Role of Vessel Maturity in Antiangiogenic Drug Efficacy

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DESCRIPTION (provided by applicant): Tumor growth is angiogenesis dependent yet tumor responses to angiogenesis inhibitors vary unpredictably. We propose that a dominant variable governing a tumor's response to these drugs is the maturation state of its vasculature. Anti-angiogenic agents target growing and newly formed vessels, while established ones are unaffected. We hypothesize that tumors with a greater proportion of established vessels may be less responsive to anti-angiogenic agents than those with more immature vessels. This work extends from our earlier studies in adipose tissue showing that vascular maturation is a determinant of a tissue's capacity to remodel. We demonstrated that a relatively immature vasculature is necessary to preserve adipose tissue plasticity after development. We further found that angiogenesis inhibitors selectively reduce adipose tissue mass in obese mice, while other organs are unaffected. We propose that vascular maturation is a regulator of a tissue's susceptibility to antiangiogenic agents has potential prognostic and therapeutic implications for the use of these agents in cancer therapy. Recognizing that tumors encompass highly diverse, genetically unstable pathologies, a second model of angiogenesis-dependent growth will be studied in parallel with tumor bearing mice. Adipose tissue, like tumors, has a substantial growth capacity, relatively immature vasculature, and is susceptible to angiogenesis inhibitors. However, it is a non-transformed, normal tissue with tightly regulated, stable growth patterns. Comparing both models is expected to reveal common mechanism relating vessel maturation with tissue remodeling and responses to angiogenesis inhibitors. We will characterize vascular maturation in terms of molecular (angiopoietin/tie system) and cellular (pericytes) markers and examine the effect of perturbing this parameter on tissue susceptibility to angiogenesis inhibitors in tumor bearing mice and in obese mice. Understanding this relationship may enable a more predictable, effective use of angiogenesis inhibitors for the treatment of cancers.