Pirfenidone Inhibits Pancreatic Cancer Desmoplasia by Regulating Stellate Cells
Pirfenidone Inhibits Pancreatic Cancer Desmoplasia by Regulating Stellate Cells
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DOI：
10.1158/0008-5472.can-12-3180
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发表时间：
2013-04-01
期刊：
影响因子：
11.2
通讯作者：
Tanaka, Masao
中科院分区：
文献类型：
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作者：
Kozono, Shingo;Ohuchida, Kenoki;Tanaka, Masao
胰腺星状细胞(PSC)与胰腺癌中的促结缔组织增生有关，它增强了癌细胞的恶性程度，并对已有的治疗方法产生了抵抗。我们研究了抗纤维化药物吡非尼酮是否能抑制结缔组织增生，并对胰腺癌起到抗肿瘤作用。原代PSCs取自手术过程中获得的胰腺癌组织。在体外，吡非尼酮以剂量依赖的方式抑制PSCs的增殖、侵袭和迁移。虽然未经处理的PSCs的培养上清增加了胰腺癌细胞(PCC)的增殖、侵袭和迁移，但吡非尼酮处理的PSCs的上清液减少了这些影响。PSCs经PCC培养上清液培养后，血小板衍生生长因子-A、肝生长因子、I型胶原、纤维连接蛋白和Periostin的产生增加，而吡非尼酮可显著降低这一作用。小鼠右侧皮下植入PCCs(Suit-2细胞)和PSCs，左侧仅植入PCCs。这些小鼠口服吡非尼酮显著减少了联合移植的PCCs和PSCs的肿瘤生长，但不是单独的PCCs。吡非尼酮还可减少PSCs的增殖，减少I型胶原和Periostin在肿瘤中的沉积。在由PCCs和PSCs共同植入的原位肿瘤小鼠中，吡非尼酮抑制肿瘤生长，减少腹膜播散性结节的数量，并降低肝转移的发生率。与单独使用吡非尼酮或吉西他滨相比，吡非尼酮联合吉西他滨更有效地抑制原位肿瘤的生长。综上所述，我们的研究结果表明，吡非尼酮是一种很有前途的抗胰腺癌药物，因为它通过调节PSCs来抑制促结缔组织增生。巨蟹座；73(7)；2345-56。(C)2013年AACR。
Pancreatic stellate cells (PSC), which are implicated in desmoplasia in pancreatic cancer, enhance the malignancy of cancer cells and confer resistance to established treatments. We investigated whether the antifibrotic agent pirfenidone can suppress desmoplasia and exert antitumor effects against pancreatic cancer. Primary PSCs were established from pancreatic cancer tissue obtained during surgery. In vitro, pirfenidone inhibited the proliferation, invasiveness, and migration of PSCs in a dose-dependent manner. Although supernatants of untreated PSCs increased the proliferation, invasiveness, and migration of pancreatic cancer cells (PCC), supernatants of pirfenidone-treated PSCs decreased these effects. Exposure to PCC supernatant increased the production of platelet-derived growth factor-A, hepatic growth factor, collagen type I, fibronectin, and periostin in PSCs, which was significantly reduced by pirfenidone. Mice were subcutaneously implanted with PCCs (SUIT-2 cells) and PSCs into the right flank and PCCs alone into the left flank. Oral administration of pirfenidone to these mice significantly reduced tumor growth of co-implanted PCCs and PSCs, but not of PCCs alone. Pirfenidone also decreased the proliferation of PSCs and the deposition of collagen type I and periostin in tumors. In mice with orthotopic tumors consisting of PCCs co-implanted with PSCs, pirfenidone suppressed tumor growth, reduced the number of peritoneal disseminated nodules, and reduced the incidence of liver metastasis. Pirfenidone in combination with gemcitabine more effectively suppressed orthotopic tumor growth compared with pirfenidone or gemcitabine alone. In conclusion, our findings indicate that pirfenidone is a promising antitumor agent for pancreatic cancer, owing to its suppression of desmoplasia through regulating PSCs. Cancer Res; 73(7); 2345-56. (C)2013 AACR.