Bridging the Species Gap: Morphological and Molecular Comparison of Feline and Human Intestinal Carcinomas

SIMPLE SUMMARY: Colorectal cancer (CRC) is the second leading cause of cancer deaths in humans (2020) but modeling late-stage human CRC, including high tumor budding and metastatic activity, experimentally in mouse models is a major challenge. In the present study, histopathological, immunohistochemical and molecular features of spontaneous intestinal carcinomas in cats were evaluated with a special focus on their potential applicability as a valuable model for human CRC. Feline intestinal tumors display aggressive growth patterns and adequately model invasive late-stage human CRC. They exhibit the same histological subtypes and display strikingly high tumor budding activity, both of which are highly significant prognostic factors in human CRC. Moreover, human and feline colorectal tumors harbor the same mutations of the CTNNB1 gene, encoding β-catenin. Our data indicate that feline intestinal carcinomas constitute a valuable and promising in vivo model for human CRC. Further comparative oncological research, and especially investigation of the molecular landscape of feline intestinal neoplasms, is imperative. ABSTRACT: Limited availability of in vivo experimental models for invasive colorectal cancer (CRC) including metastasis and high tumor budding activity is a major problem in colorectal cancer research. In order to compare feline and human intestinal carcinomas, tumors of 49 cats were histologically subtyped, graded and further characterized according to the human WHO classification. Subsequently, feline tumors were compared to a cohort of 1004 human CRC cases. Feline intestinal tumors closely resembled the human phenotype on a histomorphological level. In both species, adenocarcinoma not otherwise specified (ANOS) was the most common WHO subtype. In cats, the second most common subtype of the colon (36.4%), serrated adenocarcinoma (SAC), was overrepresented compared to human CRC (8.7%). Mucinous adenocarcinoma (MAC) was the second most common subtype of the small intestine (12.5%). Intriguingly, feline carcinomas, particularly small intestinal, were generally of high tumor budding (Bd) status (Bd3), which is designated an independent prognostic key factor in human CRC. We also investigated the relevance of feline CTNNB1 exon 2 alterations by Sanger sequencing. In four cases of feline colonic malignancies (3 ANOS, 1 SAC), somatic missense mutations of feline CTNNB1 (p.D32G, p.D32N, p.G34R, and p.S37F) were detected, indicating that mutational alterations of the WNT/β-catenin signaling pathway potentially play an essential role in feline intestinal tumorigenesis comparable to humans and dogs. These results indicate that spontaneous intestinal tumors of cats constitute a useful but so far underutilized model for human CRC. Our study provides a solid foundation for advanced comparative oncology studies and emphasizes the need for further (molecular) characterization of feline intestinal carcinomas.