Autophagy and metastasis: another double-edged sword

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In order to metastasize, tumor cells must adapt to untoward, stressful microenvironments as they disseminate into the systemic circulation and colonize distant organ sites. Autophagy, a tightly regulated lysosomal self-digestion process that is upregulated during cellular stress, has been demonstrated to suppress primary tumor formation, but how autophagy influences metastasis remains unknown. Autophagy may inhibit metastasis by promoting antitumor inflammatory responses or by restricting the expansion of dormant tumor cells into macrometastases. Conversely, self-eating may promote metastasis by enhancing tumor cell fitness in response to environmental stresses, such as anoikis, during metastatic progression. Because autophagy is titratable, it may serve both prometastatic and antimetastatic functions depending on the contextual demands placed on tumor cells throughout the metastatic process.

Introduction

Metastasis is the primary cause of lethality in cancer patients and consists of multiple discrete steps, including: first, invasion of tumor cells from the primary tumor site; second, intravasation into the vasculature or lymphatic circulation and survival in the circulation; third, extravasation of individual tumor cells at the target organ site; and fourth, the expansion and colonization of tumor cells at the secondary site [1] (Figure 1). Despite our understanding of these basic steps, the exact mechanisms governing dissemination and metastasis remain unclear.

Cancer cells face diverse environmental and cellular stresses during every step of metastatic progression. To cope, tumor cells induce adaptive pathways, such as autophagy, a tightly regulated lysosomal self-digestion process utilized by cells under duress. Indeed, autophagy has been found to be upregulated in cancer cells during many of the principal events directing metastasis, including: hypoxia and metabolic stress; response to inflammatory signals in the tumor microenvironment; loss of cell–extracellular matrix (ECM) contact; and quiescence of solitary dormant cells [2, 3]. Here, we overview how autophagy can either promote or impede metastasis, focusing on selected steps of this complex process (Figure 1). Owing to the diametrically opposing functions of autophagy, we speculate that self-eating is titrated during metastatic progression to best meet the needs of stressed tumor cells [4].

Section snippets

Autophagy, necrosis, and inflammation during metastasis

The initial steps of metastasis require signals at the primary tumor that promote migration and local invasion and that facilitate the intravasation of tumor cells into the systemic circulation. Various cell types within the tumor microenvironment supply cancer cells with such signals [5]. In particular, inflammatory cells infiltrate tumor sites in response to necrosis resulting from hypoxia and metabolic stress, both of which commonly affect solid tumors. Although certain inflammatory cells,

Detachment-induced autophagy and anoikis resistance during metastasis

In order to metastasize, carcinoma cells must acquire the ability to survive and expand in the absence of proper ECM contact while traversing the systemic circulation and occupying a foreign microenvironment at a distant organ site [1, 16]. In normal cells, the lack of proper ECM attachment leads to apoptosis, termed anoikis [17, 18]. Anoikis maintains homeostasis in developing adult tissues; for example, anoikis promotes the clearance of epithelial cells detached from the surrounding basement

Autophagy and dormancy

Dormancy describes the remarkable ability of disseminated tumor cells (DTCs) to subsist for years to decades at distant sites without giving rise to secondary tumors. The dormant cell population may constitute only a small fraction of cells that disseminate from the primary tumor and harbor the ability to form metastases. These cells usually go undetected upon diagnosis and remain refractive to common treatments targeting proliferating cells at the primary tumor [16, 28]. Hence, understanding

Conclusion

The ability of autophagy to restrict necrosis and inflammation may limit the invasion and dissemination of tumor cells from a primary site, thereby restricting metastasis at an early step. On the other hand, autophagy may promote metastasis at later stages by protecting stressed tumor cells as they travel through the vasculature and colonize at distant sites. As a titratable process, autophagy is poised to serve both prometastatic and antimetastatic roles depending on contextual demands.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

JD is supported by grants from the NIH (RO1CA126792; CA126792-S1 ARRA), the California Tobacco Related Disease Research Program (18XT-0106), and an HHMI Physician Scientist Early Career Award. AT is supported by grants from the NIH (RO1 CA111421).

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