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

膀胱癌细胞内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)，研究了膀胱癌细胞肌动球蛋白系统的功能特性。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器，而Ca~(2+)可激活该肌球蛋白系统，导致肿瘤细胞收缩或主动运动。当癌细胞在体内实际开始运动时，假设细胞需要一些生物物质来提高胞内钙离子水平，作为此类生物物质的候选者，我们研究了缓激肽(BK)的作用。BK可诱导MBT-2细胞内Ca~(2+)、Gt~(2+)短暂升高。同时，随着Ca~(2+)水平的升高，MBT-2细胞出现收缩。BK可阻断BK诱导的钙离子瞬变，但不能被B1抑制剂阻断，提示BK的这种作用是由B2亚型介导的。当BK与MBT-2细胞孵育时，通过基质包被滤膜的MBT-2细胞的迁移数量明显多于未加BK的对照细胞。因此，BK也能诱导化学侵袭。RT-PCR结果显示B1和B2受体在人膀胱癌和小鼠膀胱癌中都有表达。B_2mRNAs的数量是B_1mRNAs的10倍。此外，在人膀胱癌组织中检测到纤溶酶原激活物的mRNAs导致BK的产生，因此本研究结果提示BK可能通过动员Ca~(2+)和激活肌球蛋白系统(运动器)而诱导膀胱癌细胞的运动性运动，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.