The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms
The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms
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DOI：
10.1158/0008-5472.can-05-1716
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发表时间：
2006-01-15
期刊：
影响因子：
11.2
通讯作者：
Nelson, PS
中科院分区：
文献类型：
--
作者：
Bavik, C;Coleman, I;Nelson, PS
发展前列腺癌的最大危险因素是高龄。老年人中癌症发生频率的潜在分子和生理学因素包括通过基因组维持，表观遗传基因沉默，氧化应激，免疫监测丧失，端粒功能障碍，慢性炎症的丧失以及组织微观环境的变化而导致体细胞突变的积累。在这种情况下，前列腺癌变的过程可以通过内在细胞改变与外部微环境和宏观环境之间的相互作用来影响，这两种环境都因衰老而发生了很大变化。在这项研究中，我们试图表征在前列腺成纤维细胞衰老过程中发生的分子改变，以鉴定能够促进前列腺上皮的增殖并潜在地促进肿瘤进展的老年组织微环境中的因素。我们评估了导致细胞衰老的三种机制：氧化应激，DNA损伤和复制性疲惫。我们确定了一个一致的基因表达程序，其中包括能够影响相邻前列腺上皮生长的旁分泌因子的子集。衰老前列腺成纤维细胞的直接共培养和条件培养基分别刺激了上皮细胞增殖，分别为3倍和2倍。在衰老的前列腺成纤维细胞的细胞外环境中，旁分泌作用蛋白成纤维细胞生长因子7，肝细胞生长因子和两次释放蛋白（AREG）升高。单独的外源AREG刺激了前列腺上皮细胞的生长，中和抗体和较小的干扰RNA靶向AREG减弱了，但并未完全消除衰老成纤维细胞调节培养基的生长促进作用。这些结果支持这样一个概念，即前列腺微环境中与衰老相关的变化可能有助于前列腺肿瘤的发展。
The greatest risk factor for developing carcinoma of the prostate is advanced age. Potential molecular and physiologic contributors to the frequency of cancer occurrence in older individuals include the accumulation of somatic mutations through defects in genome maintenance, epigenetic gene silencing, oxidative stress, loss of immune surveillance, telomere dysfunction, chronic inflammation, and alterations in tissue microenvironment. In this context, the process of prostate carcinogenesis can be influenced through interactions between intrinsic cellular alterations and the extrinsic microenvironment and macroenvironment, both of which change substantially as a consequence of aging. In this study, we sought to characterize the molecular alterations that occur during the process of prostate fibroblast senescence to identify factors in the aged tissue microenvironment capable of promoting the proliferation and potentially the neoplastic progression of prostate epithelium. We evaluated three mechanisms leading to cell senescence: oxidative stress, DNA damage, and replicative exhaustion. We identified a consistent program of gene expression that includes a subset of paracrine factors capable of influencing adjacent prostate epithelial growth. Both direct coculture and conditioned medium from senescent prostate fibroblasts stimulated epithelial cell proliferation, 3-fold and 2-fold, respectively. The paracrine-acting proteins fibroblast growth factor 7, hepatocyte growth factor, and amphiregulin (AREG) were elevated in the extracellular environment of senescent prostate fibroblasts. Exogenous AREG alone stimulated prostate epithelial cell growth, and neutralizing antibodies and small interfering RNA targeting AREG attenuated, but did not completely abrogate the growth-promoting effects of senescent fibroblast conditioned medium. These results support the concept that aging-related changes in the prostate microenvironment may contribute to the progression of prostate neoplasia.