Cancer Res Treat.  2017 Oct;49(4):915-926. 10.4143/crt.2016.322.

Patient-Derived Xenograft Models of Epithelial Ovarian Cancer for Preclinical Studies

• Heo EJ
• Cho YJ
• Cho WC
• Hong JE
• Jeon HK
• Oh DY
• Choi YL
• Song SY
• Choi JJ
• Bae DS
• Lee YY
• Choi CH
• Kim TJ
• Park WY
• Kim BG
• Lee JW

• KMID: 2394811
• DOI: http://doi.org/10.4143/crt.2016.322

Abstract

PURPOSE
Patient-derived tumor xenografts (PDXs) can provide more reliable information about tumor biology than cell line models. We developed PDXs for epithelial ovarian cancer (EOC) that have histopathologic and genetic similarities to the primary patient tissues and evaluated their potential for use as a platform for translational EOC research.
MATERIALS AND METHODS
We successfully established PDXs by subrenal capsule implantation of primary EOC tissues into female BALB/C-nude mice. The rate of successful PDX engraftment was 48.8% (22/45 cases). Hematoxylin and eosin staining and short tandem repeat analysis showed histopathological and genetic similarity between the PDX and primary patient tissues.
RESULTS
Patients whose tumors were successfully engrafted in mice had significantly inferior overall survival when compared with those whose tumors failed to engraft (p=0.040). In preclinical tests of this model, we found that paclitaxel-carboplatin combination chemotherapy significantly deceased tumor weight in PDXs compared with the control treatment (p=0.013). Moreover, erlotinib treatment significantly decreased tumor weight in epidermal growth factor receptor-overexpressing PDX with clear cell histology (p=0.023).
CONCLUSION
PDXs for EOC with histopathological and genetic stability can be efficiently developed by subrenal capsule implantation and have the potential to provide a promising platform for future translational research and precision medicine for EOC.

Keyword

Patient-derived xenograft model; Subrenal capsule implantation; Ovarian epithelial cancer; Precision medicine; Molecular targeted therapy

MeSH Terms

Animals
Biology
Cell Line
Drug Therapy, Combination
Eosine Yellowish-(YS)
Epidermal Growth Factor
Erlotinib Hydrochloride
Female
Hematoxylin
Heterografts*
Humans
Mice
Microsatellite Repeats
Molecular Targeted Therapy
Ovarian Neoplasms*
Precision Medicine
Translational Medical Research
Tumor Burden
Eosine Yellowish-(YS)
Epidermal Growth Factor
Erlotinib Hydrochloride
Hematoxylin

Figure

• 

  Fig. 1. Progression-free survival (A) and overall survival (B) of epithelial ovarian cancer patients according to the engraftment status of their patient-derived tumor xenografts using Kaplan-Meier plots and the log-rank test. Patients whose tumors successfully engrafted in mice had significantly inferior overall survival (p=0.040) and a trend of inferior progression-free survival (p=0.210).

• 

  Fig. 2. Histopathologic comparison between patients’ primary tumors and their patient-derived tumor xenografts (PDXs) tumors (H&E staining, ×100) revealed a similar architectural pattern of nesting configuration and comparable cytologic atypia. (A) A representative case of serous carcinoma (upper panel, OV-40) and clear cell carcinoma (CCC; lower panel, OV-64). Histopathologic comparison between cell line xenografts and PDXs (H&E staining; upper panels, ×100; lower panels, ×200) revealed a similar architectural pattern of nesting configuration and comparable cytologic atypia. (B) Comparison between the HeyA8 cell-line xenograft and PDXs of serous carcinoma (left panel), and the RMG1 cell-line xenograft and PDX of clear cell carcinoma (right panel).

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  Fig. 3. Validation of histopathologic and genetic stability of patient-derived tumor xenografts (PDXs) compared with primary tumors in a representative case of epithelial ovarian cancer with high-grade serous carcinoma. (A) H&E staining showed that morphology and tissue architecture were preserved. (B) Short tandem repeat analysis for 15 loci on different chromosomes showed almost identical banding patterns between PDXs and primary patient’s tumor.

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  Fig. 4. Effect of combination paclitaxel-carboplatin chemotherapy in patient-derived tumor xenografts (PDXs) model. (A) Diagram of the experimental design. A PDXs model of high-grade papillary serous ovarian cancer (OV-41) was generated and serially passaged in vivo to up to M3 PDXs (OV-41-M3). The PDXs were treated intraperitoneally with combination chemotherapy. (B) The tumor weight of PDXs that received combination chemotherapy was significantly decreased relative to phosphate buffered saline–treated controls (p=0.008).

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  Fig. 5. Effect of epidermal growth factor receptor (EGFR) inhibitor (erlotinib) on cell line xenografts and patient-derived tumor xenografts (PDXs) of clear cell carcinoma. (A) EGFR protein expression was variable in ovarian cancer cell lines of clear cell carcinoma. In xenografts of RMG1, which had the strongest expression of EGFR, erlotinib significantly decreased the tumor weight relative to the control (p=0.029). (B) PDXs of OV-64, which had low EGFR expression, did not show the erlotinib effect. In PDXs of OV-68, which had strong EGFR expression, erlotinib significantly decreased the tumor weight compared with the control (p=0.023).

Reference

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