Dataset Information

Characterisation and use of orthotopically grownHapT1tumours in its homologous host as a preclinical model to evaluate novel drugs against desmoplastic pancreatic cancer

ABSTRACT: The major objective of this study was to characterise theHapT1 orthotopic hamster pancreatic tumor as a preclinical model of desmoplastic pancreatic ductal adenocarcinoma; and use this model to validate the efficacy of drugs that kills activated pancreatic stellate cells (PSCs)in vitro. Experimentaldesign: Commercially procured HapT1 pancreatic cancer (PCA) cell line was implanted in the pancreas of its syngeneic host, Syrian golden hamster (Mesocricetusauratus). After certain time period the primary and secondary tumors were harvested for histological andimmunophynotypical analysis. PSCs of hamsters were harvested, cultured and characterised. The in-cultured activated rodent PSCs and commercially procured human PSCs were used to check the cytotoxic effect of Disulfiram (DSF) in presence and absence of copper (Cu )in vitro. Finally, theHapT1 orthotopic tumor model was used to check the efficacy of DSF in vivo.

INSTRUMENT(S): Bruker Daltonics maXis series

ORGANISM(S): Cricetulus Griseus (chinese Hamster) (cricetulus Barabensis Griseus)

TISSUE(S): Pancreatic Ductal Adenocarcinoma Cell, Pancreatic Stellate Cell

DISEASE(S): Pancreatic Ductal Carcinoma

SUBMITTER: Shantibhusan Senapati

LAB HEAD: Dr. Shantibhusan Senapati

PROVIDER: PXD003385 | Pride | 2018-10-26

REPOSITORIES: Pride

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Publications

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

Suklabaidya Sujit S Das Biswajit B Ali Syed Azmal SA Jain Sumeet S Swaminathan Sharada S Mohanty Ashok K AK Panda Susen K SK Dash Pujarini P Chakraborty Subhankar S Batra Surinder K SK Senapati Shantibhusan S

Oncotarget 20160701 27

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 morphologica ...[more]

PMID: 27259232

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Project description:The heterotransplantation of human tumors to immune-deprived rodents has become an important preclinical tool for evaluating human tumor biology and responsiveness to therapeutic agents, based on the supposition that they reflect their original human origin. However, we demonstrate that such tumors can in fact change genetically, either by becoming tumors of the animal recipient or by becoming a hybrid of the human tumor and the animal hostâs cells. Three human tumors transplanted to the cheek pouch of golden hamsters resulted in permanently transplantable tumors that metastasize in the hamsters. Based on diverse lines of evidence, these transplants from a human glioblastoma multiforme and two Hodgkin lymphomas were malignant hybrids, showing both human and hamster genes in the malignant tumor cells, while retaining the morphology of the original human tumors. We demonstrate that even after being preserved for over 40 years in paraffin blocks, microarray analysis of RNA from these transplants disclosed over 3000 human genes derived from all 23 human chromosome pairs amongst these tumor transplants. A total of 3759 probe sets (ranging from 1040 to 1303 in each transplant) detected human gene transcripts in formalin-fixed, paraffin-embedded sections of the 3 hybrid tumors stored for over 40 years; the probe sets unambiguously map to 3107 unique Human Entrez Gene IDs and are representative of all human chromosomes, although, by karyology, one of the hybrid tumors (GB-749) had a total of 15 human chromosomes in its cells. Among the genes mapped, 39 probe sets, representing transcripts from 33 human genes , were detected in all hybrid tumor samples. Five of these 33 genes encode transcription factors that regulate cell growth and differentiation, five encode cell adhesion and transmigration-associated proteins known to participate in oncogenesis and/or metastasis and invasion, and additional genes encode components of pathways involved with signal transduction, regulation of apoptosis, DNA repair, and multidrug resistance. We posit that in-vivo fusion may disclose genes implicated in tumor progression, as well as gene families coding for the organoid phenotype. Thus, cancer cells can transduce adjacent stromal cells, with the resulting progeny having permanently transcribed genes with malignant and other functions of the donor DNA. Human gene expression profiles were determined by microarray analysis for 3 different Human-Hamster hybrid tumors, two Hodgkin lymphomas (GW-532, GW-584) and a glioblastoma multiforme (GB-749), that were first generated in the hamster cheek pouch after human tumor grafting and then propagated in hamsters and in cell cultures for years. Human gene expression was assessed using total RNA isolated from FFPE samples from GW-532 generations 2 and 34, GW-584 generation 28, and GB-749, in comparison to that for a Hamster control RNA sample isolated from a Hamster melanoma cell line (ATCC CCL-49). Expressed human genes were identified using MAS 5.0 signal expression values and detection P-values in the following manner: 1) Unannotated probe sets, as well as probe sets with no signal value greater than the median signal for AFFX spike-in controls with all Absent Detection Calls, were omitted from further analysis; 2) All remaining signal values for the hamster cell line sample were multiplied by the ratio of the median signal in all FFPE hybrid samples for AFFX spike-in control probe sets called present in all samples divided by the median signal for the same probe sets in the hamster CCL-49 sample; 3) Human transcripts were considered positive in a human-hamster hybrid FFPE sample if (a) a probe set signal exhibited a 2-fold or greater increase in any FFPE hybrid sample compared to the CCL-49 coontrol sample, (b) the fold change was greater than 2 standard deviations for that probe set across the FFPE samples, and (c) was called present (P) or marginal (M) for at least one or more FFPE samples.

Dataset Information

Characterisation and use of orthotopically grownHapT1tumours in its homologous host as a preclinical model to evaluate novel drugs against desmoplastic pancreatic cancer

Publications

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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