Periostin creates a tumor-supportive microenvironment in the pancreas by sustaining fibrogenic stellate cell activity
Periostin creates a tumor-supportive microenvironment in the pancreas by sustaining fibrogenic stellate cell activity
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DOI：
10.1053/j.gastro.2007.01.031
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发表时间：
2007-04-01
期刊：
影响因子：
29.4
通讯作者：
Friess, Helmut
中科院分区：
文献类型：
--
作者：
Erkan, Mert;Kleeff, Joerg;Friess, Helmut
背景与目的：胰腺癌通过刺激星状细胞(stellate cell，PSCs)产生促结缔组织增生，从而影响肿瘤的侵袭性。本研究的目的是分析PSC特异性基质蛋白Periostin对肿瘤放化疗反应的影响。方法：采用免疫组织化学方法检测新辅助放化疗前后原发灶和转移灶中的PSCs和癌细胞。定量逆转录聚合酶链式反应测定的Periostin Messenger-RNA水平与患者生存相关。通过免疫印迹和生长、克隆形成和侵袭实验评估PSCs和癌细胞之间的相互作用以及Periostin在低氧、饥饿和放化疗条件下调节细胞反应的作用。结果：Periostin Messenger-RNA水平在癌症患者中升高了42倍，并且表达增强的患者有缩短生存期的趋势(19个月对12个月；P=.14)。基质细胞是胰腺和转移部位中Periostin的唯一来源。癌细胞上清液可刺激PSCs分泌Periostin。重组Periostin增加α-平滑肌肌动蛋白、Periostin、胶原-1、纤维连接蛋白和转化生长因子-β1的表达，同时降低PSC的侵袭性。这些作用可通过小干扰RNA转染抑制Periostin的表达和分泌而逆转。在癌细胞中，Periostin刺激生长，并赋予其对饥饿和缺氧的抵抗力。此外，Periostin下游的靶标胶原-1显著增加了化疗耐药性。结论：一旦受到癌细胞的刺激，即使在放射治疗的情况下，PSCs也会通过自分泌的Periostin环保持活跃，并产生过多的细胞外基质蛋白，从而创造出支持肿瘤的微环境。因此，Periostin表达增加可能反映了更具侵袭性的肿瘤表型。
Background & Aims: Pancreatic cancer creates desmoplasia by stimulating stellate cells (PSCs), thereby influencing tumor aggressiveness. The aim of this study was to analyze the impact of the PSC-specific matrix protein periostin on tumor responses to radiochemotherapy. Methods: PSCs and cancer cells in primary and metastatic lesions of patients treated with or without neoadjuvant radiochemotherapy were evaluated by immunohistochemistry. Periostin messenger-RNA levels determined by quantitative reverse-transcription polymerase chain reaction were correlated to patient survival. Interactions between PSCs and cancer cells and the effects of periostin in modulating cellular responses under conditions of hypoxia, starvation, and radiochemotherapy were assessed by immunoblotting and by growth, clonogenicity, and invasion assays. Results: Periostin messenger-RNA levels were elevated 42-fold in cancer, and patients with increased expression had a tendency toward shorter survival (19 vs 12 months; P = .14). Stromal cells were the only source of periostin in the pancreas and in metastatic sites. Cancer cell supernatants stimulated periostin secretion from PSCs. Recombinant periostin increased alpha-smooth muscle actin, periostin, collagen-1, fibronectin, and transforming growth factor-beta 1 expression while decreasing PSC invasiveness. These effects were reversed by silencing periostin expression and secretion by small interfering RNA transfection. In cancer cells, periostin stimulated growth and conferred resistance to starvation and hypoxia. In addition, the periostin downstream target collagen-1 significantly increased chemo resistance. Conclusions: Once stimulated by cancer cells, PSCs remain active via an autocrine periostin loop even under radiotherapy and produce excessive extracellular matrix proteins, creating a tumor-supportive microenvironment. Increased periostin expression may therefore reflect a more aggressive tumor phenotype.