Abstract
It is well established that the secretion of thrombospondin-1 (TSP-1) by activated stromal cells and its accumulation in the tumor microenvironment during dysplasia inhibits primary tumor growth through inhibition of angiogenesis. This inhibitory function of TSP-1 is actuated either by inhibiting MMP9 activation and the release of VEGF from extracellular matrix or by an interaction with CD36 on the surface of endothelial cells resulting in an increase in apoptosis. In contrast, several published articles have also shown that as tumor cells become more invasive and enter the early stage of carcinoma, they up-regulate TSP-1 expression, which may promote invasion and migration. In our in vivo studies using the polyoma middle T antigen (PyT) transgenic mouse model of breast cancer, we observed that the absence of TSP-1 significantly increased the growth of primary tumors, but delayed metastasis to the lungs. In this study, we propose a mechanism for the promigratory function of TSP-1 in mouse mammary tumor cells in vitro. We demonstrate the correlations between expression of TSP-1 and its receptor integrin α3β1, which is considered a promigratory protein in cancer cells. In addition we propose that binding of TSP-1 to integrin α3β1 is important for mediating actin filament polymerization and therefore, cell motility. These findings can help explain the dual functionality of TSP-1 in cancer progression.
Highlights
Thrombospondin-1 (TSP-1) is a 450 kDa trimeric multi-domain extracellular calcium-binding glycoprotein that is expressed by most cell types including fibroblasts, platelets, endothelial cells, monocytes, and epithelial cells
Isolation of Mouse Mammary Tumor Cells To investigate the role of TSP-1 expression in mediating cancer cell migration, we isolated tumor epithelial cells from mammary tumors of wild-type and TSP-1-null polyoma middle T antigen (PyT) mice at 90 days of age[37]
To ensure our tumor epithelial cell isolates were free of fibroblasts, we tested our cells for the presence of α-smooth muscle actin and fibroblast activated protein (FAP), markers for tumor-associated fibroblasts[19, 37]
Summary
Thrombospondin-1 (TSP-1) is a 450 kDa trimeric multi-domain extracellular calcium-binding glycoprotein that is expressed by most cell types including fibroblasts, platelets, endothelial cells, monocytes, and epithelial cells. TSP-1 binds to a variety of cell surface receptors and extracellular matrix proteins in a cell and concentration-. TSP-1 can bind to CD36 and CD47 through its type-1 repeats and carboxyl-terminal domain to inhibit cell proliferation and promote anti-angiogenic events 8, 16. The amino-terminal heparin binding domain of TSP-1 interacts with a variety of cell surface proteins, including heparin sulfate proteoglycan, calreticulin, and integrins such as α3β1 to modulate cell adhesion and motility in a cell specific manner[9, 10, 12, 22, 29]. Secretion of TSP-1 by activated stromal cells including fibroblasts inhibits primary tumor growth and invasiveness by inhibiting
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