Characterization and use of HapT1-derived homologous tumors as a preclinical model to evaluate therapeutic efficacy of drugs against pancreatic tumor desmoplasia
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...
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| Published in | Oncotarget Vol. 7; no. 27; pp. 41825 - 41842 |
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| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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Impact Journals LLC
05.07.2016
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| Abstract | 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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| AbstractList | 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. 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. 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.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. |
| Author | Jain, Sumeet Das, Biswajit Dash, Pujarini Batra, Surinder K. Senapati, Shantibhusan Chakraborty, Subhankar Suklabaidya, Sujit Swaminathan, Sharada Panda, Susen K. Mohanty, Ashok K. Ali, Syed Azmal |
| AuthorAffiliation | 4 Department of Bioengineering, School of Chemical and Biotechnology, SASTRA University, Thanjavur, Tamil Nadu, India 6 Mayo Clinic, Division of Gastroenterology and Hepatology, Rochester, Minnesota, MN, USA 7 Department of Biochemistry and Molecular Biology, Buffett Cancer Center, Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, USA 3 Proteomics and Structural Biology Laboratory, Animal Biotechnology Department, National Diary Research Institute, Haryana, India 1 Tumor Microenvironment and Animal Models Laboratory, Department of Translational Research, Institute of Life Sciences, Bhubaneswar, Odisha, India 2 Manipal University, Manipal, Karnataka, India 5 Department of Veterinary Pathology, Odisha University of Agriculture and Technology, Bhubaneswar, Odisha, India |
| AuthorAffiliation_xml | – name: 7 Department of Biochemistry and Molecular Biology, Buffett Cancer Center, Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, USA – name: 1 Tumor Microenvironment and Animal Models Laboratory, Department of Translational Research, Institute of Life Sciences, Bhubaneswar, Odisha, India – name: 2 Manipal University, Manipal, Karnataka, India – name: 3 Proteomics and Structural Biology Laboratory, Animal Biotechnology Department, National Diary Research Institute, Haryana, India – name: 6 Mayo Clinic, Division of Gastroenterology and Hepatology, Rochester, Minnesota, MN, USA – name: 4 Department of Bioengineering, School of Chemical and Biotechnology, SASTRA University, Thanjavur, Tamil Nadu, India – name: 5 Department of Veterinary Pathology, Odisha University of Agriculture and Technology, Bhubaneswar, Odisha, India |
| Author_xml | – sequence: 1 givenname: Sujit surname: Suklabaidya fullname: Suklabaidya, Sujit organization: Tumor Microenvironment and Animal Models Laboratory, Department of Translational Research, Institute of Life Sciences, Bhubaneswar, Odisha, India, Manipal University, Manipal, Karnataka, India – sequence: 2 givenname: Biswajit surname: Das fullname: Das, Biswajit organization: Tumor Microenvironment and Animal Models Laboratory, Department of Translational Research, Institute of Life Sciences, Bhubaneswar, Odisha, India, Manipal University, Manipal, Karnataka, India – sequence: 3 givenname: Syed Azmal surname: Ali fullname: Ali, Syed Azmal organization: Proteomics and Structural Biology Laboratory, Animal Biotechnology Department, National Diary Research Institute, Haryana, India – sequence: 4 givenname: Sumeet surname: Jain fullname: Jain, Sumeet organization: Tumor Microenvironment and Animal Models Laboratory, Department of Translational Research, Institute of Life Sciences, Bhubaneswar, Odisha, India, Manipal University, Manipal, Karnataka, India – sequence: 5 givenname: Sharada surname: Swaminathan fullname: Swaminathan, Sharada organization: Department of Bioengineering, School of Chemical and Biotechnology, SASTRA University, Thanjavur, Tamil Nadu, India – sequence: 6 givenname: Ashok K. surname: Mohanty fullname: Mohanty, Ashok K. organization: Proteomics and Structural Biology Laboratory, Animal Biotechnology Department, National Diary Research Institute, Haryana, India – sequence: 7 givenname: Susen K. surname: Panda fullname: Panda, Susen K. organization: Department of Veterinary Pathology, Odisha University of Agriculture and Technology, Bhubaneswar, Odisha, India – sequence: 8 givenname: Pujarini surname: Dash fullname: Dash, Pujarini organization: Tumor Microenvironment and Animal Models Laboratory, Department of Translational Research, Institute of Life Sciences, Bhubaneswar, Odisha, India – sequence: 9 givenname: Subhankar surname: Chakraborty fullname: Chakraborty, Subhankar organization: Mayo Clinic, Division of Gastroenterology and Hepatology, Rochester, Minnesota, MN, USA – sequence: 10 givenname: Surinder K. surname: Batra fullname: Batra, Surinder K. organization: Department of Biochemistry and Molecular Biology, Buffett Cancer Center, Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, USA – sequence: 11 givenname: Shantibhusan surname: Senapati fullname: Senapati, Shantibhusan organization: Tumor Microenvironment and Animal Models Laboratory, Department of Translational Research, Institute of Life Sciences, Bhubaneswar, Odisha, India |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27259232$$D View this record in MEDLINE/PubMed |
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| Keywords | HapT1 pancreatic stellate cells pancreatic cancer hamster homologous orthotopic model desmoplasia |
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| SubjectTerms | Acetylcysteine - administration & dosage Animals Antineoplastic Combined Chemotherapy Protocols - pharmacology Cell Line, Tumor Disulfiram - administration & dosage Fibrosis - prevention & control Guinea Pigs Humans Pancreas - drug effects Pancreas - pathology Pancreatic Neoplasms - drug therapy Pancreatic Stellate Cells - drug effects Pyridones - administration & dosage Rats Research Paper Xenograft Model Antitumor Assays - methods |
| Title | 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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