Development of new therapeutic modalities based on the analysis of the pathogenesis and biological features of leiomyoma

在子宫平滑肌瘤的增殖过程中，Ref-1的转录后修饰在体内和体外均与子宫平滑肌瘤细胞的增殖有关。子宫肥大细胞可促进平滑肌细胞的增殖。通过对sFRP1 （Wnt信号调节因子）、S100A11 （S100蛋白家族）和PEP-19的研究，提出了平滑肌瘤细胞的抗凋亡特性。此外，Ref-1、S100A11和β catenin被认为参与了平滑肌肉瘤的病理生理过程。关于平滑肌瘤的发病机制，我们推测平滑肌细胞增生导致的平滑肌瘤是在月经周期反复缺血-再灌注应激下存活下来的肌层组织。体内肌层的血供已知减少子宫收缩，尤其是月经。在月经周期的每个黄体期，子宫肌平滑肌抑制增殖活动，为怀孕做准备。然而，如果没有怀孕，小马的子宫肌平滑肌的增殖活动可能会在月经时中断。子宫肌收缩，导致月经停止，可能导致子宫肌平滑肌细胞缺血/缺氧状态。这些处于增殖期的细胞可发生缺血性损伤。提示这些损伤的小马可能成为平滑肌瘤祖细胞的候选者。体细胞突变很可能在这些细胞存活多次重复的月经周期后被诱导。在这方面，免疫组织化学我们发现很少p53或p21阳性细胞在子宫肌层只在月经周期的卵泡期。这高度提示经期存在平滑肌细胞DNA损伤，这些细胞会在细胞周期阻滞中得到修复或通过凋亡消除。如果DNA受损的细胞可能获得表达sFRP1、S100A11等抗凋亡分子，这些细胞就成为平滑肌瘤细胞前体的候选细胞。在治疗方面，曲尼司特作为肥大细胞稳定剂抑制纤维化或纤维化，成为一种新的治疗药物的候选。曲尼司特以剂量依赖的方式抑制培养的平滑肌瘤细胞的增殖，而没有任何细胞毒性作用。我们还证明子宫动脉栓塞成功地缩小了弥漫性平滑肌瘤病的子宫大小，这表明这种手术可能是治疗这种顽固性疾病而不丧失生育能力的一种新的治疗方式。少

Regarding the proliferation of uterine leiomyoma, the posttranscriptional modification of Ref-1 was revealed to associate with the proliferation of leiomyoma cells in vivo and in vitro. Mast cells in the uterus were suggested to enhance the proliferation of smooth muscle cells. Apoptosis-resistant character of leiomyoma cells was suggested through the studies of sFRP1 (a modulator of Wnt signaling), S100A11 (S100 protein family), and PEP-19. In addition, Ref-1, S100A11, and β catenin were suggested to be involved in the pathophysiology of leiomyosarcoma.Regarding the pathogenesis of leiomyoma, we hypothesize that leiomyomas resale from proliferation of smooth muscle cells is the myometrial tissue that survives the repeated ischemic-reperfusion stress experienced during the menstrual cycle. The blood supply to the myometrium in vivo is knows to decrease daring uterine contraction, particularly daring menstruation. In each luteal phase of the menstrual cycle, myometrial smooth muscles ex … More hibit proliferative activity, in preparation for pregnancy. However, if pregnancy does not occur, the proliferative activity of the myometrial smooth muscle colts may be interrupted at the time of menstruation. Myometrial contraction, winch results in the cessation of menstrual blinding, probably induces an ischemic / hypoxic state in the myometrial smooth muscle cells. Ischemic injury could occur in these cells which are in the proliferative phase. It is suggested that them injured colts could become candidates for progenitor cells of leiomyomas. Somatic mutation could well be induced in these cells after surviving many repeats of the menstrual cycle. In this respect, immunohistochemically we found e few p53- or p21-positive cells in the myometrium exclusively in the follicular phase of the menstrual cycle. This highly suggests that there exists smooth muscle cells that were injured their DNA during the menses, and these cells would be repaired during the cell-cycle arrest or eliminated through apoptosis. If the cells with injured DNA may acquire apoptosis-resistance expressing molecules such as sFRP1 and S100A11, these cells become the candidates of the precursor of leiomyoma cell.Regarding the treatment, tranilast that suppresses fibrosis or arts as a mast cell stabilizer, became a candidate of a new therapeutic agent. Tranilast inhibited the proliferation of cultured leiomyoma cells in a dose-dependent manner without any cytotoxic effort. We also demonstrated that uterine arterial embolization successfully reduced the uterine size of diffuse leiomyomatosis, suggesting that this procedure may be a premising new therapeutic modality for this intractable disease without loss of fertility. Less