Abstract
Comparative oncology aims at speeding up developments for both, human and companion animal cancer patients. Following this line, carcinoembryonic antigen (CEA, CEACAM5) could be a therapeutic target not only for human but also for canine (Canis lupus familiaris; dog) patients. CEACAM5 interacts with CEA-receptor (CEAR) in the cytoplasm of human cancer cells. Our aim was, therefore, to phylogenetically verify the antigenic relationship of CEACAM molecules and CEAR in human and canine cancer.Anti-human CEACAM5 antibody Col-1, previously being applied for cancer diagnosis in dogs, immunohistochemically reacted to 23 out of 30 canine mammary cancer samples. In immunoblot analyses Col-1 specifically detected human CEACAM5 at 180 kDa in human colon cancer cells HT29, and the canine antigen at 60, 120, or 180 kDa in CF33 and CF41 mammary carcinoma cells as well as in spontaneous mammary tumors. While according to phylogenicity canine CEACAM1 molecules should be most closely related to human CEACAM5, Col-1 did not react with canine CEACAM1, -23, -24, -25, -28 or -30 transfected to canine TLM-1 cells. By flow cytometry the Col-1 target molecule was localized intracellularly in canine CF33 and CF41 cells, in contrast to membranous and cytoplasmic expression of human CEACAM5 in HT29. Col-1 incubation had neither effect on canine nor human cancer cell proliferation. Yet, Col-1 treatment decreased AKT-phosphorylation in canine CF33 cells possibly suggestive of anti-apoptotic function, whereas Col-1 increased AKT-phosphorylation in human HT29 cells. We report further a 99% amino acid similarity of human and canine CEA receptor (CEAR) within the phylogenetic tree. CEAR could be detected in four canine cancer cell lines by immunoblot and intracellularly in 10 out of 10 mammary cancer specimens from dog by immunohistochemistry. Whether the specific canine Col-1 target molecule may as functional analogue to human CEACAM5 act as ligand to canine CEAR, remains to be defined. This study demonstrates the limitations of comparative oncology due to the complex functional evolution of the different CEACAM molecules in humans versus dogs. In contrast, CEAR may be a comprehensive interspecies target for novel cancer therapeutics.
Highlights
Comparative oncology trials represent a novel preclinical infrastructure for speeding up the development of anticancer therapeutics [1] [2]
CEACAM5 and canine CEACAM1-related molecules revealed amino acid sequence identities ranging from 42 – 59% and similarities between 55% and 72%. (b) A phylogenetic tree was constructed using MEGA5 from N domain exon nucleotide sequences of selected human and canine CEACAM1-related CEACAMs and CEACAM19, respectively. It shows that CEACAM1-related CEACAMs between the different species are more closely related than CEACAM1-related and other CEACAM types within the same species. (c) Especially the N domain of human CEACAM5 contains multiple regions that are highly similar to regions of canine CEACAM1-related CEACAM N domains
Using Col-1 monoclonal anti-CEACAM5 antibody we have previously developed a mimotope-based anti-CEACAM5 vaccine for the treatment of human carcinoma
Summary
Comparative oncology trials represent a novel preclinical infrastructure for speeding up the development of anticancer therapeutics [1] [2]. 30 to 50% of all canine mammary tumors are malignant and 50 to 75% of these recur or metastasize within 1 to 2 years [11] [12]. For these reasons more effective therapy strategies are urgently needed for companion animals, at the same time their disease mirrors the settings of human oncology patients. Immunological targeting of cancer for diagnosis and therapy is much more advanced in humans[13] [14]. We suggest that careful, comparative evaluation of most important tumor targets should be undertaken to increase the basic knowledge for comparative studies
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