Proliferative and Invasive Colorectal Tumors in Pet Dogs Provide Unique Insights into Human Colorectal Cancer

  • Jin Wang
    Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA
  • Tianfang Wang
    Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA
  • Yanfang Sun
    Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA
  • Yuan Feng
    Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA
  • William C. Kisseberth
    Department of Veterinary Clinical Sciences, the Ohio State University College of Veterinary Medicine, Columbus, OH 43210, USA
  • Carolyn J. Henry
    College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA
  • Irene Mok
    Flint Animal Cancer Center, Colorado State University, Fort Collins, CO 80525, USA
  • Susan E. Lana
    Flint Animal Cancer Center, Colorado State University, Fort Collins, CO 80525, USA
  • Kevin Dobbin
    Department of Biostatistics, University of Georgia, Athens, GA 30602, USA
  • Nicole Northrup
    College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA
  • Elizabeth W. Howerth
    College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA
  • Shaying Zhao
    Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA

Description

<jats:p>Spontaneous tumors in pet dogs represent a valuable but undercharacterized cancer model. To better use this resource, we performed an initial global comparison between proliferative and invasive colorectal tumors from 20 canine cases, and evaluated their molecular homology to human colorectal cancer (CRC). First, proliferative canine tumors harbor overactivated WNT/β-catenin pathways and recurrent CTNNB1 (β-catenin) mutations S45F/P, D32Y and G34E. Invasive canine tumors harbor prominent fibroblast proliferation and overactivated stroma. Both groups have recurrent TP53 mutations. We observed three invasion patterns in canine tumors: collective, crypt-like and epithelial–mesenchymal transition (EMT). We detected enriched Helicobacter bilis and Alistipes finegoldii in proliferative and crypt-like tumors, but depleted mucosa-microbes in the EMT tumor. Second, guided by our canine findings, we classified 79% of 478 human colon cancers from The Cancer Genome Atlas into four subtypes: primarily proliferative, or with collective, crypt-like or EMT invasion features. Their molecular characteristics match those of canine tumors. We showed that consensus molecular subtype 4 (mesenchymal) of human CRC should be further divided into EMT and crypt-like subtypes, which differ in TGF-β activation and mucosa-microbe content. Our canine tumors share the same pathogenic pathway as human CRCs. Dog-human integration identifies three CRC invasion patterns and improves CRC subtyping.</jats:p>

Journal

  • Cancers

    Cancers 10 (9), 330-, 2018-09-14

    MDPI AG

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