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Review
. 2017 Mar 23;36(12):1619-1630.
doi: 10.1038/onc.2016.333. Epub 2016 Sep 5.

Autophagy in cancer metastasis

E E Mowers  1   2 , M N Sharifi  1   3   4 , K F Macleod  1   4
Affiliations
Review

Autophagy in cancer metastasis

E E Mowers et al. Oncogene. .

Abstract

Autophagy is a highly conserved self-degradative process that has a key role in cellular stress responses and survival. Recent work has begun to explore the function of autophagy in cancer metastasis, which is of particular interest given the dearth of effective therapeutic options for metastatic disease. Autophagy is induced upon progression of various human cancers to metastasis and together with data from genetically engineered mice and experimental metastasis models, a role for autophagy at nearly every phase of the metastatic cascade has been identified. Specifically, autophagy has been shown to be involved in modulating tumor cell motility and invasion, cancer stem cell viability and differentiation, resistance to anoikis, epithelial-to-mesenchymal transition, tumor cell dormancy and escape from immune surveillance, with emerging functions in establishing the pre-metastatic niche and other aspects of metastasis. In this review, we provide a general overview of how autophagy modulates cancer metastasis and discuss the significance of new findings for disease management.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic illustrating roles of autophagy in the metastatic cascade. Autophagy increases as tumor cells progress to invasiveness and this in turn is linked to increased cell motility, EMT, a stem cell phenotype, secretion of pro-migratory factors, release of MMPs, drug resistance and escape from immune surveillance at the primary site in some tumors. Many aspects of these autophagy-dependent changes during acquisition of invasiveness also likely contribute to the ability of disseminating tumor cells to intravasate, survive and migrate in the circulation before extravasating at secondary site. At the secondary site, autophagy is required to maintain tumor cells in a dormant state, possibly through its ability to promote quiescence and a stem cell phenotype, that in turn is linked to tumor cell survival and drug resistance. Emerging functions for autophagy in metastasis include a role in establishing the pre-metastatic niche as well as promoting tumor cell survival, escape from immune surveillance and other aspects required to ultimately grow out an overt metastasis.
Figure 2
Figure 2
Autophagy promotes tumor cell motility. Autophagy promotes tumor cell motility through various mechanisms including: (a) promoting a stem cell phenotype that may be linked to as association of increased autophagy in response to stresses such as hypoxia and TGF-β, with EMT; (b) promoting survival in response to matrix detachment; (c) modulating levels of RhoA and Rho signaling while conversely being induced by Rho signaling; (d) through coordinated control of autophagy and FAK via FIP200; (e) a role in promoting focal adhesion turnover both directly and via regulation of SRC activity; (f) autophagy-dependent production of secreted factors that promote invasion, such as IL-6 and MMP2.
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