Molecular regulation of angiogenesis during tumor progression

Children'S Hospital Boston, Boston MA

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Abstract

Significant progress has been made in understanding the process of angiogenesis, however relatively little is known about the molecules and mechanisms that initiate the acquisition of the angiogenic phenotype during tumor progression. We have recently established an in vivo tumor model that reliably recapitulates the transition from the pre-angiogenic to the angiogenic phenotype. Using this model,we have reported that MMPs, VEGF, bFGF and HIF-1alpha play an important role in activatingthe angiogenic program. Through transcriptional profiling of pre-angiogenic and angiogenic tumor nodules, we have identified and verified the differential expression of specific transcription factors, one of whichis ZNF24, a Cys2/His2 transcription factor, in this model and a second tumor system in which IVlDA-MB231 human breast carcinoma cells were studied under hypoxicand norrnoxic conditions,we found that ZNF24 is a negative regulator of VEGF expression in tumor cells. These studies lead us to hypothesize that ZNF24, and perhaps other members of the Cys2/His2 transcription factor family, regulate VEGF expression during the initiation of angiogenesis. The expedments proposed in Aim 1 will test this hypothesis. In addition to identifying the mechanisms that activate the angiogenic program,we will identify molecular markers that might predict this on set of neovascularization during tumor progression. in Aim 2, we will determine whether urinary MMPs, alone or in combination with urinaryVEGF and bFGF, are useful in predicting the initiation of angiogenesis during tumor progression.This approach is based on our past findings that the presence of urinary MMPs can predict disease status in patients suffering from a variety of established human cancers. The experimental goals of this proposal will be addressed in the following Specific Aims: 1.To determine the role of ZNF24 and other Cys2/His2 zinc finger transcription factors during the transition to the angiogenic phenotype. 2.To determine whether urinary MMPs and other regulators of angiogenesis are predictive of the transition to the angiogenic phenotype during tumor progression.