Blood vessels in solid tumors are structurally and functionally aberrant compared to vessels in normal tissue. To elucidate the nature of these abnormal features, we examined endothelial cells derived from human glioblastoma tumors. Our results provide the first demonstration that tumor-derived brain endothelial cells (TuBEC) have properties of senescent cells. Primary cultures of TuBEC exhibit senescence-associated β-galactosidase staining, cell cycle arrest at G0/G1, and increased levels of the cell cycle inhibitors p21 and p27, compared to normal brain endothelial cells (BEC). In addition, glioblastoma tissue sections expressed senescence-associated β-galactosidase, in contrast to normal brain tissue which was negative. TuBEC also demonstrate decreased expression of cyclin A and increased expression of cyclin D1 and the tumor suppressor protein p53. In addition, TuBEC demonstrate resistance to cytotoxic and cytostatic drugs currently used for glioblastoma treatment, and increased production of growth factors, such as PDGF. Furthermore, long-term culture of BEC in glioma cell conditioned media induced the appearance of β-galactosidase positive cells in the BEC population. These findings propose a novel aspect of tumor-endothelial cell interaction, whereby tumors not only stimulate angiogenesis, but also induce endothelial cells to become senescent. Thus, these results suggest that anti-angiogenic therapies need to target the unique tumor-associated endothelial cells population as well as the actively proliferating vasculature.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]