Endocytosis and Cancer

Endocytosis entails selective packaging of cell-surface proteins, such as receptors for cytokines and adhesion components, in cytoplasmic vesicles (endosomes). The series of sorting events that determines the fate of internalized proteins, either degradation in lysosomes or recycling back to the plasma membrane, relies on intrinsic sequence motifs, posttranslational modifications (e.g., phosphorylation and ubiquitination), and transient assemblies of both Rab GTPases and phosphoinositide-binding proteins. This multicomponent process is enhanced and skewed in cancer cells; we review mechanisms enabling both major drivers of cancer, p53 and Ras, to bias recycling of integrins and receptor tyrosine kinases (RTKs). Likewise, cadherins and other junctional proteins of cancer cells are constantly removed from the cell surface, thereby disrupting tissue polarity and instigating motile phenotypes. Mutant forms of RTKs able to evade Cbl-mediated ubiquitination, along with overexpression of the wild-type forms and a variety of defective feedback regulatory loops, are frequently detected in tumors. Finally, we describe pharmacological attempts to harness the peculiar endocytic system of cancer, in favor of effective patient treatment.Cancer cells are fundamentally similar to their normal counterparts. Their differences lie in a series of relatively subtle modifications of normal physiological processes that, when combined, can create markedly altered phenotypes and behaviors. It has long been suspected that endocytosis is one such physiological process that is modified in cancer. Not only do cancer cells show alterations in the overall appearance and dynamics of the plasma membrane, but also the common inability of cancer cells to properly regulate the function of several types of receptors, including many RTKs, strongly suggests an inability to internalize, recycle, or degrade these key cancer drivers. In recent years, there has been considerable progress made toward understanding the breadth and mechanisms of alterations to the endocytic pathway that occur during cancer. Although our knowledge remains incomplete and the pathophysiological contributions of these alterations may not be wholly understood, this review considers just how profoundly the pathways of endocytosis can be modified in cancer and what this reveals about disease mechanisms and normal processes.