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Although scientists worldwide do research on tumor development and metastatic cascade of canine tumors, many molecular details of this process are still unknown. For instance, it is still an intricate problem to distinguish between a non-metastasizing and a metastasizing canine mammary carcinoma before metastases are actually detectable. Furthermore, it is unclear whether metastatic behavior is an early inherent feature or a late result of a linear malignant progression. Therefore, the present study visualized and compared the protein expression patterns of canine normal mammary gland, adenomas, non-metastasizing and metastasizing carcinomas (each n=6) by two-dimensional difference gel electrophoresis and identified subsequently differentially expressed proteins by mass spectrometry. Differentiation of nonmetastasizing and metastasizing carcinomas was based on the histological examined lymph node status at the time of surgical excision of the primary tumor mass.
The following two hypotheses were tested here:
1. The metastatic potential of canine mammary tumors is reflected in the protein expression patterns and these differentially expressed proteins reveal potential metastasis markers.
2. Carcinogenesis of canine mammary tumors is associated with malignant progression from normal mammary gland towards metastasizing carcinomas. On the molecular level, this malignant progression is associated with a continuous and linear change of quantitative protein expression levels over the subsequent stages of malignancy.
In total, 48 different proteins featured significant changes in the comparisons: normal mammary gland versus adenomas, adenomas versus non-metastasizing carcinomas and non-metastasizing versus metastasizing carcinomas. Most of them followed three major expression patterns, which were designated as “adenoma pattern”, “carcinoma pattern” and “metastasis pattern”. The main characteristic of these patterns was a stepwise but not linear increase or decrease in protein expression with a subsequent persistence on the same expression level in the consecutive tumor stages. Interestingly, the comparison of nonmetastasizing and metastasizing carcinomas revealed the majority of differentially expressed proteins, notwithstanding their histological similarity. Since many of these proteins have been described as relevant for carcinogenesis and metastasis in other species or other cancer types before, they may serve as potential metastasis markers for canine mammary tumors in the future.
In conclusion, the first hypothesis was supported since metastasis-associated proteins were identifiable in the present global protein analysis. On the contrary, the second hypothesis was not supported since no continuous and linear change of quantitative protein expression levels was detectable over the different stages of increasing malignancy.