Periprostatic Adipose Tissue as a Modulator of Prostate Cancer Aggressiveness
Periprostatic Adipose Tissue as a Modulator of Prostate Cancer Aggressiveness
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DOI：
10.1016/j.juro.2009.06.015
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发表时间：
2009-10-01
影响因子：
6.6
通讯作者：
Ornstein, David K.
中科院分区：
文献类型：
--
作者：
Finley, David S.;Calvert, Valerie S.;Ornstein, David K.
目的：脂肪组织被认为与多种疾病状态（包括前列腺癌）的发病机制有关。我们研究了前列腺周围脂肪组织分泌的细胞因子和生长因子与侵袭性前列腺癌病理特征的关联。材料和方法：从接受根治性前列腺切除术的患者身上采集前列腺周围脂肪组织，培养24小时以产生条件培养基或立即速冻用于功能信号分析。使用前列腺周围脂肪组织条件培养基的多重分析来检测细胞因子水平，并与来自 7 名患者的患者匹配血清进行比较。通过酶联免疫吸附测定进一步分析了 45 名患者血清和前列腺周围脂肪组织条件培养基中的白细胞介素 6，并将其与年龄、体重指数和格里森评分等临床变量相关联。通过免疫组织化学测定前列腺周围脂肪组织中白细胞介素6的表达。采用反相蛋白微阵列技术分析前列腺周围脂肪组织中的细胞信号网络。结果：前列腺周围脂肪组织条件培养基中的白细胞介素6约为患者匹配血清的375倍，且水平与病理分级相关。通过对前列腺周围脂肪组织的细胞信号传导分析进一步扩展了这一发现，结果表明，高级别肿瘤（格里森评分 4 或 5 的任何组成部分）的 Stat3 磷酸化程度更高。 结论：较高的格里森评分与条件培养基来源的白细胞介素 6 的高水平相关。此外，对前列腺周围脂肪组织的细胞信号传导分析发现了与格里森评分相关的激活信号传导分子，包括 STAT3。由于 STAT3 受白细胞介素 6 调节，这些发现表明前列腺周围脂肪组织可能通过作为白细胞介素 6 的来源来调节前列腺癌的侵袭性。此外，我们发现脂肪中炎症细胞数量较少，表明脂肪细胞是白细胞介素 6 的主要分泌者。
Purpose: Adipose tissue has been suggested to contribute to the pathogenesis of various disease states, including prostate cancer. We investigated the association of cytokines and growth factors secreted by periprostatic adipose tissue with pathological features of aggressive prostate cancer.Materials and Methods: Periprostatic adipose tissue was harvested from patients undergoing radical prostatectomy and cultured for 24 hours to generate conditioned medium or snap frozen immediately for functional signaling profiling. Multiplex analysis of the periprostatic adipose tissue conditioned medium was used to detect cytokine levels and compared to patient matched serum from 7 patients. Interleukin-6 in serum and periprostatic adipose tissue conditioned medium was further analyzed by enzyme-linked immunosorbent assay and correlated with clinical variables, such as age, body mass index and Gleason score, in 45 patients. Interleukin-6 expression in periprostatic adipose tissue was determined by immunohistochemistry. Reverse phase protein microarray technology was used to analyze cell signaling networks in periprostatic adipose tissue.Results: Interleukin-6 in periprostatic adipose tissue conditioned medium was approximately 375 times greater than that in patient matched serum and levels correlated with pathological grade. This finding was further extended by cell signaling analysis of periprostatic adipose tissue, which showed greater phosphorylation on Stat3 with high grade tumors (any component of Gleason score 4 or 5).Conclusions: Higher Gleason score correlated with high levels of conditioned medium derived interleukin-6. Moreover, cell signaling analysis of periprostatic adipose tissue identified activated signaling molecules, including STAT3, that correlated with Gleason score. Since STAT3 is interleukin-6 regulated, these findings suggest that periprostatic adipose tissue may have a role in modulating prostate cancer aggressiveness by serving as a source of interleukin-6. Also, we found low numbers of inflammatory cells in the fat, suggesting that adipocytes are the major secretors of interleukin-6.