In order to metastasize, carcinoma cells must acquire the ability to survive and expand in absence of proper ECM contact while traversing the systemic circulation and occupying a foreign microenvironment at a distant organ site [1
]. In normal cells, the lack of proper ECM attachment leads to apoptosis, termed anoikis [17
]. Anoikis maintains homeostasis in developing and adult tissues; for example, anoikis promotes the clearance of epithelial cells detached from the surrounding basement membrane during ductal elongation in the mouse mammary gland [19
Therefore, for tumor cells to survive and metastasize, they must activate mechanisms to resist anoikis [17
]. For example, in a model of gastric cancer, cells that demonstrate enhanced adhesion independent growth in vitro due to anti-apoptotic factor overexpression also exhibit enhanced peritoneal dissemination in vivo [20
]. Moreover, the neurotrophic tyrosine kinase receptor, TrkB, has been identified as a potent anoikis suppressor. Importantly, TrkB overexpression in non-malignant cells facilitates the robust formation of lung and heart metastases following intravenous injection, indicating that anoikis resistance is both necessary and sufficient for metastasis [21
]. As exemplified by this study, the aberrant activation of growth factor pathways is a common mechanism utilized by cancerous cells to evade anoikis; in fact, oncogenes that activate key growth factor signals, such as the Ras/MAPK and PI3K/Akt pathways, protect cancer cells from death [17
]. However, recent work indicates that autophagy is another mechanism that protects matrix-detached epithelial cells from anoikis [2
Detachment-induced autophagy was first observed during luminal clearance in mammary epithelial acini grown in three-dimensional (3D) cultures [23
]. Subsequent experiments delineated that autophagy is induced upon either substratum detachment or β1 integrin receptor blockade [22
]. Although autophagy was initially hypothesized to promote the death of detached cells, these studies revealed that autophagy protects epithelial cells from anoikis. Autophagy inhibition via RNAi-mediated knockdown of autophagy regulators (ATGs) enhanced detachment-induced cell death and accelerated luminal clearance in 3D mammary epithelial cultures [22
]. Collectively, these data support a role for autophagy in mediating anoikis resistance; such protection may be particularly important during the later stages of cancer dissemination and metastasis where tumor cells are required to adapt to aberrant cell-ECM interactions in the systemic circulation and at distant organ sites ().
Currently, the precise function of detachment-induced autophagy during anoikis remains unclear. Integrin engagement amplifies signals transmitted by growth factor receptor pathways, which together coordinate proper nutrient uptake and metabolism [24
]. Similar to its role in starvation, autophagy in ECM-detached cells may compensate for the loss of extrinsic signals promoting nutrient and energy metabolism [2
]. In the context of a rapidly growing tumor with high energy and biosynthetic demands, detachment-induced autophagy may promote the fitness of cells deprived of ECM contact. Alternatively, since autophagy is initially upregulated in stressed regions of primary tumors, sustained self-eating may further enable the pro-metastatic phenotype as primary tumor cells receive microenvironmental signals stimulating ECM detachment and migration.
Indeed, protection from anoikis has been shown to facilitate both the survival and expansion of metastatic cells [17
]. Nonetheless, a specific requirement for detachment-induced autophagy during metastasis has yet to be demonstrated in vivo. Interestingly, processes associated with anchorage independent growth appear to serve as a useful indicator of poor clinical outcome, as the expression profile of breast and lung tissue from metastatic cancers correlates well with that of breast cancer cell line exhibiting a strong anchorage independent growth phenotype [27
]. If autophagy does in fact serve a critical role in promoting anoikis resistance, self-eating also may correlate with poor prognosis with regard to metastatic disease.