Abstract
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.
Highlights
The pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) is characterized by dense desmoplastic stroma and resultant hypoxia, which drives angiogenesis, immune suppression, and numerous signaling events that promote cancer progression, metastasis, and poor patient survival.[31,32,33,34] The influence of hypoxia on stromal composition and secreted extracellular protein such as lumican is not clearly understood
We observed that hypoxia significantly reduced lumican expression and secretion from pancreatic stellate cells but not cancer cells
Our results revealed that hypoxia stimulates hypoxia-inducible factor (HIF)-1α and AMP-regulated protein kinase (AMPK) activation, which leads to autophagy and subsequent reduction in cellular and secreted lumican (Figure 1)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive malignancy with a high incidence of distant metastasis[1] and is projected to be the second leading cause of cancer death by 20302. PDAC exhibits extensive desmoplastic stroma, which derives from activated pancreatic stellate cells This activation results in proliferation, leading to the production of collagen, laminin, fibronectin[3], and lumican[4] within the extracellular matrix (ECM). Secreted 70-kDa lumican by PDAC cells stimulated growth and inhibited invasion of human pancreatic cancer. It activated ERK signaling, induced α3 integrin expression, and decreased active matrix metalloproteinase-923. A key finding in our previous study was that the activated pancreatic stellate cells within the TME are the principle source of stromal lumican, and the presence of lumican within the stroma of a primary PDAC tumor is associated with decreased metastasis and prolonged survival in early-stage pancreatic cancer[12,13]. Lumican is shown to have an anti-tumor role in a context-dependent manner, and the conflicting results regarding the precise role of lumican in tumor progression and regression depend on the specific correlation between lumican tissue-specific abundance, distribution, and stage of disease in PDAC
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