Molecular Approach to Uterine Leiomyosarcoma: LMP2-Deficient Mice as an Animal Model of Spontaneous Uterine Leiomyosarcoma

Abstract

Uterine leiomyosarcoma (LMS) develops more often in the muscle tissue layer of the uterine body than in the uterine cervix. The development of gynecologic tumors is often correlated with female hormone secretion; however, the development of uterine LMS is not substantially correlated with hormonal conditions, and the risk factors are not yet known. Importantly, a diagnostic-biomarker which distinguishes malignant LMS from benign tumor leiomyoma (LMA) is yet to be established. Accordingly, it is necessary to analyze risk factors associated with uterine LMS, in order to establish a treatment method. LMP2-deficient mice spontaneously develop uterine LMS, with a disease prevalence of ~40% by 14 months of age. We found LMP2 expression to be absent in human LMS, but present in human LMA. Therefore, defective LMP2 expression may be one of the risk factors for LMS. LMP2 is a potential diagnostic-biomarker for uterine LMS, and may be targeted-molecule for a new therapeutic approach.

Figure 1

Mediation of the proteasomal degradation pathway to antigen presentation by MHC class I. The immunoproteasomal degradation pathway is essential for antigen presentation by MHC class I. Defecive LMP2 expression results in tissue- and substrate-dependent abnormalities of immunoproteasomal functions. Therefore an impaired proteasome may promote the initial development of disease including tumorigenesis.

Figure 2

Histological findings of uterine leiomyosarcoma in LMP2-deficient mice. Histological findings of uterine LMS in LMP2-deficient mice ((a) to (c)). Among the histological findings of uterine LMS in LMP2-deficient mice, a cytoskeleton, which is characteristic of uterine LMS, is observed. ((b) and (c) magnification x400) Panel (e), in LMP2-deficient females, uterine LMS is observed at 6 months of age. The incidence at age 14 months is as high as 40% (e). The curve indicating the incidence of mouse uterine LMS is very similar to that indicating the incidence of human uterine LMS, which is observed after menopause. In mice with tumors of the uterus, significant weight loss is observed. Thus, a tumor that develops in the uterus is diagnosed as malignant, that is, uterine LMS.

Figure 3

Model of the mechanism for development of uterine leiomyosarcoma. In LMP2-deficient cells, levels of the antioncogenic factor IRF-1, p21^WAF are significantly reduced. Reduced expression of the calponin h1 transcript, which contributes to cell proliferation and tumorigenesis in uterine smooth muscle cells, is detected in uterine LMS tissues. Cell cycle regulatory factors, CDK2/Cyclin E, are markedly activated. The inactivation of such antioncogenic factors is considered to transform LMP2-deficient cells into malignant tumor cells.