Date of Graduation
8-2014
Document Type
Dissertation (PhD)
Program Affiliation
Cancer Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Candelaria Gomez-Manzano, M.D.
Committee Member
Gary Gallick, Ph.D.
Committee Member
Sadhan Majumder, Ph.D.
Committee Member
Russell Broaddus, M.D., Ph.D.
Committee Member
Carlos Caulin, Ph.D.
Abstract
Strong pre-clinical and clinical data supporting the effectiveness of bevacizumab, a humanized monoclonal anti-VEGF antibody, for the treatment of gliomas led to its accelerated approval for the treatment of patients with recurrent glioma. However, despite strong anti-tumor effects, upon treatment with bevacizumab, patients will invariably recur with a tumor characterized by enhanced invasiveness and resistance to therapy. This study aims to elucidate the mechanisms leading to this enhanced malignancy with the hope of uncovering new potential therapeutic targets for combined treatment. Using tissue sections from U87-derived glioma bearing mice treated with or without aflibercept (another anti-VEGF antibody) we have gathered evidence of a significant increase in the number of Tie2 expressing monocytes (TEMs) within the tumor after treatment, particularly around areas of invasion. TEMs are a pro-angiogenic subset of circulating monocytes that express the Tie2 receptor. Our data demonstrates that TEMs have higher expression and activity of pro-invasive molecules, such as MMP2 and MMP9, than their Tie2 negative counterparts and are able to increase glioma cell invasion in vitro, suggesting an active role of these cells in the invasive process observed after treatment. Furthermore, we have shown that expression of angiopoietin 2 (Ang2), a Tie2 ligand, is dramatically increased in the periphery of the tumor after aflibercept treatment. Interestingly, our data provides evidence that Ang2 is chemoattractant to TEMs, both in vitro and in vivo suggesting a potential mechanism of recruitment of these cells to the tumor. These data suggests an active role of the Ang-Tie2 pathway, and in particular Ang2, in the invasive recurrence of GBM following anti-VEGF therapy and that targeting it in combination with anti-VEGF therapy could lead to improved outcomes. Supporting this idea, we were able to observe a dramatic decrease in the invasive phenotype after anti-VEGF treatment when we inhibited the Ang-Tie2 pathway in combination with an anti-VEGFR antibody. These results have important implications for patients with GBM since a decrease in the invasive pattern upon recurrence after anti-angiogenesis therapy could potentially render the tumors amenable to surgical excision upon recurrence. This in turn can lead to improved patient survival.
Keywords
Tie2 expressing monocytes, Ang2, angiopoietin-2, glioma, glioblastoma, angiogenesis, bevacizumab, anti-angiogenesis, invasion, tumor microenvironment