PublisherThe University of Arizona.
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AbstractCancerous tumors have an irregular and chaotic vascular system that poorly deliver oxygen to target tissues. Local oxygen deficiency, or hypoxia, acts as a critical barrier to chemotherapeutic and radiation treatment methods, which both rely on adequate circulation for efficacy. Tumors also exhibit enhanced release of Vascular Endothelial Growth Factor (VEGF), which can disrupt conducted signaling along endothelial cells lining vessel walls. We propose that a primary cause of vascular malformation is the impairment of anti-shunt mechanisms, specifically the loss of conducted responses. We use a theoretical model for 3-dimensional growth (angiogenesis), remodeling (structural adaptation), and elimination (pruning) of microvascular networks in early stage tumors (dimensions of 1 mm x 1 mm x 200 μm). We simulate conditions of the tumor microenvironment by elevating the release of a pro-angiogenic factor (VEGF) from an exponentially expanding spherical volume. We find that the reduction of conducted responses decreases oxygen levels. However, the deficiency was not to the extent of hypoxia observed in tumors, because the model also generated higher vascular densities than physiological. Considering the effect of other growth factors including angiopoietin-2, a destabilization factor upregulated in tumors, may resolve this discrepancy. Future work is necessary to determine the effect of impaired conducted responses on the development of tumor microvascular networks.
Degree ProgramPhysiology and Medical Sciences