Abstract
Versican expression promotes tumor growth by destabilizing focal cell contacts, thus impeding cell adhesion and facilitating cell migration. It not only presents or recruits molecules to the cell surface, but also modulates gene expression levels and coordinates complex signal pathways. Previously, we suggested that the interaction between versican and human epidermal growth factor receptors may be directly associated with tumor aggressiveness. Thus, the expression of EGFR and HER-2 in these neoplasms may contribute to a better understanding of the progression mechanisms in malignant mammary tumors. The purpose of this study was to correlate the gene and protein expressions of EGFR and HER2 by RNA In Situ Hybridization (ISH) and immunohistochemistry (IHC), respectively, and their relationship with the versican expression in carcinomas in mixed tumors and carcinosarcomas of the canine mammary gland. The results revealed that EGFR mRNA expression showed a significant difference between in situ and invasive carcinomatous areas in low and high versican expression groups. Identical results were observed in HER-2 mRNA expression. In immunohistochemistry analysis, neoplasms with low versican expression showed greater EGFR immunostaining in the in situ areas than in invasive areas, even as the group presenting high versican expression displayed greater EGFR and HER-2 staining in in situ areas. Significant EGFR and HER-2 mRNA and protein expressions in in situ carcinomatous sites relative to invasive areas suggest that these molecules play a role during the early stages of tumor progression.
Highlights
The tumor microenvironment responds to tumor epithelial cells and supports carcinogenesis, but actively contributes to tumor progression and metastasis [1]
A better understanding of the relationship between versican and cell surface receptors in spontaneous tumors in canine mammary glands may contribute to identifying new tumor progression markers
These results suggested that other cell factors might be involved in activating this molecule and led us to investigate the interaction mechanisms between stromal versican and cell surface receptors in spontaneous mammary tumors in dogs
Summary
The tumor microenvironment responds to tumor epithelial cells and supports carcinogenesis, but actively contributes to tumor progression and metastasis [1]. It has been shown that the C-terminal domain of versican modulates epidermal growth factor receptors type 1 (EGFR) and β1- integrin linkage Together, these molecules regulate cell proliferation [9] and migration of neoplastic cells in the stroma [10,11,12]. V3 versican isoform directly or indirectly interferes with the interaction of the heterodimer between EGFR and epidermal growth factor receptors type 2 (HER2) in MeWo melanoma cells. This phenomenon alters the ERK1/2 and p38 MAPK signalling pathways and regulates cell proliferation and migration [10]. It seems that versican presents or recruits molecules to the cell surface, and modulates gene expression levels and coordinates complex signal pathways [13]
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