Main author: Clara Valls Ferré
Institution or Company: Department of Anatomy, BioMedical Center, University of Iceland
Co-Author, Institution or Company:
Gudrún Valdimarsdóttir, Department of Anatomy, BioMedical Center, University of Iceland.
Introduction: Breast cancer is the most common cancer in women worldwide and the prognosis of patients worsens significantly with the diagnosis of metastases. The molecular interactions between disseminated cancer cells and their microenvironment are poorly characterized. Recent evidence suggests that disseminated tumour cells residing close to stable endothelium stay dormant. However, upon activation cues in the tumour microenvironment, angiogenesis can be triggered and breast cancer cells can exit the dormancy state, starting proliferating and developing metastasis. Thrombospondin-1 (TSP-1) is an extracellular secreted glycoprotein and an angiogenesis inhibitor expressed in resting endothelial cells. TGFβ acts through ALK receptors having a two-sided role, suppressing and promoting angiogenesis.
Methods: Our hypothesis is that endothelial derived TSP-1 suppresses metastatic growth but, when the tumour microenvironment gets activated and angiogenesis takes places, the TSP-1 break is relieved and metastasis promoted.
To understand the mechanistic molecular basis of the complex TGF-β signalling pathway and the interplay between the tumour cells and the microenvironment we performed in vitro studies on cancer cells and studied the effect of ALK1 inhibition and TSP-1 knockdown on the expression of angiogenic and TGFβ family components using mouse models.
Results: We demonstrated that TGFβ induces TSP-1 expression in endothelial cells. We found that TSP-1 seems to regulate the metastasis inhibition in a quiescent endothelial scenario. The angiogenic activation leads to the TSP-1 break suppression and then metastatic growth is enhanced.
Conclusions: This insight will have huge impact on metastasis prevention therapeutic tools development in breast cancer patients, envisioning a combined target molecular therapy to inhibit angiogenesis.
