Thrombospondin-1 Modulates Actin Filament Remodeling and Cell Motility in Mouse Mammary Tumor cells in Vitro.
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 ourin vivostudies 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 cellsin 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.
Department of Pathology, Division of Experimental Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
Dorothy
D
Ndishabandi
Department of Pathology, Division of Experimental Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
Cameron
C
Duquette
Department of Pathology, Division of Experimental Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
Ghita El-Moatassim
GE
Billah
Department of Pathology, Division of Experimental Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
Millys
M
Reyes
Department of Pathology, Division of Experimental Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
Mark
M
Duquette
Department of Pathology, Division of Experimental Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
Jack
J
Lawler
Department Pediatrics, Division of Genetics, Boston Children's Hospital and Harvard Medical School Boston, MA.
Shideh
S
Kazerounian
Thrombospondin-1; actin filaments; breast cancer; integrin α3β1; metastasis