The Role of Matrix Metalloproteinase in the Intimal Sarcoma-Like Cells Derived from Endarterectomized Tissues from a Chronic Thromboembolic Pulmonary Hypertension Patient

Sarcoma-like cells (SCLs) were derived from endarterectomized tissue of a single chronic thromboembolic pulmonary hypertension (CTEPH) patient during incubation of those thrombi at second passage as described at our previous report. These cells had malignant potential, with an increased expression of matrix metalloproteinase-14 (MMP-14), leading to tumor emboli within pulmonary arteries in in vivo studies. The purpose of this study was to perform a more detailed evaluation of the characteristics of SCLs, and to elucidate the role of the increased expression of MMP-14 expression in the growth and death of these cells. In order to elucidate the characteristics of SCLs and to confirm the protein expression of MMP-14, three-dimentional culture, invasion assays, a Western blot analysis and immunohistochemical studies were performed. To examine the role of MMP-14 in tumorigenesis, the metalloproteinase inhibitor, batimastat, was administered to SCID mice which were subcutaneously injected with SCLs. Those mice were sacrificed on day 14 and the tumor volume was evaluated. A Western blot analysis showed the increased expression of MMP-14 in comparison to the expression in lung adenocarcinoma cells (A549). Immunohistochemistry showed that SCLs were positive for vimentin, MMP-14, MMP-2 and CD44. However, endothelial markers, such as CD31 and von Willebrand factor (vWF), were negative. The in vivo studies demonstrated that batimastat could suppress the growth of the subcutaneous tumors formed by the SCLs. This study suggested that MMPs had critical roles on the pathological activities of SCLs and that batimastat might have anti-proliferative and anti-invasive effects on these cells.