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

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.

The Endothelin Receptor Blocker Bosentan Inhibits Doxorubicin-Induced Cardiomyopathy

“…Therefore, the use of endothelin receptor antagonists, including bosentan, as anticancer drugs has been addressed in experimental and clinical settings (25)(26)(27)(28).…”

Vasculopathy in scleroderma

“…For instance, bosentan alleviates increased neovascularization and leaky vessels in cerebrovascular system of a type 2-diabetic animal model and inhibits tumor vascularization and bone metastasis in an animal model of breast carcinoma cell metastasis [106,107]. This is also the case in SSc because the number of nailfold ramified capillaries, which reflect activated angiogenesis, is decreased after a one-year administration of bosentan [108].…”

The Endothelin Axis Stimulates the Expression of Pro-Inflammatory Cytokines and Pro-Migratory Molecules in Breast Cancer

“…All experiments were approved by the Institutional Animal Care and Use Committee (IACUC) and conform to the Care and Use of Laboratory Animals guidelines. Mice were fitted with sterile titanium SFCs, as described previously (25,30). Briefly, animals were fitted with sterile titanium SFCs (Department of Experimental Surgery, Heidelberg, Germany).…”

“…Moreover, ETs also favored tumor cell migration and the growth of metastases as suggested by treatments targeting the ET axis (24)(25)(26). Some ET effects have been attributed to specific isoforms, with the increased resistance to hypoxia and promotion of immune cell infiltration associated with ET-2 binding to endothelin receptor B (ET B R) in breast cancer (19).…”

“…Antagonists to ET A R lead to reduced hypoxia and more efficient chemotherapy in breast cancer and reduced bone metastases (22,27). Using the skin-fold chamber (SFC) technology in an immunocompetent murine model, we have shown that Bosentan R , a dual antagonist to ETRs, was associated with alteration in the local vascularization, a decrease in tumor growth, and bone explant tumor infiltration (25). Antagonists to ET B R were also associated with increased chemotherapy efficiency but appeared to act through an autocrine loop (8,28).…”