Characterization and use of HapT1-derived homologous tumors as a preclinical model to evaluate therapeutic efficacy of drugs against pancreatic tumor desmoplasia
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Sujit Suklabaidya1,2, Biswajit Das1,2, Syed Azmal Ali3, Sumeet Jain1,2, Sharada Swaminathan4, Ashok K. Mohanty3, Susen K. Panda5, Pujarini Dash1, Subhankar Chakraborty6, Surinder K. Batra7, Shantibhusan Senapati1
1Tumor Microenvironment and Animal Models Laboratory, Department of Translational Research, Institute of Life Sciences, Bhubaneswar, Odisha, India
2Manipal University, Manipal, Karnataka, India
3Proteomics and Structural Biology Laboratory, Animal Biotechnology Department, National Diary Research Institute, Haryana, India
4Department of Bioengineering, School of Chemical and Biotechnology, SASTRA University, Thanjavur, Tamil Nadu, India
5Department of Veterinary Pathology, Odisha University of Agriculture and Technology, Bhubaneswar, Odisha, India
6Mayo Clinic, Division of Gastroenterology and Hepatology, Rochester, MN, USA
7Department of Biochemistry and Molecular Biology, Buffett Cancer Center, Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, USA
Keywords: pancreatic cancer, desmoplasia, HapT1, pancreatic stellate cells, hamster homologous orthotopic model
Received: March 04, 2016 Accepted: May 17, 2016 Published: May 31, 2016
Desmoplasia in human pancreatic cancer (PC) promotes cancer progression and hinders effective drug delivery. The objectives of this study were to characterize a homologous orthotopic model of PC in Syrian golden hamster and investigate the effect of anti-fibrotic (pirfenidone), antioxidant (N-acetyl cysteine, NAC) and anti-addiction (disulfiram, DSF) drugs on desmoplasia and tumor growth in this model. The HapT1 PC cells when implanted orthotopically into hamsters formed tumors with morphological, cellular and molecular similarities to human PC. Protein profiling of activated hamster pancreatic stellate cells (ha-PSCs) revealed expression of proteins involved in fibrosis, cancer cells growth and metastasis. Pirfenidone, suppressed growth of HapT1 cells and the desmoplastic response in vivo; these effects were enhanced by co-administration of NAC. Disulfiram alone or in combination with copper (Cu) was toxic to HapT1 cells and PSCs in vitro; but co-administration of DSF and Cu accelerated growth of HapT1 cells in vivo. Moreover, DSF had no effect on tumor-associated desmoplasia. Overall, this study identifies HapT1-derived orthotopic tumors as a useful model to study desmoplasia and tumor-directed therapeutics in PC. Pirfenidone in combination with NAC could be a novel combination therapy for PC and warrants investigation in human subjects.
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