DISCOVERIES (ISSN 2359-7232), 2014, October-December

CITATION: 

Ndishabandi D, Duquette C, Billah GE, Reyes M, Duquette M, Lawler J, Kazerounian S. Thrombospondin-1 Modulates Actin Filament Remodeling and Cell Motility in Mouse Mammary Tumor cells in Vitro. Discoveries 2014, Oct-Dec; 2(4): e31. DOI: 10.15190/d.2014.23

Submitted: July 25, 2014; Revised: September 9, 2014; Accepted: September 18, 2014; Published: October 8, 2014; 

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Thrombospondin-1 Modulates Actin Filament Remodeling and Cell Motility in Mouse Mammary Tumor cells in Vitro

Dorothy Ndishabandi, Cameron Duquette, Ghita El-Moatassim Billah, Millys Reyes, Mark Duquette, Jack Lawler, Shideh Kazerounian*

(1) Department of Medicine, Division of Genetics, Boston Children’s Hospital, Boston, MA; 

(2) Department of Pathology, Division of Experimental Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA

*Correspondence to: Shideh Kazerounian, Ph.D., Department of Pediatrics, Division of Genetics, Boston Children's Hospital, Harvard Medical School, 3 BlackFan Circle, Center for Life Sciences, Boston, MA 02115; Phone: (617)355-7748; Fax: (617)730-0253; E-mail: shideh.kazerounian@childrens.harvard.edu

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 pro-migratory function of TSP-1 in mouse mammary tumor cells in vitro. We demonstrate a correlation of TSP-1 expression and its receptor integrin 3β1, which is considered a pro-migratory 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.

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