טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentMunster Mijal
SubjectRole of microparticles in tumor growth and angiogenesis
following cytotoxic drug therapy
DepartmentDepartment of Medicine
Supervisor Professor Yuval Shaked
Full Thesis textFull thesis text - English Version


Abstract

Rebound angiogenesis is commonly seen following treatment with maximum tolerated dose (MTD) chemotherapy. Our previous studies demonstrated that acute mobilization and tumor homing of bone marrow derived endothelial precursor cells promote angiogenesis, and subsequent tumor regrowth. Since microparticles (MPs) - small fragments of plasma membrane released by activated cells extracted from circulating blood of cancer patients - can support tumor growth, we asked whether they also participate in rebound angiogenesis following MTD chemotherapy. The aim of our study was to evaluate the impact of tumor derived MPs following exposure to chemotherapy and/or antiangiogenic drug on angiogenesis and study whether MPs can explain the rapid tumor cell repopulation found after such therapy. Our results show that tumor cells exposed to paclitaxel (PTX) chemotherapy exert increased number of MPs. These MPs are more proangiogenic then MPs extracted from control group, as they express increased levels of VEGF, when compared to MPs from control cells. Furthermore, we found that MPs derived from tumor cells exposed to chemotherapy recruit higher numbers of BMDCs to Matrigel plugs implanted in mice but had minor effects on microvessel density assessed by CD31 immunostaining. Moreover, MPs intravenously injected to the tail vein of mice resulted in an increased mobilization of BMDCs to peripheral blood and an induction in bone-marrow cell migration using the modified Boyden Chamber assay. Interestingly, MPs derived from tumor cells exposed to chemotherapy inhibited endothelial cell migration, invasion, and microvessel sprouting. The combination of an anti-angiogenic drug - a VEGF neutralizing antibody - with paclitaxel significantly reduced the VEGF content in MPs, and as a result diminished the colonization of BMDCs in Matrigel plugs, the mobilization of BMDCs to peripheral blood and its angiogenic activity. These results suggest that MPs derived from tumor cells can induce systemic vasculogenesis, but may not affect local angiogenesis following chemotherapy. The addition of an anti-angiogenic therapy alternates the proangiogenic properties of MPs and therefore inhibits rebound angiogenesis and/or vasculogenesis. Our results further demonstrate yet another possible mechanism to explain how antiangiogenic drug, indirectly, can inhibit systemic angiogenesis induced by MPs.