Moreover, the extent of the EPR effect is affected by the intricate interaction between tumor cells and stromal compartment (consisting of extracellular matrix and stromal cells), and the deregulated production of angiogenic and cytokines molecules (e.g., vascular endothelial growth factor, hypoxia-inducible factor 1-alpha, bradykinin, nitric oxide, peroxynitrite, prostaglandins, interleukins, and interferons) in the tumor microenvironment.28,54. This evidence concerns the gene HIF1A and neoplasm.