Hypoxia Triggers Hedgehog-Mediated Tumor–Stromal Interactions in Pancreatic Cancer

Abstract

Pancreatic cancer is characterized by a desmoplastic reaction that creates a dense fibroinflammatory microenvironment, promoting hypoxia and limiting cancer drug delivery due to decreased blood perfusion. Here we describe a novel tumor-stroma interaction that may help explain the prevalence of desmoplasia in this cancer. Specifically, we found that activation of HIF-1α by tumor hypoxia strongly activates secretion of the sonic hedgehog ligand SHH by cancer cells which in turn causes stromal fibroblasts to increase fibrous tissue deposition. In support of this finding, elevated levels of HIF-1α and SHH in pancreatic tumors were determined to be markers of decreased patient survival. Repeated cycles of hypoxia and desmoplasia amplified each other in a feed forward loop that made tumors more aggressive and resistant to therapy. This loop could be blocked by HIF-1α inhibition, which was sufficient to block SHH production and HH signaling. Taken together, our findings suggest that increased HIF-1α produced by hypoxic tumors triggers the desmoplasic reaction in pancreatic cancer, which is then amplified by a feed forward loop involving cycles of decreased blood flow and increased hypoxia. our findings strengthen the rationale for testing HIF inhibitors may therefore represent a novel therapeutic option for pancreatic cancer.

Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma

“…Gene expression analyses suggested that only murine stroma but not tumor epithelium could respond to SMO antagonist explaining the lack of response in vitro (12,13). Coculture experiments further showed the paracrine activation of Hh signaling in lung and pancreatic cancer (14,15). These highlight the importance of Hh signaling in tumor and thus serve as a rational for a treatment targeting cancer (11).…”

“…We therefore focused on the effects of vismodegib in stroma to understand the mechanisms leading to the reduced proliferation hence tumor growth delay. Previous experiments suggest that antagonization of Hh pathway in fibroblasts reduces the production of ECM, cytokines, and growth factors (13)(14)(15). Therefore, we analyzed mRNA levels of the ECM molecules Fibronectin (Fn1) and Collagen (Col1a2).…”

Curcumin inhibits hypoxia-induced epithelial-mesenchymal transition in pancreatic cancer cells via suppression of the hedgehog signaling pathway

“…Hh signaling plays an important role in the initiation and progression of pancreatic cancer (15). As shown in Fig.…”

FBW7 (F-box and WD Repeat Domain-Containing 7) Negatively Regulates Glucose Metabolism by Targeting the c-Myc/TXNIP (Thioredoxin-Binding Protein) Axis in Pancreatic Cancer

“…Pancreatic cancer is characterized by extensive desmoplasia that is caused by the dense stromal fibroinflammatory reaction of fibroblasts, which leads to a reduced nutrient and oxygen supply, resulting in a severe hypoxic tumor microenvironment (9,10). To adapt and survive in this hostile environment, cancer cells must rely on their ability to reprogram canonical metabolic pathways to ensure that their needs for macromolecule synthesis and essential energy demands are met (11,12).…”