Development of new cancer therapy by regulating cytoskeleton and cancer-cell transformation

通过调节细胞骨架和癌细胞转化开发新的癌症疗法

• 批准号: 16591326
• 负责人: NAKAMURA Masafumi
• 金额: $ 2.3万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591326/
• 关键词: Hedgehog; cancer; invasion; EMT; Cyclopamine; pancreatic cancer; breast cancer; colon cancer; シクロパミン; 微小管; 細胞変形能

The dynamics of the cytoskeleton including centrosomes-microtubules system is the basic mechanism for cancer -cell movement contributing to cancer invasion. We before proposed that developing the methods of regulating cytoskeleton in cancer cells might bring a strategy of cancer therapy. 1: In this project, we found that Hedgehog (HH) signaling pathway had changed its activity under the influence of paclitaxel, stabilizer of microtubules and attenuating the dynamics of cytoskeleton. 2: We also revealed that HH signaling was activated in breast, pancreatic and gastric cancers through immunostaining, real time RT-PCR and western-blotting of the surgically resected specimens or cancer cell lines. Shh, a ligand of the HH signal, is often up-regulated and leading its signal activation in cancer tissues and cell lines. Anti-Shh mAb as well as cyclopamine, a specific inhibitor of HH pathway, suppressed the signal in cancer cells, confirming the ligand-dependent activation of the HH signal in cancer. Interestingly, the activity of HH signaling was suppressed in colorectal cancers and up-regulation of HH signal suppressed the colorectal cancer-cell growth. This reverse effect of HH signaling pathway is consistent with its role in the development, survival effect in the foregut and inducing apoptosis in the hindgut. 3: When we suppressed the HH signal activity by cyclopamine in pancreatic cancer cells, their ability of invasion was attenuated in vitro as well as their growth. In contrast with cyclopamine, excess Shh activated their invasiveness. The mechanism by which Shh accelerate the pancreatic cancer invasion included up-regulation of their random movement controlled by cytoskeleton.

包括中心体-微管系统在内的细胞骨架的动力学是癌细胞运动促进肿瘤侵袭的基本机制。我们之前提出，发展调节癌细胞细胞骨架的方法可能会带来一种癌症治疗的策略。1.在本课题中，我们发现Hedgehog(HH)信号通路在微管稳定剂紫杉醇的影响下改变了其活性，减弱了细胞骨架的动力学。2：我们还通过对手术切除的标本或癌细胞系进行免疫染色、实时RT-PCR和Western-blotting，发现HH信号在乳腺癌、胰腺癌和胃癌中被激活。Shh是HH信号的配体，在肿瘤组织和细胞系中经常上调并领导其信号激活。抗Shh单抗和HH途径的特异性抑制剂环丙胺抑制了癌细胞中的HH信号，证实了HH信号在肿瘤中的配体依赖的激活。有趣的是，HH信号在结直肠癌中的活性被抑制，HH信号的上调抑制了结直肠癌细胞的生长。HH信号通路的这种逆转作用与其在前肠发育、存活效应和诱导后肠细胞凋亡中的作用是一致的。3.通过抑制环丙胺对胰腺癌细胞HH信号的激活，抑制了胰腺癌细胞的体外侵袭能力和生长能力。与环多巴胺相反，过量的Shh激活了它们的侵袭性。Shh促进胰腺癌侵袭的机制包括上调细胞骨架控制的细胞随机运动。

项目成果

Nuciear Factor κΒ Contridutes to Hedgehog Signaling Pathway Activation through Sonic Hedgehog Induction in Pancreatic Cancer

Nuciear 因子 κB 通过 Sonic Hedgehog 诱导在胰腺癌中促进 Hedgehog 信号通路激活

• 期刊: Cancer Research (in press)
• 作者: Nakashima H;et al.
• 通讯作者: et al.

Immunohistochemical staining of Hedgehog pathway-related proteins in human thymomas.

人胸腺瘤中 Hedgehog 通路相关蛋白的免疫组织化学染色。

• 发表时间: 2005
• 期刊: Anticancer Research 25
• 作者: Tasaki A;Akiyoshi T;Koga K;Nakashima H;Yamanaka N;Kubo M;Matsumoto K;Kojima M;Tanaka M Nakamura M;Katano M
• 通讯作者: Katano M

Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer

• DOI: 10.1158/0008-5472.can-04-0416
• 发表时间: 2004-09-01
• 期刊: CANCER RESEARCH
• 影响因子: 11.2
• 作者: Kubo, M;Nakamura, M;Katano, M
• 通讯作者: Katano, M

Immunohistochemical staining of Hedgehog pathway-related proteins in human thymomas

人胸腺瘤中 Hedgehog 通路相关蛋白的免疫组织化学染色

• 发表时间: 2005
• 期刊: Anticancer Research 25
• 作者: Tasaki A;Akiyoshi T;Koga K;Nakashima H;Yamanaka N;Kubo M;Matsumoto K;Kojima M;Tanaka M Nakamura M;Katano M;Deitch EA;Kim R.;Tasaki A. et al.
• 通讯作者: Tasaki A. et al.

Hedgehog signaling pathway is a possible therapeutic target for gastric cancer

• DOI: 10.1002/jso.20606
• 发表时间: 2007-01-01
• 期刊: JOURNAL OF SURGICAL ONCOLOGY
• 影响因子: 2.5
• 作者: Yanai, Kosuke;Nagai, Shuntaro;Katano, Mitsuo
• 通讯作者: Katano, Mitsuo