High-grade astrocytomas, which are invariably deadly and minimally responsive to therapy, are characterized by their highly invasive and angiogenic properties. Despite frequent Pten inactivation in aggressive astrocytoma, the mechanism(s) of Pten astrocytoma suppression have not been explored. These mechanisms were investigated in a genetically engineered mouse model in which astrocytespecific inactivation of pRb family proteins (pRb, p107 and p130) predisposes to high-grade astrocytoma. Cre-dependent conditional Pten-null alleles were introduced into this background, and the consequences of Pten inactivation were assessed in vivo after focal retroviral Cre delivery and in vitro in primary astrocytes derived from the mice. As the cover figure indicates, results demonstrate that PTEN deficiency contributes to tumor progression via multiple mechanisms, including suppression of apoptosis, increased cell invasion and angiogenesis, all of which are hallmarks of high grade astrocytoma. Signaling pathway-specific inhibitors were further used to delineate the PTEN-regulated pathways involved in apoptosis suppression and invasiveness, indicating effective targets for therapy. For details, see the article on page 5172 of this issue.