title: Extracellular lumican inhibits pancreatic cancer cell growth and is associated with prolonged survival after surgery.
abstract: OBJECTIVE
  To evaluate the relevance between lumican expression patterns and the clinical course of patients with pancreatic ductal adenocarcinoma (PDAC), and to investigate the role of lumican in PDAC progression.
  
  
  METHODS
  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
  There is a positive association between stromal lumican in primary PDAC tumors and prolonged survival after tumor resection. Lumican plays a restrictive role in EGFR-expressing pancreatic cancer progression.
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xinqun
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Surgery, Mayo Clinic, Rochester, Minnesota.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Truty
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ya'an
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Department of Hepato-Biliary and Pancreatic Surgery, Edouard Herriot Hospital, HCL, Lyon, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Chopin-Laly
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ran
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: David
authors.initials: D
authors.lastname: Roife
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Deyali
authors.initials: D
authors.lastname: Chatterjee
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: E
authors.initials: E
authors.lastname: Lin
authors.affiliation: Department of Surgery, University of Florida, Gainesville, Florida.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Thomas
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Katz
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. jbflemin@mdanderson.org.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Fleming
mesh_terms: D000818:Animals; D017209:Apoptosis; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000601:surgery; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007632:Keratan Sulfate / Q000235:genetics / Q000378:metabolism*; D000071234:Lumican; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D063868:Patient Outcome Assessment; D011379:Prognosis; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000604306:LUM protein, human; D000071234:Lumican; D007632:Keratan Sulfate; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt