Roles for Autophagy in Esophageal Carcinogenesis: Implications for Improving Patient Outcomes

Abstract

Esophageal cancer is among the most aggressive forms of human malignancy with five-year survival rates of <20%. Autophagy is an evolutionarily conserved catabolic process that degrades and recycles damaged organelles and misfolded proteins to maintain cellular homeostasis. While alterations in autophagy have been associated with carcinogenesis across tissues, cell type- and context-dependent roles for autophagy have been reported. Herein, we review the current knowledge related to autophagy in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), the two most common subtypes of esophageal malignancy. We explore roles for autophagy in the development and progression of ESCC and EAC. We then continue to discuss molecular markers of autophagy as they relate to esophageal patient outcomes. Finally, we summarize current literature examining roles for autophagy in ESCC and EAC response to therapy and discuss considerations for the potential use of autophagy inhibitors as experimental therapeutics that may improve patient outcomes in esophageal cancer.

Keywords: autophagy; esophageal adenocarcinoma; esophageal cancer; esophageal squamous cell carcinoma; esophagus.

Figure 1

Molecular regulation of autophagy. Mammalian target of rapamycin 1 (mTORC1) acts a critical negative regulator of autophagy under nutrient-rich conditions. AMP-activated kinase (AMPK) serves a key positive regulator of autophagy in response to energy depletion. AMPK promotes AV initiation and nucleation through assembly of the Unc51-like kinase 1 (ULK1) complex. For nucleation to continue, Beclin-1 must dissociate from Bcl2 in order to interact with vacuolar sorting protein (VPS)34, a class III PI3 Kinase. AV elongation to surround p62/SQSTM1-associated cargo proteins involves cleavage of Microtubule-associated protein light chain 3 (LC3) by autophagy-related (ATG)4, generating LC3-I. LC3-I is then lipidated (generating LC3-II) through addition of phosphatidylethanolamine (PE) by two ubiquitin-like conjugation systems consisting of various ATGs. Following closure, AVs undergo fusion with lysosomes where acid hydrolase enzymes break down autophagic cargo so that their constituents can be used for biosynthesis of macromolecules.

Figure 2

Alterations in autophagy in response esophageal cancer-associated factors. Esophageal squamous cell carcinoma (ESCC) occurs in the proximal portion of the esophagus as esophageal keratinocytes undergo malignant transformation. The schematic above the dotted line depicts how the listed cellular and environmental factors have been demonstrated to impact autophagy in ESCC as well as the effects of autophagy activation and inhibition upon ESCC cells. Esophageal adenocarcinoma (EAC) occurs in the distal portion of the esophagus as esophageal epithelium is displaced by a specialized intestinal metaplasia, Barrett’s esophagus (BE), in response to gastroesophageal reflux disease (GERD). The schematic below the dotted line depicts how bile/acid reflux impacts autophagy in the early premalignant states of GERD and BE as well as in dysplastic BE and EAC.

Figure 3

Summary of studies investigating effects of autophagy on therapeutic response in esophageal cancer. Therapeutic interventions that activate autophagy to limit cell death are shown in the yellow circle, while therapies that activate autophagy to promote cell death are shown in the blue circle. Esomeprazole is present in the overlapping space between the two circles as it has been shown to activate autophagy to limit cell death and also promote cell death in a context-dependent manner.