Autophagy-induced tumor dormancy in ovarian cancer

Abstract

Autophagy--a process of "self-eating" that involves enzymatic digestion and recycling of cellular constituents in response to stress--contributes to both cancer cell death and survival. In this issue of the JCI, Lu et al. report that controlled induction of tumor suppressor gene aplasia Ras homolog member I (ARHI) results in autophagic cell death of human ovarian cancer cells in vitro (see the related article beginning on page 3917). However, within xenograft tumors in mice, multiple factors within the tumor microenvironment switched ARHI-induced autophagy to a mechanism of tumor cell survival, leading to tumor dormancy. Since ARHI expression is suppressed in the majority of breast and ovarian cancers but is high in premalignant lesions, ARHI-induced autophagy could be manipulated for therapeutic benefit.

Figure 1. Consequences of forced expression of the tumor suppressor gene ARHI in ovarian cancer.

In their study in this issue of the JCI, Lu et al. (8) report that controlled expression of the tumor suppressor gene ARHI in human ovarian cancer cells leads to autophagy. (A) ARHI expression was associated with interrupted PI3K signaling, which resulted in reversible (under conditions of transient ARHI expression) or irreversible (under conditions of chronic ARHI expression) autophagic cell death in vitro. (B) In contrast, ARHI-induced autophagy contributed to cell survival and tumor dormancy in ovarian cancer xenografts in mice, due to partially restored PI3K signaling from elements of the tumor microenvironment.

Figure 2. The magnitude of autophagy may determine the fate of cancer cells in vivo.

This conceptual model proposes a relationship between the magnitude of cancer cell autophagy and its consequences on cell death and cell survival. As reported by Lu et al., expression of the tumor suppressor gene ARHI suppresses signal transduction through PI3K signaling, while factors within the tumor microenvironment maintain PI3K signaling within tumor cells (8). The magnitude of autophagy may be inversely proportional to PI3K signaling, and thresholds may exist within cancer cells for the magnitude of autophagy that leads to cell death versus the magnitude of autophagy that leads to cell survival.