Yoshida Masaki, Miyasaka Yoshihiro, Ohuchida Kenoki, Okumura Takashi, Zheng Biao, Torata Nobuhiro, Fujita Hayato, Nabae Toshinaga, Manabe Tatsuya, Shimamoto Masaya, Ohtsuka Takao, Mizumoto Kazuhiro, Nakamura Masafumi
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Cancer Sci. 2016 Oct;107(10):1443-1452. doi: 10.1111/cas.13024. Epub 2016 Sep 24.
Desmoplasia contributes to the aggressive behavior of pancreatic cancer. However, recent clinical trials testing several antifibrotic agents on pancreatic cancer have not shown clear efficacy. Therefore, further investigation of desmoplasia-targeting antifibrotic agents by another mechanism is needed. Calpeptin, an inhibitor of calpains, suppressed fibroblast function and inhibited fibrosis. In this study, we investigated the anticancer effects of calpeptin on pancreatic cancer. We investigated whether calpeptin inhibited tumor progression using a mouse xenograft model. We used quantitative RT-PCR to evaluate the expression of calpain-1 and calpain-2 mRNA in pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs). We also undertook functional assays, including proliferation, migration, and invasion, to evaluate the inhibitory effects of calpeptin on PCCs and PSCs. Quantitative RT-PCR indicated that PCCs and PSCs expressed calpain-2 mRNA. Calpeptin reduced tumor volume (P = 0.0473) and tumor weight (P = 0.0471) and inhibited the tumor desmoplastic reaction (P < 0.001) in xenograft tumors in nude mice. Calpeptin also inhibited the biologic functions of PCCs and PSCs including proliferation (P = 0.017), migration (P = 0.027), and invasion (P = 0.035) in vitro. Furthermore, calpeptin reduced the migration of PCCs and PSCs by disrupting the cancer-stromal interaction (P = 0.0002). Our findings indicate that calpeptin is a promising antitumor agent for pancreatic cancer, due not only to its suppressive effect on PCCs and PSCs but also its disruption of the cancer-stromal interaction.
促纤维组织增生作用促使胰腺癌呈现侵袭性。然而，近期针对胰腺癌开展的多项抗纤维化药物临床试验并未显示出明确疗效。因此，需要通过另一种机制对靶向促纤维组织增生的抗纤维化药物进行进一步研究。钙蛋白酶抑制剂钙肽素可抑制成纤维细胞功能并抑制纤维化。在本研究中，我们探究了钙肽素对胰腺癌的抗癌作用。我们使用小鼠异种移植模型研究钙肽素是否抑制肿瘤进展。我们采用定量逆转录聚合酶链反应（qRT-PCR）评估钙蛋白酶-1和钙蛋白酶-2 mRNA在胰腺癌细胞（PCCs）和胰腺星状细胞（PSCs）中的表达。我们还进行了包括增殖、迁移和侵袭在内的功能测定，以评估钙肽素对PCCs和PSCs的抑制作用。定量逆转录聚合酶链反应表明，PCCs和PSCs表达钙蛋白酶-2 mRNA。钙肽素可减小裸鼠异种移植瘤的肿瘤体积（P = 0.0473）和肿瘤重量（P = 0.0471），并抑制肿瘤促纤维组织增生反应（P < 0.001）。钙肽素在体外还可抑制PCCs和PSCs的生物学功能，包括增殖（P = 0.017）、迁移（P = 0.027）和侵袭（P = 0.035）。此外，钙肽素通过破坏癌-基质相互作用减少PCCs和PSCs的迁移（P = 0.0002）。我们的研究结果表明，钙肽素是一种有前景的胰腺癌抗肿瘤药物，这不仅是因为其对PCCs和PSCs具有抑制作用，还因为其对癌-基质相互作用的破坏作用。
