Molecular Mechanisms in Brain Metastasis

Although responsible for the vast majority of cancer deaths [1], understanding of the molecular mechanisms underlying metastasis lags far behind that of other aspects of carcinogenesis. Of all sites of metastases, those to the central nervous system (CNS) result in disproportionate disability and death [2, 3], reflecting both the physiologic primacy of the CNS and our insufficient understanding of this site of metastasis. Metastasis is perhaps the most overt expression of cancer’s evolutionary dynamics. A central tenant of this paradigm is that tumor heterogeneity provides the necessary variability to allow cancer to adapt to and ultimately flourish within a target secondary organ [4]. In support of this, genomic investigative approaches have found that cancer cells metastatic to the CNS are genetically divergent from their preceding primary tumors [5] and display decreased genetic heterogeneity consistent with a founder effect [6]. It is tempting to posit that common genetic drivers for brain metastasis may result from such selective processes, somatically acquired and selected during tumor evolution. However, despite large-scale efforts, genetic changes have not been found to dictate site of metastasis [4, 7].