Characterization of a Large Panel of Patient-Derived Tumor Xenografts Representing the Clinical Heterogeneity of Human Colorectal Cancer
- 30 September 2012
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 18 (19), 5314-5328
- https://doi.org/10.1158/1078-0432.ccr-12-0372
Abstract
Patient-derived xenograft models are considered to represent the heterogeneity of human cancers and advanced preclinical models. Our consortium joins efforts to extensively develop and characterize a new collection of patient-derived colorectal cancer (CRC) models. From the 85 unsupervised surgical colorectal samples collection, 54 tumors were successfully xenografted in immunodeficient mice and rats, representing 35 primary tumors, 5 peritoneal carcinoses and 14 metastases. Histologic and molecular characterization of patient tumors, first and late passages on mice includes the sequence of key genes involved in CRC (i.e., APC, KRAS, TP53), aCGH, and transcriptomic analysis. This comprehensive characterization shows that our collection recapitulates the clinical situation about the histopathology and molecular diversity of CRC. Moreover, patient tumors and corresponding models are clustering together allowing comparison studies between clinical and preclinical data. Hence, we conducted pharmacologic monotherapy studies with standard of care for CRC (5-fluorouracil, oxaliplatin, irinotecan, and cetuximab). Through this extensive in vivo analysis, we have shown the loss of human stroma cells after engraftment, observed a metastatic phenotype in some models, and finally compared the molecular profile with the drug sensitivity of each tumor model. Through an experimental cetuximab phase II trial, we confirmed the key role of KRAS mutation in cetuximab resistance. This new collection could bring benefit to evaluate novel targeted therapeutic strategies and to better understand the basis for sensitivity or resistance of tumors from individual patients.Keywords
Other Versions
This publication has 24 references indexed in Scilit:
- Molecular profiling of patient-derived breast cancer xenograftsBreast Cancer Research, 2012
- Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomesNature Medicine, 2011
- Guidelines for the welfare and use of animals in cancer researchBritish Journal of Cancer, 2010
- Genome remodelling in a basal-like breast cancer metastasis and xenograftNature, 2010
- Establishment and Characterization of a Panel of Human Uveal Melanoma Xenografts Derived from Primary and/or Metastatic TumorsClinical Cancer Research, 2010
- PIK3CA Mutations in Colorectal Cancer Are Associated with Clinical Resistance to EGFR-Targeted Monoclonal AntibodiesCancer Research, 2009
- Human xenograft models as useful tools to assess the potential of novel therapeutics in prostate cancerBritish Journal of Cancer, 2008
- The Catalogue of Somatic Mutations in Cancer (COSMIC)Current Protocols in Human Genetics, 2008
- Clonogenic assay with established human tumour xenograftsEuropean Journal Of Cancer, 2004
- The UCSC Genome Browser DatabaseNucleic Acids Research, 2003