Bosentan® inhibits tumor vascularization and bone metastasis in an immunocompetent skin-fold chamber model of breast carcinoma cell metastasis

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Abstract
Angiogenic factors including endothelin-1 (ET-1) play a key role in the progression of breast metastases to bone. We investigated the impact of ET-1 on the development of bone metastases in an immunocompetent murine skin-fold chamber model. Murine mammary carcinoma 4T1 was injected in a skin-fold chamber implanted on CB6 mice along with bone explants. Furthermore, mice were treated with or without a dual selective antagonist of both ET-1 receptors. The progression of the vascularization within the chamber was monitored over time by intravital microscopy (IVM). The tumor growth and the development of bone metastases were assessed by cytokeratin-19 gene expression and histological studies. Results indicate that this new model associated with IVM allows for the continuous monitoring of the change in vascularization associated with the development of bone metastases. Additionally, treatment with an antagonist of both ET-1 receptors was associated with the presence of significantly less vessels near the tumor mass compared to control mice. These changes were correlated with smaller tumor masses and reduced bone invasion (P < 0.05). Thus, in an immunocompetent murine model of breast carcinoma metastases to bone, our data support the hypothesis that vascularization plays a role in tumor development and progression and that ET-1 specifically modulates the angiogenesis associated with breast metastases to the bone.