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

Gastroenterology. 2015 Dec;149(7):1932-1943.e9. doi: 10.1053/j.gastro.2015.07.058. Epub 2015 Aug 7.

Abstract

Background & aims: 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.

Keywords: Drug Delivery; Pancreatic Cancer; Stroma; Tumor Microenvironment.

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / metabolism
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / mortality
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Collagen / metabolism
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / metabolism
  • Deoxycytidine / pharmacology
  • Drug Resistance, Neoplasm
  • Gene Knockdown Techniques
  • Humans
  • Mice, Inbred C57BL
  • Mice, Nude
  • Mice, Transgenic
  • Molecular Targeted Therapy
  • Neoplasm Staging
  • Osteonectin / metabolism
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / mortality
  • Pancreatic Neoplasms / pathology
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Pyrazoles / metabolism
  • Pyrazoles / pharmacology*
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology*
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects*
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Stromal Cells / drug effects*
  • Stromal Cells / metabolism
  • Stromal Cells / pathology
  • Time Factors
  • Transcription Factors / genetics
  • Transfection
  • Tumor Burden
  • Tumor Microenvironment*
  • Xenograft Model Antitumor Assays

Substances

  • AZD 1480
  • Osteonectin
  • Pyrazoles
  • Pyrimidines
  • Receptors, Transforming Growth Factor beta
  • SPARC protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse
  • Transcription Factors
  • transcription factor PTF1
  • Deoxycytidine
  • Collagen
  • gemcitabine
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)