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Oncogene. 2016 Jan 21;35(3):290-300. doi: 10.1038/onc.2015.94. Epub 2015 Apr 20.

XactMice: humanizing mouse bone marrow enables microenvironment reconstitution in a patient-derived xenograft model of head and neck cancer.

Author information

1
Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine.
2
Department of Dermatology, University of Colorado School of Medicine.
3
Department of Biostatistics and Informatics, University of Colorado School of Medicine.
4
Department of Radiation Oncology, University of Colorado School of Medicine.
5
Department of Pathology, University of Colorado School of Medicine.
6
Department of Otolaryngology, University of Colorado School of Medicine.
7
Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado School of Medicine, Aurora, CO, USA.

Abstract

The limitations of cancer cell lines have led to the development of direct patient-derived xenograft models. However, the interplay between the implanted human cancer cells and recruited mouse stromal and immune cells alters the tumor microenvironment and limits the value of these models. To overcome these constraints, we have developed a technique to expand human hematopoietic stem and progenitor cells (HSPCs) and use them to reconstitute the radiation-depleted bone marrow of a NOD/SCID/IL2rg(-/-) (NSG) mouse on which a patient's tumor is then transplanted (XactMice). The human HSPCs produce immune cells that home into the tumor and help replicate its natural microenvironment. Despite previous passage on nude mice, the expression of epithelial, stromal and immune genes in XactMice tumors aligns more closely to that of the patient tumor than to those grown in non-humanized mice-an effect partially facilitated by human cytokines expressed by both the HSPC progeny and the tumor cells. The human immune and stromal cells produced in the XactMice can help recapitulate the microenvironment of an implanted xenograft, reverse the initial genetic drift seen after passage on non-humanized mice and provide a more accurate tumor model to guide patient treatment.

PMID:
25893296
PMCID:
PMC4613815
DOI:
10.1038/onc.2015.94
[Indexed for MEDLINE]
Free PMC Article

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