Establishment of newly treatment strategies for suppressing desmoplasitic reactions in pancreatic cancer

我们研究了抗纤维化药物吡非尼酮(PF)对胰腺癌是否具有抑制结缔组织增生和抗肿瘤作用。PF以剂量依赖的方式抑制PSCs的增殖、侵袭和迁移。PF处理的PSCs上清液可减弱促进胰腺癌细胞增殖、侵袭和迁移的能力。胰腺癌细胞培养上清液可促进PSCs中PDGF-A、HGF、I型胶原、纤维连接蛋白和Periostin的产生，而PF可明显抑制这一作用。在体内，只有当胰腺癌细胞与PSCs共移植时，PF才能显著抑制肿瘤的生长，并减少肿瘤中PSCs的数量和I型胶原和Periostin的沉积。吉西他滨和PF联合治疗比单独使用吉西他滨和PF更有效地抑制体内肿瘤的生长。这些结果表明，PF可能通过抑制PSCs和产生与肿瘤-间质相互作用相关的生长因子和间质成分而成为靶向促结缔组织增生症的药物。

We investigated whether the antifibrotic agent, pirfenidone(PF), suppress desmoplasia and exert anti-tumor effects for pancreatic cancer. PF inhibited proliferation, invasiveness and migration of PSCs in the dose-dependent manner. The supernatants of PSCs treated with PF attenuated capacity to promote proliferation, invasiveness and migration of pancreatic cancer cells. The supernatants of pancreatic cancer cells increased production of PDGF-A, HGF, collagen type I, Fibronectin, and periostin in PSCs, and the increase were significantly reduced by PF. In vivo, PF significantly suppressed the tumor growth only when pancreatic cancer cells were co-transplanted with PSCs and decreased numbers of PSCs and deposition of collagen type I and periostin in tumors. Combination treatment with gemcitabine and PF more effectively suppressed in vivo tumor growth than gemcitabine alone and PF alone groups. These results indicate that PF could be promising agents targeting desmoplasia by suppression of PSCs and production of growth factors and stromal components related to tumor-stromal interactions.