SummaryMalignant brain tumors, such as glioblastoma, are characterized by extensive angiogenesis and permeability of the blood-brain barrier (BBB). The infiltration of glioma cells away from the primary tumor mass is a pathological characteristic of glial tumors. The infiltrating tumor cells represent a significant factor in tumor recurrence following surgical debulking, radiation, and chemotherapy treatments. Vascular endothelial growth factor (VEGF)-mediated vascular permeability (VP) has been associated with the progression of glioma tumor growth and infiltration into surrounding normal brain parenchyma. While VEGF induces a robust VP response in control mice (src +/+ or src +/− ), the VP response is blocked in src −/− mice that demonstrate a 'leakage-resistant phenotype' in the brain. We used the Src-deficient mouse model to determine the role of Src in the maintenance of the BBB following orthotopic implantation and growth of glioma cells in the brain. Although solid tumor growth was the same in control and src −/− mice, the infiltrating component of glioma growth was reduced in src −/− mice. Characterization of the expression and localization of the extracellular matrix (ECM) protein fibrinogen was evaluated to determine the effect of a Src-mediated VP defect in the host compartment. These studies indicate that the reduced VP of host brain blood vessels of src −/− mice mediates a reduction in glioma cell invasion in a mouse brain tumor xenograft model.

Direct proliferative effects of estrogen (E 2 ) on estrogen receptor-positive tumors are well documented; however, the potential for E 2 to mediate effects selective for the host (i.e., angiogenesis, vascular permeability, or stromal effects), which influence tumor growth and/or metastasis, has received less attention. In this study, we examine the capacity for E 2 to promote tumor growth and/or metastasis independent of direct effects on tumor cells. In these studies, we distinguish host versus tumor compartment components of E 2 action in tumor growth and metastasis by analysis of E 2 -nonresponsive tumor cells implanted in ovariectomized (OVX) mice that contain s.c. implants of placebo (OVX) or E 2 -containing slowrelease pellets (OVX + E 2 ). We show that the D121 lung carcinoma cell line is E 2 -nonresponsive, and following s.c. implantation in OVX versus OVX + E 2 mice, E 2 action on the host compartment leads to an increase in spontaneous metastasis but not primary tumor growth or neovascularization. Similarly, experimental lung metastasis of E 2 -nonresponsive 4T1 mammary carcinoma cells also leads to increased tumor burden in the lungs of OVX + E 2 mice. These results suggest that the E 2 status of the host compartment influences late steps in tumor cell metastasis that can provide important insights into the role of E 2 in the tumor versus host compartments. (Cancer Res 2006; 66(7): 3667-72)