Abstract | PURPOSE: EXPERIMENTAL DESIGN: One hundred thirty-one patient tumors were chosen for tissue microarray staining, and Cox regression analysis was used to test the associations between lumican expression and clinical, pathologic, and oncologic outcomes in all patients. Primary PDAC cells and recombinant human lumican protein were used to establish a working model to mimic the in vivo interactions between stromal lumican and PDAC cells. Using this model, we tested the effects of lumican on EGFR signaling via Akt and hypoxia-inducible factor-1α (HIF1α) and its subsequent influence on glucose consumption, lactate production, intracellular ATP, and apoptotic cell death. RESULTS:
Lumican was present in the stroma surrounding PDAC cells in roughly one-half of primary tumors and the direct xenografts. Patients with stromal lumican were associated with a profound reduction in metastatic recurrence after surgery and 3-fold longer survival than patients without stromal lumican. In PDAC cells, extracellular lumican reduced EGFR expression and phosphorylation through enhanced dimerization and internalization of EGFR and the resultant inhibition of Akt kinase activity. Lumican also reduced HIF1α expression and activity via Akt. PDAC cells with enhanced HIF1α activity were resistant to lumican-induced inhibition of glucose consumption, lactate production, intracellular ATP, and apoptosis. CONCLUSIONS:
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Authors | Xinqun Li, Mark A Truty, Ya'an Kang, Xavier Chopin-Laly, Ran Zhang, David Roife, Deyali Chatterjee, E Lin, Ryan M Thomas, Huamin Wang, Matthew H Katz, Jason B Fleming |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 20
Issue 24
Pg. 6529-40
(Dec 15 2014)
ISSN: 1557-3265 [Electronic] United States |
PMID | 25336691
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | ©2014 American Association for Cancer Research. |
Chemical References |
- Chondroitin Sulfate Proteoglycans
- Hypoxia-Inducible Factor 1, alpha Subunit
- LUM protein, human
- Lumican
- Keratan Sulfate
- ErbB Receptors
- Proto-Oncogene Proteins c-akt
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Topics |
- Animals
- Apoptosis
- Carcinoma, Pancreatic Ductal
(genetics, metabolism, mortality, pathology, surgery)
- Cell Line, Tumor
- Cell Proliferation
- Chondroitin Sulfate Proteoglycans
(genetics, metabolism)
- Disease Models, Animal
- ErbB Receptors
(metabolism)
- Extracellular Space
(metabolism)
- Gene Expression
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit
(metabolism)
- Keratan Sulfate
(genetics, metabolism)
- Lumican
- Pancreatic Neoplasms
(genetics, metabolism, mortality, pathology, surgery)
- Patient Outcome Assessment
- Prognosis
- Protein Transport
- Proto-Oncogene Proteins c-akt
(metabolism)
- Signal Transduction
- Tumor Burden
- Xenograft Model Antitumor Assays
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