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Cancers 2018, 10(9), 330; https://doi.org/10.3390/cancers10090330

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

1
Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA
2
Department of Veterinary Clinical Sciences, the Ohio State University College of Veterinary Medicine, Columbus, OH 43210, USA
3
College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA
4
Flint Animal Cancer Center, Colorado State University, Fort Collins, CO 80525, USA
5
Department of Biostatistics, University of Georgia, Athens, GA 30602, USA
6
College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA
*
Author to whom correspondence should be addressed.
Received: 2 September 2018 / Revised: 12 September 2018 / Accepted: 12 September 2018 / Published: 14 September 2018
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Abstract

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. View Full-Text
Keywords: spontaneous canine colorectal tumors; human-dog comparison; cancer cell proliferation and gene mutations; cancer cell invasion and stromal activation; CMS4 and crypt-like or EMT invasion spontaneous canine colorectal tumors; human-dog comparison; cancer cell proliferation and gene mutations; cancer cell invasion and stromal activation; CMS4 and crypt-like or EMT invasion
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Wang, J.; Wang, T.; Sun, Y.; Feng, Y.; Kisseberth, W.C.; Henry, C.J.; Mok, I.; Lana, S.E.; Dobbin, K.; Northrup, N.; Howerth, E.W.; Zhao, S. Proliferative and Invasive Colorectal Tumors in Pet Dogs Provide Unique Insights into Human Colorectal Cancer. Cancers 2018, 10, 330.

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