Abstract
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. 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). 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. 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.
Highlights
Colorectal cancer is the second leading cause of death from cancer worldwide [1]
Surgical resection combined with adjuvant therapy is mostly effective at the early stages of the disease, both subsequent relapse and Authors' Affiliations: 1Translational Program, Stem Cells and Cancer Laboratory; 2Molecular Oncology Group; 3Genomics Cancer Group; and 4Translational Genomics Group, Vall d'Hebron Institute of Oncology (VHIO); 5Parc de Recerca Biomedica de Barcelona (PRBB), Centre d'Imatge Molecular (CRC) Corporacio Sanitaria; Departments of 6Pathology, 7Medical Oncology, and 8HBP Surgery and Transplantation, Vall d'Hebron University Hospital, Universidad Autonoma de Barcelona; and 9General Surgery Service, Vall d'Hebron University Hospital, Barcelona, Spain
We have developed a preclinical model of colon cancer metastasis by injecting patientderived colon cancer cells into the cecum wall of NODSCID mice and following tumor evolution by positron emission tomography (PET)
Summary
Colorectal cancer is the second leading cause of death from cancer worldwide [1]. surgical resection combined with adjuvant therapy is mostly effective at the early stages of the disease, both subsequent relapse and Authors' Affiliations: 1Translational Program, Stem Cells and Cancer Laboratory; 2Molecular Oncology Group; 3Genomics Cancer Group; and 4Translational Genomics Group, Vall d'Hebron Institute of Oncology (VHIO); 5Parc de Recerca Biomedica de Barcelona (PRBB), Centre d'Imatge Molecular (CRC) Corporacio Sanitaria; Departments of 6Pathology, 7Medical Oncology, and 8HBP Surgery and Transplantation, Vall d'Hebron University Hospital, Universidad Autonoma de Barcelona; and 9General Surgery Service, Vall d'Hebron University Hospital, Barcelona, SpainNote: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).Ó2013 American Association for Cancer Research.diagnosis at late stage with metastasis are frequent and responsible for the majority of patient deaths. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Diagnosis at late stage with metastasis are frequent and responsible for the majority of patient deaths. At these advanced stages, resistance to conventional therapies are frequent and treatments are quite ineffective [2]. A better understanding of the mechanisms driving drug-response and metastasis is crucial in order to better guide treatment decisions and improve patient outcomes
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