Establishment and characterization of patient-derived xenograft (PDX) models from peritoneal metastasis of colorectal carcinoma as novel platform for drug testing and biomarker evaluation

Background: Colorectal carcinoma (CRC) is associated with high incidence and high mortality rate, particularly if metastasized to distant sites. One important site for CRC metastasis is the peritoneum. At time of first diagnosis 4 to 7% of the patients suffer from peritoneal metastasis (PM) of CRC....

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Bibliographic Details
Published in:European journal of cancer (1990) 2016-12, Vol.69, p.S112-S113
Main Authors: Walther, W, Pachmayr, E, Brzezycha, B, Büttner, B, Rau, B, Stein, U
Format: Article
Language:English
Subjects:
Animal models
Biomarkers
Colorectal cancer
Colorectal carcinoma
Diaphragm
Drug testing
Drugs
Evaluation
Gene expression
Hematology, Oncology and Palliative Medicine
Histology
Histopathology
Immunohistochemistry
Immunosuppressive agents
In vivo methods and tests
Irinotecan
Kidneys
Metastases
Metastasis
Mice
Molecular chains
Monoclonal antibodies
Omentum
Ovaries
Patients
Peritoneum
Polymerase chain reaction
Surgery
Targeted cancer therapy
Transplantation
Tumors
Xenografts
Xenotransplantation
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Summary:Background: Colorectal carcinoma (CRC) is associated with high incidence and high mortality rate, particularly if metastasized to distant sites. One important site for CRC metastasis is the peritoneum. At time of first diagnosis 4 to 7% of the patients suffer from peritoneal metastasis (PM) of CRC. The PM is associated with poor prognosis and limited therapeutic options. Therefore, availability of adequate in vivo models for PM could significantly promote the evaluation of chemosensitivity of PM towards standard, targeted and novel drugs as well as analysis of novel prognostic or even predictive biomarkers. Such models could be employed for patient stratification and individualized concepts to improve the therapeutic outcome of PM patients. During the last decade patient-derived xenograft(PDX) mouse models have gained importance, since they closely resemble the molecular and biological features of the original primary tumors. So far no PM PDX models have been established from CRC. We therefore focused on the establishment of a novel CRC PM panel of PDX as useful platform for preclinical studies. Material and Methods: For the PDX establishment colorectal surgical specimens were subcutaneously (s.c.) transplanted onto NOD scid gamma (NSG) immunocompromized mice. Engrafted tumors were transferred to NMRI nu/nu mice for further passaging. Engrafted tumors were characterized by histopathology and gene expression analyses using real-time RT-PCR and immunohistochemistry. Chemosensitivity of PDX models was evaluated in vivo by application of a panel of conventional chemotherapeutic and targeted drugs. Results: For PDX establishment 58 CRC surgical specimens (taken from peritoneum and omentum) were transplanted onto NSG mice. From those, currently 19 PDX have engrafted, growing stably on NMRI nu/nu mice. Histopathological evaluation revealed maintenance of the CRC histology of the PDX. For selected PDX, orthotopic transplantation into the peritoneum revealed their potential to form tumors in kidney, ovaries and abdominal diaphragm. The chemosensitivity testing of conventional and of targeted drugs in 10 of the PM PDX models revealed heterogeneous response of the PDX, particularly for 5-FU. irinotecan, docetaxel, cetuximab. erlotinib and regorafenib. More interestingly, different responses were observed in PDX from omentum vs. peritoneum, derived from the same patient, indicating some heterogeneity within the PM. Conclusions: This PDX mouse model panel of the CRC PM
ISSN:0959-8049
1879-0852
DOI:10.1016/S0959-8049(16)32934-3