The role of angiogenesis, growth arrest and autophagy in human ovarian cancer xenograft models for tumor dormancy

The concept of tumor dormancy has been developed to explain a prolonged interval between primary therapy and the recurrence of metastatic disease. The process of dormancy may be driven or supported by several different mechanisms including angiogenesis and the tumor microenvironment, cell cycle arrest, immune surveillance, and autophagy. One xenograft model for dormancy in ovarian cancer emphasizes the importance of an effective and stable tumor microvasculature. In another xenograft model of dormancy in ovarian cancer, autophagy appears to be important for sustaining dormant cancer cells under nutrient poor conditions. Autophagy plays an ambiguous role in cancer pathophysiology. As a cellular defense mechanism, loss of autophagy has been implicated in tumor progression in several models, but autophagy can also provide a survival mechanism for dormant cancer cells. ARHI (DIRAS 3) is a maternally imprinted tumor suppressor gene that is downregulated in 60% of human ovarian cancers associated with decreased progression free survival. Re-expression of ARHI blocks proliferation, inhibits migration, prevents angiogenesis and induces autophagy and tumor dormancy. Treatment of mice bearing ARHI-induced dormant xenografts with chloroquine, a functional inhibitor of autophagy, delays the outgrowth of tumor transplants, consistent with a role for autophagy in sustaining nutrient deprived cancer cells. This mechanism may extend beyond ovarian cancer, as downregulation of ARHI has been found in breast, lung, prostate, pancreatic, and thyroid cancers. This review considers the role of multiple mechanisms for dormancy in epithelial ovarian cancers that may provide new targets for eliminating dormant cancer cells.