Sensitizing tumor vascular endothelial cells to anti-angiogenic therapy.
Published: 2004
Language: eng
Number of pages: 152
Description: The expansion of a tumor mass beyond microscopic sizes is largely contingent on the recruitment of a vascular network. Interference of this angiogenic process impedes the delivery of nutrients and oxygen to the tumor such that tumors often stop growing, and in certain cases even start regressing. Unlike conventional anti-cancer strategies that directly target the tumor compartment, various anti-angiogenic strategies are instead directed towards the vascular compartment. Because the endothelial cells (ECs) that comprise the tumor vessels are genetically stable, such therapies would presumably circumvent or significantly delay acquired drug resistance, a major limitation of current therapies.Together, these studies show that the abundance of angiogenic growth factors within the tumor mass may provide robust survival signals for vascular ECs, which in turn appear to be drug resistant. Because this drug resistance mechanism is not driven by EC genetic mutations, it is expected that specifically abrogating EC survival mechanisms would sensitize ECs to a number of anti-angiogenic treatment strategies. Hence, these studies provide a rationale for the judicious combination of anti-angiogenic strategies with agents that interfere with EC survival. Such strategies could include the use of conventional chemotherapeutic drugs, particularly microtubule inhibitors such as paclitaxel, taxotere, vinblastine and epothilone B, as de facto antioangiogenic EC targeting agents.We further show that VEGF, particularly when combined with bFGF, allows vascular ECs to resist the cytotoxic effects of various chemotherapeutic drugs including tubulin-interfering and DNA damaging agents. Moreover, in the absence of any vascular growth factors, the overexpression of survivin could recapitulate this phenomenon while the overexpression of a dominant-interfering mutant of survivin could abrogate VEGF-mediated survival. Thus, it is possible that VEGF promotes EC chemoresistance primarily, or at least in part, though the induction of survivin.Here, we show that the high concentration of survival factors present within the tumor microenvironment may permit ECs to survive in otherwise cytotoxic conditions. Indeed, we and others show that various angiogenic growth factors, including Vascular Endothelial Growth Factor (VEGF), can induce a robust survival response in ECs secondary to the activation of downstream survival pathways. In particular, the activation of the survivin pathway is shown to play a pivotal role in the survival of ECs as a result of activation by various angiogenic factors including VEGF and basic fibroblast growth factor (bFGF) and more recently angiopoietin 1 (Ang1) and placental-like growth factor (PlGF).
Notes: Adviser:  Robert S. Kerbel.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-10, Section: B, page: 5003.