Epithelial ovarian cancer is the most common cancer of the female reproductive organs, with about 22,000 new cases diagnosed each year in the United States. Approximately 14, 000 women die each year from ovarian cancer in the US, the high mortality related to the fact that 80% of patients are diagnosed with disease that has spread from the ovary to involve other areas of the body. The five-year survival rate for ovarian cancer has changed very little over the last 20 years and new treatment options are urgently needed. Ovarian cancer, like many other types of cancer, obtain nutrients and oxygen by inducing the growth of new blood vessels, a process termed angiogenesis. It is now known that shutting off angiogenesis can starve tumors by depriving them of important nutrients and oxygen, and thus represents a potentially important strategy for cancer treatment. The inner surface of blood vessels is made up of specialized cells called endothelial cells. Since treatments that reduce the growth of endothelial cells can shut off angiogenesis and result in tumor death, much work has been done to understand the molecules involved in this process. In that regard, a molecule known as thrombospondin-1 (TSP-1) is important because it is the first naturally occurring protein inhibitor of angiogenesis to be identified. A portion of TSP-1 known as 3TSR interacts with another protein called CD36, which is found on the surface of endothelial cells, causing the endothelial cells to stop growing. As a result, angiogenesis is reduced and tumor cells that depend on angiogenesis die. We have also made the surprising discovery that 3TSR causes ovarian cancer cells to die through a direct inhibitory effect against the tumor itself. This effect may be due to the fact that ovarian cancer cells, like endothelial cells, express CD36. The concurrent inhibition of the growth of ovarian cancer and endothelial cells with 3TSR markedly limits the ability of tumors to grow in mice.
The thrombospondins (TSPs) are a family of five extracellular calcium-binding proteins that bind to cell surface receptors including integrins and proteoglycans. Through these interactions, the thrombospondins regulate cellular proliferation, migration, differentiation and apoptosis. Members of the thrombospondin gene family are involved in angiogenesis, tumor progression, wound healing, and bone dysplasias. The laboratory uses biochemical, molecular biological and cell biological techniques to understand the function of the thrombospondins in these various disease states. In addition, genetic approaches including characterization of mutations in the human genome and the production of knockout mice are employed.
Through the interaction with extracellular matrix proteins and proteases, TSP-1 and -2 have been shown to regulate matrix structure. At the cell surface, TSP-1 has been shown to regulate migration, proliferation and survival through the interaction with proteoglycans, integrins and CD36. The goal of our research is to obtain a detailed comprehension of the structure and function of the members of the TSP gene family. TSP-1 and -2 are potent endogenous inhibitors of angiogenesis and tumor progression. Ongoing experiments indicate that specific structures with in the type 1 repeats (TSRs) of TSP-1 and -2 mediate this activity. We are currently working to identify signaling molecules and other membrane proteins that collaborate with CD36 to inhibit endothelial cell function. These studies may identify novel targets for the inhibition of angiogenesis and tumor growth.
Cartilage oligomeric matrix protein (COMP) is the fifth member of the TSP gene family. COMP affects cellular attachment, proliferation, and influences chondrogenesis. It also affects extracellular matrix structure through interactions with collagens, matrilines, and proteoglycans. The importance of COMP to cartilage synthesis and function is underscored by findings that COMP mutations lead to pseudoachondroplasia and a subgroup of multiple epiphyseal dysplasia designated EDM1. The lab is using structural and biochemical approaches to identify functional sites within COMP for protein and proteoglycan binding. In addition, the effect of disease causing mutations on COMP structure and function are being explored.
Selected Recent Publications
1. Yee KO, Connolly CM, Duquette M, Kazerounian S, Washington R, Lawler J. The effect of thrombospondin-1 on breast cancer metastasis. Breast Cancer Res Treat 2009; 114(1): 85-96
2. Tan K, Duquette M, Joachimiak A, Lawler J. The crystal structure of the signature domain of cartilage oligomeric matrix protein: implications for collagen, glycosaminoglycan and integrin binding. FASEB J. 2009, 23(8): 2490-501.
3. Zhang X, Kazerounian S, Duquette M, Perruzzi C, Nagy JA, Dvorak HF, Parangi S, Lawler J.Thrombospondin-1 modulates vascular endothelial growth factor activity at the receptor level. FASEB J. 2009, 23(10):3368-76
4. Kazerounian S, Duquette M, Reyes MA, Lawler JT, Song K, Perruzzi C, Primo L, Khosravi-Far R, Bussolino F, Rabinovitz I, Lawler J. Priming of the vascular endothelial growth factor signaling pathway by thrombospondin-1, CD36, and spleen tyrosine kinase Blood. 2011; 117(17):4658-66
5. Xie L, Duncan MB, Pahler J, Sugimoto H, Martino M, Lively J, Mundel T, Soubasakos M, Rubin K, Takeda T, Inoue M, Lawler J, Hynes RO, Hanahan D, Kalluri R. Counter-balancing angiogenic regulatory factors control the rate of cancer progression and survival in a stage-specific manner. Proc Natl Acad Sci U S A. 2011; 14; 108(24):9939-44.
6. Dews M, Tan GS, Hultine S, Raman P, Choi J, Duperret EK, Lawler J, Bass A, Tomas-Tikhonenko A. Masking epistasis between Myc and TGFβ pathways in anti-angiogenesis-mediated colon cancer suppression. J. National Cancer Institute. 2014; 106(4):dju043.
7. Duquette M, Nadler M, Okuhera D, Thompson J, Shuttleworth T, Lawler J. Members of the thrombospondin gene family bind stromal interaction molecule 1 and regulate calcium channel activity. Matrix Biology 2014. In press.
8. Russell S, Duquette M, Liu J, Drapkin R, Lawler J, Petrik J. Combined therapy with Thrombospondin-1 type I repeats (3TSR) and chemotherapy induces regression and significantly improves survival in a preclinical model of advanced stage epithelial ovarian cancer. FASEB J. 2014. In press.
1. Adams JC, Lawler J. The Thrombospondins in Extracellular Matrix, Hynes RO and Yamada K (eds). Cold Spring Harbor Press. Cold Spring Harbor, NY, 2011.
2. Lawler PR, Lawler J. Molecular basis for the regulation of angiogenesis by thrombospondin-1 and -2 in Angiogenesis from Development to Pathology, Klagsbrun M and D’Amore P (eds). Cold Spring Harbor Press. Cold Spring Harbor, NY, 2012.
3. Nucera C, Lawler J, Parangi S. BRAF(V600E) and microenvironment in thyroid cancer: a functional link to drive cancer progression. Cancer Res. 2011, 71(7):2417-22.
Schematic diagram of the thrombospondin gene family and the type 1 repeat superfamily: