Potential mechanisms for disparate rates of brain metastases in males and females. The process of metastasis to the brain involves distinct steps dependent on different genes, pathways and mechanisms. The initial stage (1) involves tumor cell intrinsic mechanisms for the degradation of the extracellular matrix and activation of migratory pathways. This process is often referred to as epithelial to mesenchymal transition (EMT). Pictured is a lung cancer primary tumor and the hematogenous dissemination of lung cancer cells. For metastases to the brain, cells that gain access to the circulatory system and avoid natural killer (NK) cell deletion must cross the blood brain barrier (2). Once present in the brain parenchyma, the lung cancer cells must condition the brain microenvironment for continued growth (3). This process involves secretion of cytokines that induce a microenvironmental response. Pictured is the action of the lung cancer cells on an astrocyte. (4) The activated astrocytes secrete cytokines and growth factors such as interleukin (IL)-6 that promote tumor growth and protect secondary tumors from the cytotoxic effects of chemotherapy.