Senescent stromal-derived osteopontin promotes preneoplastic cell growth.
Senescent stromal-derived osteopontin promotes preneoplastic cell growth.
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DOI：
10.1158/0008-5472.can-08-2970
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发表时间：
2009-02-01
期刊：
影响因子：
11.2
通讯作者：
Stewart, Sheila A.
中科院分区：
文献类型：
--
作者：
Pazolli, Ermira;Luo, Xianmin;Brehm, Sarah;Carbery, Kelly;Chung, Jun Jae;Prior, Julie L.;Doherty, Jason;Demehri, Shadmehr;Salavaggione, Lorena;Piwnica-Worms, David;Stewart, Sheila A.
组织微环境的改变与细胞自主遗传变化协作，促进肿瘤进展。研究表明，从肿瘤中分离的成纤维细胞在异种移植模型中刺激肿瘤前细胞和肿瘤细胞的生长，从而强调了肿瘤进展中微环境的重要性。类似地，衰老的成纤维细胞在体外和体内促进癌前细胞生长。由于衰老细胞随着年龄的增长而积累，因此假设它们的存在促进了老年个体中的癌前细胞生长和肿瘤形成。为了鉴定直接负责刺激癌前细胞生长的衰老基质因子，我们进行了全基因组转录谱分析，并将衰老成纤维细胞与年轻的成纤维细胞进行了比较。我们发现骨桥蛋白（OPN）是衰老成纤维细胞中最高的转录本之一。重要的是，通过RNAi降低OPN蛋白水平并不影响成纤维细胞的衰老诱导;然而，它在体外和体内显著降低了衰老成纤维细胞的促生长活性，表明OPN是肿瘤前细胞生长的旁分泌刺激所必需的。此外，我们发现重组OPN足以刺激癌前细胞生长。最后，我们证明OPN在DMBA/TPA治疗小鼠后出现的肿瘤前病变内的衰老基质中表达，表明基质源性OPN介导的信号传导事件影响肿瘤进展。
Alterations in the tissue microenvironment collaborate with cell autonomous genetic changes to contribute to neoplastic progression. The importance of the microenvironment in neoplastic progression is underscored by studies demonstrating that fibroblasts isolated from a tumor stimulate the growth of preneoplastic and neoplastic cells in xenograft models. Similarly, senescent fibroblasts promote preneoplastic cell growth in vitro and in vivo. Because senescent cells accumulate with age, their presence is hypothesized to facilitate preneoplastic cell growth and tumor formation in older individuals. To identify senescent stromal factors directly responsible for stimulating preneoplastic cell growth, we carried out whole genome transcriptional profiling and compared senescent fibroblasts to their younger counterparts. We identified osteopontin (OPN) as one of the most highly elevated transcripts in senescent fibroblasts. Importantly, reduction of OPN protein levels by RNAi did not impact senescence induction in fibroblasts; however, it dramatically reduced the growth-promoting activities of senescent fibroblasts in vitro and in vivo, demonstrating that OPN is necessary for paracrine stimulation of preneoplastic cell growth. In addition, we found that recombinant OPN was sufficient to stimulate preneoplastic cell growth. Finally, we demonstrate that OPN is expressed in senescent stroma within preneoplastic lesions that arise following DMBA/TPA treatment of mice, suggesting that stromal-derived OPN-mediated signaling events impact neoplastic progression.