Format

Send to

Choose Destination
Nat Biotechnol. 2015 Jun;33(6):656-60. doi: 10.1038/nbt.3239. Epub 2015 May 25.

Comprehensive models of human primary and metastatic colorectal tumors in immunodeficient and immunocompetent mice by chemokine targeting.

Author information

1
1] Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA. [2] Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
2
Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
3
Department of Cell Biology, Albert Einstein College of Medicine, New York, New York, USA.
4
Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.
5
Department of Surgery, Weill Cornell Medical College, New York, New York, USA.
6
Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, New York, USA.
7
Department of Pathology, University of California, Irvine, Irvine, California, USA.
8
School of Electrical and Computer Engineering, Cornell University, Ithaca, New York, USA.
9
1] Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA. [2] School of Electrical and Computer Engineering, Cornell University, Ithaca, New York, USA.
10
College of Veterinary Medicine and Biological Sciences, Cornell University, Ithaca, New York, USA.
11
1] Department of Medicine, Weill Cornell Medical College, New York, New York, USA. [2] Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Abstract

Current orthotopic xenograft models of human colorectal cancer (CRC) require surgery and do not robustly form metastases in the liver, the most common site clinically. CCR9 traffics lymphocytes to intestine and colorectum. We engineered use of the chemokine receptor CCR9 in CRC cell lines and patient-derived cells to create primary gastrointestinal (GI) tumors in immunodeficient mice by tail-vein injection rather than surgery. The tumors metastasize inducibly and robustly to the liver. Metastases have higher DKK4 and NOTCH signaling levels and are more chemoresistant than paired subcutaneous xenografts. Using this approach, we generated 17 chemokine-targeted mouse models (CTMMs) that recapitulate the majority of common human somatic CRC mutations. We also show that primary tumors can be modeled in immunocompetent mice by microinjecting CCR9-expressing cancer cell lines into early-stage mouse blastocysts, which induces central immune tolerance. We expect that CTMMs will facilitate investigation of the biology of CRC metastasis and drug screening.

PMID:
26006007
PMCID:
PMC4532544
DOI:
10.1038/nbt.3239
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center