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.
Highlights
Spontaneous canine cancers represent one of the best animal models of human cancers [1,2,3,4,5,6,7,8,9,10,11].Being naturally occurring, heterogeneous and with an intact immune system, they capture the essence of human cancer, unlike most genetically modified or xenograft rodent models
We found that stromal signatures derived from human colorectal cancer (CRC) [32] are activated in canine invasive tumors, compared to proliferative tumors
To investigate epithelial–mesenchymal transition (EMT) in these canine tumors, we examined its signatures from human CRC [26,35]
Summary
Spontaneous canine cancers represent one of the best animal models of human cancers [1,2,3,4,5,6,7,8,9,10,11].Being naturally occurring, heterogeneous and with an intact immune system, they capture the essence of human cancer, unlike most genetically modified or xenograft rodent models. Spontaneous canine cancers represent one of the best animal models of human cancers [1,2,3,4,5,6,7,8,9,10,11]. Cancers 2018, 10, 330 better resemble humans in biology, e.g., similar telomere and telomerase activities [12] and more frequent spontaneous cancers of epithelial origin [2,8,9,10,11], unlike mice [13]. Unlike human cancers where hundreds of thousands of cancer cases have been characterized with genome-wide approaches [14,15,16,17,18,19,20,21], far fewer canine cancers have been studied. We have a limited molecular understanding of canine cancers, which makes this immensely valuable resource significantly understudied and underused
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