Metabolic Contributions to Anoikis-Resistance in Metastatic Dissemination

Extracellular matrix (ECM) attachment is crucial to prevent programmed death in many epithelial and endothelial cell types. Normally, cells that disengage from the ECM are eliminated via a specific programmed cell death mechanism known as anoikis. This form of programmed cell death also constitutes a major physiological barrier to cancer metastasis, since cancer cells must be able to resist anoikis to survive in circulation before forming metastatic colonies in distant organs. Although much of the classical apoptotic signaling events that regulate anoikis have been well-characterized, preclinical research now demonstrates that ECM detachment disrupts multiple processes, such as nutrient acquisition, that are crucial for cell survival. Cell metabolism and apoptosis are intrinsically linked, as metabolites are used as signaling molecules for cellular survival signaling and several metabolic and apoptogenic pathways converge on the mitochondria. Thus, accumulating evidence now links cellular metabolism after matrix detachment to both anoikis induction and anoikis resistance. Accordingly, the metabolic regulation of anoikis has become a topic of interest in cancer metastasis, since metabolic phenotypes of viable circulating cancer cells differ in comparison to proliferative cancer cells of the original primary tumor. In this chapter, we will discuss ECM detachment-induced alterations in cellular metabolism, with a special focus on the balance of bioenergetics and redox status in relation to anoikis susceptibility. Furthermore, this chapter will discuss how reprogrammed cellular metabolism contributes to anoikis resistance and metastatic potential in human cancer cells.