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

Overview

MeSH

  • Animals
  • Blastocyst
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Mice
  • Neoplasm Metastasis
  • Receptors, Notch
  • Signal Transduction
  • Xenograft Model Antitumor Assays

MeSH Major

  • Colorectal Neoplasms
  • Disease Models, Animal
  • Liver Neoplasms, Experimental
  • Receptors, CCR

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.

publication date

  • June 2015

has subject area

  • Animals
  • Blastocyst
  • Cell Line, Tumor
  • Colorectal Neoplasms
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Liver Neoplasms, Experimental
  • Mice
  • Neoplasm Metastasis
  • Receptors, CCR
  • Receptors, Notch
  • Signal Transduction
  • Xenograft Model Antitumor Assays

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4532544

Digital Object Identifier (DOI)

  • 10.1038/nbt.3239

PubMed ID

  • 26006007

Additional Document Info

start page

  • 656

end page

  • 660

volume

  • 33

number

  • 6