An improved mouse orthotopic bladder cancer model exhibiting progression and treatment response characteristics of human recurrent bladder cancer
An improved mouse orthotopic bladder cancer model exhibiting progression and treatment response characteristics of human recurrent bladder cancer
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DOI：
10.3892/ol.2019.11172
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发表时间：
2020-01-01
期刊：
影响因子：
2.9
通讯作者：
Kakinuma, Chihaya
中科院分区：
文献类型：
--
作者：
Naito, Tomoharu;Higuchi, Tamami;Kakinuma, Chihaya
非肌肉浸润性(浅表性)膀胱癌一般通过手术切除，然后辅以治疗(卡介苗)。然而，膀胱癌经常会复发，在相当数量的复发病例中，癌症会进展和转移。此外，切除后残留的微小肿瘤可能会增加复发的风险。模拟膀胱微小肿瘤再生长模式的体内模型可能为改善术后治疗结果提供一个有效的实验系统。用UM-UC-3人膀胱癌细胞原位移植建立的小鼠膀胱癌模型已经建立，然而，据我们所知，还没有关于膀胱癌的连续组织学变化，包括早期变化和治疗反应的报道。在本研究中，对模型的效率进行了优化，并使用组织病理学和原位成像检查了连续变化。同时观察了顺铂(CDDP)和吉西他滨(GEM)的疗效。肿瘤种植效率达到90-100%，肌层和膀胱腔的侵袭发生在相似的21天内，采用下列改良法：i)浅层插入导管以减轻膀胱壁损伤；ii)膀胱预处理使用预热的胰酶，然后轻微的尿路钳制和体温维持以更有效地去除移行上皮；iii)UM-UC-3细胞(而不是HT1376、5637或T24肿瘤细胞)接种在添加Matrigel的培养液中。移植UM-UC-3细胞导致孤立的微小病变进展为肿瘤，侵犯膀胱腔和肌层至浆膜表面。每周静脉注射顺铂可明显抑制肿瘤生长，GEM可部分抑制肿瘤生长。因此，该模型是可靠的，病理进展和治疗反应概括了人类膀胱癌复发的特点。
Nonmuscle-invasive (superficial) bladder cancer is generally treated via surgical removal, followed by adjuvant therapy (bacillus Calmette-Guerin). However, bladder cancer can often recur, and in a substantial number of recurrent cases, the cancer progresses and metastasizes. Furthermore, residual microtumors following excision may lead to an increased risk of recurrence. An in vivo model mimicking the pattern of urinary bladder microtumor regrowth may provide an effective experimental system for improving postsurgical treatment outcomes. A mouse bladder cancer model established using orthotopic transplant of UM-UC-3 human urinary bladder carcinoma cells has been established, however, to the best of our knowledge, no report has investigated sequential histological changes, including early-phase changes and treatment responses in bladder cancer. In the present study, the efficiency of the model was optimized and the sequential changes were examined using histopathology and in situ imaging. The therapeutic effects of cisplatin (CDDP) and gemcitabine (GEM) were also examined, which are drugs that are often used for follow-up chemotherapy. Tumor-seeding efficiency reached 90-100%, with muscle layer and bladder lumen invasion occurring in similar to 21 days, using the following modifications: i) Shallow catheter insertion to mitigate bladder wall damage; ii) bladder pretreatment using prewarmed trypsin, followed by light urethral clamping and body temperature maintenance for more efficient removal of transitional epithelium; and iii) seeding with UM-UC-3 cells (rather than HT1376, 5637 or T24 tumor cells) in a medium supplemented with Matrigel. Transplant with UM-UC-3 cells resulted in isolated microlesions that progressed into tumors, invading the bladder lumen and muscle layer to the serosal surface. Tumor growth was markedly reduced by weekly intravenous injections of CDDP and partially suppressed by GEM. Therefore, this model is reliable, and pathological progression and treatment responses recapitulate the features of recurrent human bladder cancer.