Ann Surg Treat Res.  2017 Oct;93(4):173-180. 10.4174/astr.2017.93.4.173.

Establishing a colorectal cancer liver metastasis patient-derived tumor xenograft model for the evaluation of personalized chemotherapy

Affiliations
  • 1College of Pharmacy, Duksung Women's University, Seoul, Korea.
  • 2Innovative Drug Center, Duksung Women's University, Seoul, Korea.
  • 3Department of Pathology, Gangnam Severance Hospital, Yonsei University, Seoul, Korea.
  • 4Pancreatobiliary Cancer Clinic, Department of Surgery, Gangnam Severance Hospital, Yonsei University, Seoul, Korea. jspark330@yuhs.ac

Abstract

PURPOSE
In order to suggest optimal anticancer drugs for patient-tailored chemotherapy, we developed a colorectal cancer (CRC)-liver metastasis patient-derived tumor xenograft (PDTX) model.
METHODS
Tissue obtained from a patient with CRC-liver metastasis (F0) was transplanted in a nonobese female mouse with diabetic/severe combined immune deficiency (F1) and the tumor tissue was retransplanted into nude mice (F2). When tumor volumes reached ~500 mm³, the F2 mice were randomly divided into 4 groups (n = 4/group) of doxorubicin, cisplatin, docetaxel, and nontreated control groups. The tumor tissues were investigated using H&E staining, terminal deoxynucleotidyl transferase dUTP nick end labeling assays, and immunohistochemistry. To determine where the mutant allele frequencies varied across the different passages, we isolated genomic DNA from the primary tumor, liver metastasis, and PDTX models (F1/F2).
RESULTS
The physiological properties of the tumor were in accord with those of the patient's tumors. Anticancer drugs delayed tumor growth, inhibited proliferation, and caused apoptosis. Histological assessments revealed no observable heterogeneity among the intragenerational PDTX models. Target exon sequencing analysis without high-quality filter conditions revealed some genetic variations in the 83 cancer-related genes across the generations. However, when de novo mutations were defined as a total count of zero in F0 and ≥5 in F2, exactly prognostic impact of clone cancer profiling (EGFR, KRAS, BRAF, PIK3CA, NRAS, APC and TP53) were detected in the paired.
CONCLUSION
A CRC liver metastasis PDTX model was established for the evaluation of chemotherapeutic efficacy. This model retained the physiological characters of the patient tumors and potentially provides a powerful means of assessing chemotherapeutic efficacy.

Keyword

Colorectal neoplasms; Metastasis; Xenograft model antitumor assays; Sequence analysis

MeSH Terms

Animals
Apoptosis
Cisplatin
Clone Cells
Colorectal Neoplasms*
DNA
DNA Nucleotidylexotransferase
Doxorubicin
Drug Therapy*
Exons
Family Characteristics
Female
Gene Frequency
Genetic Variation
Heterografts*
Humans
Immunohistochemistry
Liver*
Mice
Mice, Nude
Neoplasm Metastasis*
Population Characteristics
Sequence Analysis
Xenograft Model Antitumor Assays
Cisplatin
DNA
DNA Nucleotidylexotransferase
Doxorubicin
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