Running head: Autophagy-Related Alterations in Human Tumors

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Macroautophagy (or autophagy) is a catabolic cellular process that is both homeostatic and stress adaptive. Normal cells rely on basal levels of autophagy to maintain cellular integrity (via turnover of long-lived proteins and damaged organelles) and increased levels of autophagy to buoy cell survival during various metabolic stresses (via nutrient and energy provision through lysosomal degradation of cytoplasmic components). Autophagy can function in both tumor suppression and tumor progression, and is under investigation in clinical trials as a novel target for anticancer therapy. However, its role in cancer pathogenesis has yet to be fully explored. In particular, it remains unknown whether in vitro observations will be applicable to human cancer patients. Another outstanding question is whether there will be tumor-specific selection for alterations in autophagy function. In this review, we survey reported mutations in autophagy genes and key autophagy regulators identified in human tumor samples, and summarize the literature documenting expression levels of autophagy genes and proteins in various cancer tissues. Though it is too early to draw inferences from this collection of in vivo studies of autophagy-related alterations in human cancers, their results highlight the challenges the field must overcome to accurately assess the scope of autophagy's predicted role in tumorigenesis. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Autophagy mediates lysosomal degradation and recycling of proteins and organelles. Preclinical studies suggest that autophagy acts as a double-edged sword in cancer pathogenesis, contributing to the integrity of the genome in pre-cancerous cells, while conferring a survival advantage to tumor cells in harsh microenvironments (e.g. therapeutic cytotoxicity). Ongoing clinical trials involving hydroxychloroquine (a lysosomal inhibitor that blocks autophagosome-lysosome fusion) are investigating whether this drug can augment the efficacy of existing anticancer agents and overcome therapeutic resistance. However, tools necessary to monitor autophagy status in patients are still under development. To identify diagnostic and prognostic biomarkers, researchers are cataloguing autophagy alterations at the DNA, RNA and protein levels in human tumor specimens. Results of these studies may provide novel biomarkers for patient stratification, identify new targets for the design of specific autophagy inhibitors, and help guide the implementation of therapeutic autophagy modulation. This review highlights recent progress in the examination of human autophagy alterations in cancer. Author manuscripts have been peer reviewed and accepted for publication …