Hypoxia-Induced Autophagy Degrades Stromal Lumican into Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma: A Mini-Review

The extracellular matrix (ECM) in the tumor microenvironment (TME) has gained considerable interest in recent years as a crucial component in fundamental cellular processes and provides novel therapeutic targets. Lumican is a class II small leucine-rich proteoglycan with a key role in ECM organization and modulation of biological functions dependent on tumor type, abundance, and stage of disease. The presence of stromal lumican in the ECM surrounding pancreatic ductal adenocarcinoma (PDAC) inhibits cancer cell replication and is associated with improved patient outcomes after multimodal therapies. In this mini-review, were-present our novel findings describing how hypoxia (1% O2) within the TME influences stromal lumican expression and secretion. We observed that hypoxia specifically inhibited lumican expression and secretion post-transcriptionally only from pancreatic stellate cells. Hypoxia-induced increased lactate production did not influence lumican expression. Notably, autophagy was induced by hypoxia in ex vivo cultures of patient-derived primary PDAC xenograft and pancreatic stellate cells; however, the cancer cells remain unaffected. Moreover, hypoxia-inducible factor (HIF)-1α expression or inhibition of AMP-regulated protein kinase (AMPK) activation within hypoxic stellate cells restored lumican expression levels. Interestingly, AMPK inhibition attenuated hypoxia-reduced phosphorylation of the mTOR/p70S6K/4EBP signaling pathway. The aim of this mini-review is to summarize our recent publication that hypoxia reduces stromal lumican in PDAC through autophagy-mediated degradation and reduction in protein synthesis within pancreatic cancer stellate cells. This may provide another plausible mechanism by which hypoxia-induced stromal autophagy leads to cancer growth.