Possible Pathophysiological Role of Vascular Endothelial Growth Factor (VEGF) and Matrix Metalloproteinases (MMPs) in Metastatic Brain Tumor-associated Intracerebral Hemorrhage

Abstract

Intratumoral hemorrhage, as one of the cerebrovascular complications in various tumor-related conditions, occurs mainly in malignant brain tumors. Recent studies have shown that the overexpression of vascular endothelial growth factor (VEGF) and metalloproteinase (MMP) may play a role for the loss of vascular integrity and the subsequent hemorrhage in several instances, in addition to their well-known properties in tumor development and metastasis. To investigate the potential role of VEGF and MMP in hemorrhagic complication of metastatic brain tumor, we estimated the expression of VEGF, MMP-2 & -9 by immunohistochemical studies in pathological specimens of metastatic brain tumors obtained from 16 patients, 7 in hemorrhagic and 9 in non-hemorrhagic group. We also examined the expression of collagen type IV, CD34, Factor VIII in order to evaluate the status of tumor vasculature. Patients in hemorrhagic group showed a higher VEGF expression with neovascularization than those in non-hemorrhagic group. The basement membranes of newly formed vessels were disrupted in cases with high expression in both MMP-2 and -9. These results indicate that rapid growing nascent blood vessels, responding vigorously to VEGF, are concentrated around the hemorrhagic tumors. Besides, these results suggest a possibility that the basement membranes of these nascent vessels could be disrupted proteolytically by MMP. We conclude that overexpression of VEGF and MMP may play a role in metastatic brain tumor-associated hemorrhage. Presumably, the underlying pathophysiological mechanisms are through rapid growth and breakdown of vessels around the tumors caused by overexpression of VEGF and MMP of tumor cells.