Stromal endothelin B receptor-deficiency inhibits breast cancer growth and metastasis

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• The endothelin (ET) axis is frequently dysregulated in various cancers.
• Previous research primarily focused on ET signaling within malignant cells, overlooking the tumor microenvironment's role.
• The stromal compartment is increasingly recognized as crucial for cancer progression.

Purpose of the Study:

• To investigate the distinct roles of endothelin receptors ET(A)R and ET(B)R in both tumor cells and the stromal compartment.
• To assess the impact of ET(B)R deficiency in the stroma on mammary adenocarcinoma growth and metastasis.
• To determine if ET(B)R function in the microenvironment is essential for tumor progression.

Main Methods:

• Utilized homozygous spotting lethal rats (sl/sl), a model with constitutive ET(B)R deficiency.
• Employing MAT B III rat mammary adenocarcinoma cells overexpressing ET(A)R and ET-1 but lacking ET(B)R.
• Restored ET(B)R function in transgenic sl/sl rats to evaluate the effects of its presence.

Main Results:

• Reduced tumor growth and metastasis were observed in ET(B)R-deficient rats.
• Lack of stromal ET(B)R did not affect angiogenesis but decreased tumor-associated macrophage infiltration.
• Reduced production of tumor necrosis factor-alpha was noted in ET(B)R-deficient stroma.
• These inhibitory effects on tumor progression were reversed upon restoration of ET(B)R function.

Conclusions:

• Tumor growth and metastasis are critically dependent on ET(B)R function within the tumor microenvironment.
• Targeting stromal ET(B)R is essential for effective endothelin receptor antagonist therapy.
• The study highlights the importance of considering the tumor microenvironment in anticancer strategies targeting the ET axis.