoietic cells - we demonstrated that the combination of AMD-3100 with PTX resulted in enhanced treated outcome, due in part to a significant reduction in angiogenesis. Overall, our results suggest that both exogenous and endogenous G-CSF induced following PTX chemotherapy promote tumor cell repopulation via systemic angiogenesis, an effect which can minimized when AMD-3100 is used. While continue focusing on PTX chemotherapy, we identified another factor which was highly expressed in the plasma of PTX treated mice i.e., IL-1β. The induction of IL-1β following PTX treatment promoted tumor cell invasion in vitro, an effect which was blocked by Anakinra (KineretÒ) - an IL-1 receptor antagonist. However, Blocking IL-1β, or its receptor, in mice, although resulted in primary tumor growth retardation, it has also accelerated metastasis spread. We found that tumors from mice treated with combined therapy of PTX and Anakinra exhibited increased number of M2 macrophages and vessel leakiness when compared to PTX monotherapy treated mice, indicating a pro-metastatic role of M2 macrophages in the post-treated IL-1β deprived microenvironment. Taken together, our results suggest that in addition to the anti-tumor activity of chemotherapy it may induce host pro-tumorigenic and pro-metastatic effects which can negate the efficacy of the therapy.