Characteristics of Leiomyosarcoma: Induction of Hematogenous Metastasis by Isolated Uterine Mesenchymal Tumor Stem-like Cells.

Abstract

Uterine leiomyosarcoma (Ut-LMS) is a refractory tumor that repeatedly recurs with hematogenous metastasis, which may be due to the presence of drug-resistant tumor stem cells. Its treatment is limited to surgical procedures. We previously reported that Ut-LMS spontaneously developed in mice deficient in the proteasome component low-molecular mass polypeptide 2 (LMP2). We showed that LMP2 expression was significantly attenuated specifically in human Ut-LMS. The aim of this study was to investigate the role of LMP2 in hematogenous metastasis using xenograft models with tumor stem-like cells. We isolated tumor stem-like cells from LMP2-negative primary human Ut-LMS cells established from a human Ut-LMS tissue using the side population (SP) procedure. These cells were used to develop xenograft models with tumor stem-like cells. Human Ut-LMS stem-like cells showed stronger hematogenous metastatic potential than normal Ut-LMS cells. Tumor stem-like cells also had the potential to differentiate into vascular endothelial cells through VEGF-A signaling. These results reflect frequent hematogenous metastasis by human Ut-LMS in clinical settings, and may lead to the development of treatments that inhibit hematogenous metastasis in Ut-LMS.