Characterization and use of HapT1-derived homologous tumors as a preclinical model to evaluate therapeutic efficacy of drugs against pancreatic tumor desmoplasia

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.

Macrophage migration inhibitory factor of Syrian golden hamster has similar structure and function as human MIF and promotes pancreatic tumor growth

“…Then cells were harvested in RLT buffer and processed for RNA isolation as described by the manufacturer (Qiagen, USA). RNA quantification was carried out using Nanodrop followed by cDNA synthesis [10]. The expression levels of Il-1, Tnf-, Vegf, and Il-6 were analyzed in all the cDNA samples through qPCR, by using gene-specific primers.…”

“…Hamsters are important animal models for studying various infectious diseases of humans [1][2][3][4][5][6][7][8]. The hamster models of pancreatic and oral cancer have gained importance in their respective fields [9][10][11][12][13][14]. Moreover, these animals have also been instrumental in studying metabolic and/or inflammatory diseases like diabetes and pancreatitis [15,16].…”

“…Involvement of MIF in a number of human diseases like pulmonary hypertension, endothelial cell growth, atherosclerosis, wound healing, viral infection, many cancers including lung, colon, prostate, breast and pancreatic cancer has bagged a significant interest in this molecule [21]. In one of our earlier published study, we have characterized HapT-1 cell line-based Syrian hamster tumor as a model of pancreatic cancer associated desmoplasia, an event which plays a key role in human pancreatic cancer progression [10]. In that study, for the first time, global proteomics analysis of whole cell lysate from hamster pancreatic stellate cells (PSCs) showed expression of macrophage migration inhibitory factor (MIF) by the cells [10].…”

“…In one of our earlier published study, we have characterized HapT-1 cell line-based Syrian hamster tumor as a model of pancreatic cancer associated desmoplasia, an event which plays a key role in human pancreatic cancer progression [10]. In that study, for the first time, global proteomics analysis of whole cell lysate from hamster pancreatic stellate cells (PSCs) showed expression of macrophage migration inhibitory factor (MIF) by the cells [10]. At that particular time, due to unavailability of information and reagents for hamster MIF, we were unable to investigate the function of this molecule in the hamster model of pancreatic cancer.…”

The pancreatic cancer microenvironment: A true double agent

“…Treatment with pirfenidone inhibited PSC growth, migration, invasion, and ECM production. In preclinical studies pirfenidone has demonstrated some promising effects in combination with gemcitabine, with β‐cyclodextrin MMP2 responsive liposome and with the antioxidant N ‐acetyl cysteine . This compound has yet to be evaluated in human trials.…”