Combined therapy with thrombospondin‐1 type I repeats (3TSR) and chemotherapy induces regression and significandy improves survival in a preclinical model of advanced stage epithelial ovarian cancer

Abstract

Most women are diagnosed with epithelial ovarian cancer (EOC) at advanced stage, where therapies have limited effectiveness and the long-term survival rate is low. We evaluated the effects of combined antiangiogenic and chemotherapy treatments on advanced stage EOC. Treatment of EOC cells with a recombinant version of the thrombospondin-1 type I repeats (3TSR) induced more apoptotic cell death (36.5 6 9.6%) in vitro compared to untreated controls (4.1 6 1.4). In vivo, tumors were induced in an orthotopic, syngeneic mouse model of advanced stage EOC. Mice were treated with 3TSR (4 mg/kg per day) alone or in combination with chemotherapy drugs delivered with maximum tolerated dose or metronomic scheduling. Pretreatment with 3TSR induced tumor regression, normalized tumor vasculature, and improved uptake of chemotherapy drugs. Combination 3TSR and metronomic chemotherapy induced the greatest tumor regression (6.2-fold reduction in size compared to PBS-treated controls) and highest survival when treatment was initiated at advanced stage. 3TSR binding to its receptor, CD36 (cluster of differentiation 36), increased binding of CD36 and SHP-1, which significantly inhibited phosphorylation of the VEGF receptor. In this study, we describe a novel treatment approach and mechanism of action with 3TSR and chemotherapy that induces regression of advanced stage EOC and significantly improves survival.-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. 29, 576-588 (2015). www.fasebj.org

Tumor-associated macrophages drive spheroid formation during early transcoelomic metastasis of ovarian cancer

“…It is known that adhesion is a necessary factor for spheroid formation, and studies have suggested that free cells detached from the primary tumor may form spheroids through the interaction between α 5 β 1 integrin and fibronec- Cell culture. The ID8 (mouse EOC line) was a gift from Jack Lawler and Carmelo Nucera at Beth Israel Deaconess Medical Center (Harvard Medical School, Boston, Massachusetts, USA) (49). SKOV3 cells (human ovarian adenocarcinoma cell line) were obtained from ATCC.…”

ASK1-dependent endothelial cell activation is critical in ovarian cancer growth and metastasis

“…The ID8 (mouse epithelial OC line) was gifted from Jack Lawler and Carmelo Nucera at Beth Israel Deaconess Medical Center, Harvard Medical School (47). SKOV3 (human ovarian adenocarcinoma cell line) were obtained from ATCC.…”

Distinct C- mannosylation of netrin receptor thrombospondin type 1 repeats by mammalian DPY19L1 and DPY19L3

“…Attachment to sulfated glycans of cell surfaces and extracellular matrix has been observed for mammalian and Plasmodium proteins (5)(6)(7). In addition, the three TSRs of thrombospondin-1 have been shown to interact with the cell surface receptor CD36 with resultant antiangiogenic effects (8) and are being explored as an anticancer therapy (9).…”