Autophagy and Cancer Dormancy

Abstract

Metastasis and relapse account for the great majority of cancer-related deaths. Most metastatic lesions are micro metastases that have the capacity to remain in a non-dividing state called "dormancy" for months or even years. Commonly used anticancer drugs generally target actively dividing cancer cells. Therefore, cancer cells that remain in a dormant state evade conventional therapies and contribute to cancer recurrence. Cellular and molecular mechanisms of cancer dormancy are not fully understood. Recent studies indicate that a major cellular stress response mechanism, autophagy, plays an important role in the adaptation, survival and reactivation of dormant cells. In this review article, we will summarize accumulating knowledge about cellular and molecular mechanisms of cancer dormancy, and discuss the role and importance of autophagy in this context.

Keywords: autophagy; cancer; dormancy; metastasis; recurrence; relapse.

Figure 1

Time-dependent progression of metastasis and dormancy. Conventional diagnostic tumor scans are able to detect tumors bigger than 1 mm³ (tumor mass = m_primary). After diagnosis with cancer (time = t₀), patient may undergo chemotherapy, radiotherapy or adjuvant therapy, yet dormant cells escape and become resistant to these treatments (time = t₂), and awaken after years or even decades (time = t₃). In tumor dormancy, tumor mass (m₁) stagnates due to limited neovascularization and constant immune cell attack that balance tumor cell demise and proliferation. After the latency period, dormant tumor cells awaken and lead to tumor outgrowth (tumor mass>m₁). In cellular dormancy, cancer cells hibernate as single cells or small clusters (tumor mass = m₁≈0) and lead to massive tumor growth (tumor mass≥m_primary) following exit from dormancy.

Figure 2

General mechanism of mammalian autophagy. Autophagy is tightly controlled by the activity of AMPK and mTOR. Under nutrient deprivation, AMPK activates autophagy, yet mTOR inhibition is relieved. Subsequent activation of ULK1 and BECN1 complexes promotes formation of phagophore. ATG5-12-16L complex and ATG8 family protein LC3 are required for elongation and closure of phagophore. Fully mature double-layered autophagosome containing cargo molecules fuses with late endosomes and lysosomes. Autophagosomes and their cargo are degraded through lysosomal enzymes and recycled into cytosol for reuse.