title: Signal Transducer and Activator of Transcription 3, Mediated Remodeling of the Tumor Microenvironment Results in Enhanced Tumor Drug Delivery in a Mouse Model of Pancreatic Cancer.
abstract: OBJECTIVE
  A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the presence of a dense desmoplastic reaction (stroma) that impedes drug delivery to the tumor. Attempts to deplete the tumor stroma have resulted in formation of more aggressive tumors. We have identified signal transducer and activator of transcription (STAT) 3 as a biomarker of resistance to cytotoxic and molecularly targeted therapy in PDAC. The purpose of this study is to investigate the effects of targeting STAT3 on the PDAC stroma and on therapeutic resistance.
  
  
  METHODS
  Activated STAT3 protein expression was determined in human pancreatic tissues and tumor cell lines. In vivo effects of AZD1480, a JAK/STAT3 inhibitor, gemcitabine or the combination were determined in Ptf1a(cre/+);LSL-Kras(G12D/+);Tgfbr2(flox/flox) (PKT) mice and in orthotopic tumor xenografts. Drug delivery was analyzed by matrix-assisted laser desorption/ionization imaging mass spectrometry. Collagen second harmonic generation imaging quantified tumor collagen alignment and density.
  
  
  RESULTS
  STAT3 activation correlates with decreased survival and advanced tumor stage in patients with PDAC. STAT3 inhibition combined with gemcitabine significantly inhibits tumor growth in both an orthotopic and the PKT mouse model of PDAC. This combined therapy attenuates in vivo expression of SPARC, increases microvessel density, and enhances drug delivery to the tumor without depletion of stromal collagen or hyaluronan. Instead, the PDAC tumors demonstrate vascular normalization, remodeling of the tumor stroma, and down-regulation of cytidine deaminase.
  
  
  CONCLUSIONS
  Targeted inhibition of STAT3 combined with gemcitabine enhances in vivo drug delivery and therapeutic response in PDAC. These effects occur through tumor stromal remodeling and down-regulation of cytidine deaminase without depletion of tumor stromal content.
authors.affiliation: Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, Florida.
authors.forename: Nagaraj S
authors.initials: NS
authors.lastname: Nagathihalli
authors.affiliation: Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Castellanos
authors.affiliation: Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Chanjuan
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Yugandhar
authors.initials: Y
authors.lastname: Beesetty
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Reyzer
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Richard
authors.initials: R
authors.lastname: Caprioli
authors.affiliation: Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Walsh
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Skala
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Harold L
authors.initials: HL
authors.lastname: Moses
authors.affiliation: Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, Florida. Electronic address: nmerchant@miami.edu.
authors.forename: Nipun B
authors.initials: NB
authors.lastname: Merchant
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000378:metabolism / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D055785:Gene Knockdown Techniques; D006801:Humans; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D015676:Osteonectin / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011720:Pyrazoles / Q000378:metabolism / Q000494:pharmacology*; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection; D047368:Tumor Burden; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: C545606:AZD 1480; D015676:Osteonectin; D011720:Pyrazoles; D011743:Pyrimidines; D018125:Receptors, Transforming Growth Factor beta; C577241:SPARC protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D014157:Transcription Factors; C062602:transcription factor PTF1; D003841:Deoxycytidine; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D000093542:Gemcitabine
keywords: Drug Delivery; Pancreatic Cancer; Stroma; Tumor Microenvironment