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

关于子宫肌瘤的增殖，在体内和体外，Ref-1的转录后修饰与子宫肌瘤细胞的增殖有关。子宫中的肥大细胞可能促进了平滑肌细胞的增殖。通过对Wnt信号调节因子SFRP1、S100蛋白家族S100A11和PEP-19的研究，揭示了子宫肌瘤细胞的抗凋亡特性。此外，REF-1、S100A11和β连接素可能参与了子宫肌肉瘤的病理生理过程。对于子宫肌瘤的发病机制，我们假设子宫肌瘤是在月经周期中反复经历的缺血再灌注应激中存活的肌层组织。众所周知，体内子宫肌层的血液供应可以减少大胆的子宫收缩，特别是大胆的月经。在月经周期的每个黄体期，子宫肌层平滑肌除…外更多的抑制增殖活动，为怀孕做准备。然而，如果没有怀孕，子宫肌层平滑肌的增殖活动可能会在月经时中断。子宫肌层收缩导致月经失明的停止，可能导致子宫肌层平滑肌细胞的缺血/缺氧状态。处于增殖期的细胞可发生缺血性损伤。提示损伤后的小马驹有可能成为肌瘤前体细胞的候选细胞。在经历了多次月经周期的重复后，很可能会在这些细胞中诱发体细胞突变。在这方面，免疫组织化学我们发现，仅在月经周期的卵泡期，子宫肌层中只有很少的p53或p21阳性细胞。这高度提示月经期间存在损伤DNA的平滑肌细胞，这些细胞会在细胞周期停滞时被修复或通过细胞凋亡被消除。如果DNA损伤的细胞可能获得抗凋亡的表达分子如SFRP1和S100A11，这些细胞可能成为子宫肌瘤细胞的候选细胞。在治疗方面，曲尼司特作为肥大细胞稳定剂或抑制纤维化的曲尼司特，成为新的治疗药物的候选药物。曲尼司特以剂量依赖的方式抑制培养的子宫肌瘤细胞的增殖，且无任何细胞毒性作用。我们还证明，子宫动脉栓塞术成功地缩小了弥漫性子宫肌瘤病的子宫大小，这表明该手术可能是一种在不损失生育能力的前提下治疗这种顽固性疾病的新方法。较少

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