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Clin Cancer Res. 2013 Dec 15;19(24):6787-801. doi: 10.1158/1078-0432.CCR-12-1740. Epub 2013 Oct 29.

A personalized preclinical model to evaluate the metastatic potential of patient-derived colon cancer initiating cells.

Author information

1
Authors' Affiliations: Translational Program, Stem Cells and Cancer Laboratory; Molecular Oncology Group; Genomics Cancer Group; and Translational Genomics Group, Vall d'Hebron Institute of Oncology (VHIO); Parc de Recerca Biomèdica de Barcelona (PRBB), Centre d'Imatge Molecular (CRC) Corporació Sanitària; Departments of Pathology, Medical Oncology, and HBP Surgery and Transplantation, Vall d'Hebron University Hospital, Universidad Autónoma de Barcelona; and General Surgery Service, Vall d'Hebron University Hospital, Barcelona, Spain.

Abstract

PURPOSE:

Within the aim of advancing precision oncology, we have generated a collection of patient-derived xenografts (PDX) characterized at the molecular level, and a preclinical model of colon cancer metastasis to evaluate drug-response and tumor progression.

EXPERIMENTAL DESIGN:

We derived cells from 32 primary colorectal carcinomas and eight liver metastases and generated PDX annotated for their clinical data, gene expression, mutational, and histopathological traits. Six models were injected orthotopically into the cecum wall of NOD-SCID mice in order to evaluate metastasis. Three of them were treated with chemotherapy (oxaliplatin) and three with API2 to target AKT activity. Tumor growth and metastasis progression were analyzed by positron emission tomography (PET).

RESULTS:

Patient-derived cells generated tumor xenografts that recapitulated the same histopathological and genetic features as the original patients' carcinomas. We show an 87.5% tumor take rate that is one of the highest described for implanted cells derived from colorectal cancer patients. Cecal injection generated primary carcinomas and distant metastases. Oxaliplatin treatment prevented metastasis and API2 reduced tumor growth as evaluated by PET.

CONCLUSIONS:

Our improved protocol for cancer cell engraftment has allowed us to build a rapidly expanding collection of colorectal PDX, annotated for their clinical data, gene expression, mutational, and histopathological statuses. We have also established a mouse model for metastatic colon cancer with patient-derived cells in order to monitor tumor growth, metastasis evolution, and response to treatment by PET. Our PDX models could become the best preclinical approach through which to validate new biomarkers or investigate the metastatic potential and drug-response of individual patients.

PMID:
24170545
DOI:
10.1158/1078-0432.CCR-12-1740
[Indexed for MEDLINE]
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