Tumor Cell Invasion or Metastasis Related to Calcium Sensitivity of Intracellular Locomotive Apparatus in Bladder Cancer

膀胱癌细胞内运动器官钙敏感性与肿瘤细胞侵袭或转移的关系本研究首先利用小鼠膀胱肿瘤细胞（MBT-2细胞），评估了膀胱癌细胞中肌动球蛋白系统的功能特征。结果提示MBT-2细胞具有由肌动蛋白和肌球蛋白组成的运动装置，Ca^<2+>可激活该运动系统，导致肿瘤细胞收缩或主动运动。当癌细胞真正开始在体内活动时，假设细胞需要一些能够提高细胞质Ca^<2+>水平的生物物质。作为此类生物物质的候选物，我们研究了缓激肽（BK）的作用。BK可诱导MBT-2细胞胞质Ca^<2+>浓度瞬间升高。在Ca^<2+>水平升高的同时，MBT-2细胞出现收缩。BK诱导的Ca^<2+>瞬变可被B2抑制剂阻断，而不被B_1抑制剂阻断，表明BK的这种作用是由B_2亚型介导的。当MBT-2细胞与BK孵育时，通过基质包覆滤膜的细胞数量明显大于不含BK的对照组，因此BK也显示出诱导化学侵袭的作用。RT-PCR结果显示，B_1和B_2受体mrna在人膀胱癌和小鼠膀胱癌中均有表达。B_2 mrna的数量是B_1 mrna的10倍。此外，在人类膀胱癌中检测到引起BK产生的纤溶酶原激活物的mrna。因此，本研究结果提示BK可能通过调动Ca^<2+>，激活肌动球蛋白系统（运动器官），诱导膀胱癌细胞的运动运动，从而导致肿瘤细胞的侵袭和转移。

Tumor Cell Invasion or Metastasis Related to Calcium Sensitivity of IntracellularLocmotive Apparatus in Bladder CancerAt first, using mouse bladder tumor cells (MBT-2 cells), the present study evaluated the functional characteristics of the actomyosin system in bladder cancer cells. The results suggest that MBT-2 cells possess a locomotive apparatus consisting of actin and myosin, and that Ca^<2+> can activate this actomyosin system, leading to the contraction or active locomotory movement of tumor cells. When cancer cells actually begin to move in the in vivo situation, it is assumed that the cells need some biological substances which can elevate the cytoplasmic Ca^<2+> level.As a candidate of such biological substances, we studied the effect of bradykinin (BK). BK was demonstrated to induce the transient rise of cytoplasmic concentration of Ca^<2+> in MBT-2 cells. Simultaneously with the increase in Ca^<2+> level, MBT-2 cells showed contraction. BK-induced Ca^<2+> transients were blocked by B2 inhibitor, but not by B_1 inhibitor, suggesting that this action of BK is mediated by B_2 subtypes.When MBT-2 cells were incubated with BK, the number of cells migrated through matrigel-coated filter was significantly greater than the control without BK.Thus, BK was also shown to induce chemoinvasion.RT-PCR clearly showed B_1 and B_2 receptor mRNAs were expressed in human bladder cancer and mouse bladder cancer. The amounts of B_2 mRNAs were 10 times greater than that of B_1 mRNAs. In addition, mRNAs of plasminogen activator, which cause a BK generation, were detected in human bladder cancer.Thus, the results from this study suggest that BK may induce locomotory movement of bladder cancer cells by mobilizing Ca^<2+> and activating actomyosin system (locomotory apparatus), which result in tumor cell invasion and metastasis.