Contribution of Fibroblast and Mast Cell (Afferent) and Tumor (Efferent) IL-6 Effects within the Tumor Microenvironment
Contribution of Fibroblast and Mast Cell (Afferent) and Tumor (Efferent) IL-6 Effects within the Tumor Microenvironment
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DOI：
10.1007/s12307-012-0098-7
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发表时间：
2012-04-01
影响因子：
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通讯作者：
Ackland, M. Leigh
中科院分区：
文献类型：
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作者：
Hugo, Honor J.;Lebret, Stephanie;Ackland, M. Leigh
癌症发生后过度活跃的炎症反应导致癌症被描述为“永远无法愈合的伤口”。这些炎症反应通过 NFkB 引发信号，导致 IL-6 的产生，而 IL6 又被证明可以在体外诱导乳腺癌细胞上皮细胞向间质细胞的转变，这表明这种细胞因子在癌细胞侵袭中的作用。我们之前已经证明，源自癌症相关成纤维细胞的条件培养基在 PMC42-LA 乳腺癌细胞中诱导上皮细胞向间质细胞转变 (EMT)，现在我们已经鉴定出该培养基中存在 IL-6。我们进一步表明，与正常成纤维细胞相比，癌症相关成纤维细胞系中 IL-6 的表达量高出约 100 倍。 MCF-7、MDA MB 468 和 MDA MB 231 异种移植物中小鼠特异性（基质）和人类特异性（肿瘤）IL-6 mRNA 表达的比较也表明基质而不是肿瘤是 IL-6 表达显着较高的来源。肥大细胞 (MC) 存在于炎症性癌症相关基质中，激活的 MC 会分泌 IL-6。与 MDA MB 231 异种移植物相比，我们观察到 MDA MB 468 具有更高的 MC 指数（每个异种移植物切片的肥大细胞平均数量/平均肿瘤大小），其中所有 MC 均呈活性（脱颗粒）。这种较高的 MC 指数与 MDA MB 468 异种移植物中较高的小鼠特异性 IL-6 表达相关，表明 MC 是基质 IL6 的重要来源。此外，这些异种移植物上位于 IL-6 受体下游的 pSTAT3 的免疫组织化学表明 pSTAT3 和肥大细胞阳性细胞之间存在频繁的相关性。对患者组织中 IL-6 表达的公开数据库的分析显示，与炎性乳腺癌 (IBC) 和侵袭性非炎性乳腺癌 (non-IBC) 患者的邻近组织上皮相比，激光捕获显微切割基质中的 IL-6 更高，并且我们表明乳腺癌细胞系的 Basal 与 Luminal 分子/表型分组中的 IL-6 表达显着更高。最后，我们讨论传入和传出 IL-6 通路如何参与正反馈循环来决定肿瘤进展。
Hyperactive inflammatory responses following cancer initiation have led to cancer being described as a 'wound that never heals'. These inflammatory responses elicit signals via NFkB leading to IL-6 production, and IL6 in turn has been shown to induce epithelial to mesenchymal transition in breast cancer cells in vitro, implicating a role for this cytokine in cancer cell invasion. We previously have shown that conditioned medium derived from cancerassociated fibroblasts induced an Epithelial to Mesenchymal transition (EMT) in PMC42-LA breast cancer cells and we have now identify IL-6 as present in this medium. We further show that IL-6 is expressed approximately 100 fold higher in a cancer-associated fibroblast line compared to normal fibroblasts. Comparison of mouse-specific (stroma) and human-specific (tumor) IL-6 mRNA expression from MCF-7, MDA MB 468 and MDA MB 231 xenografts also indicated the stroma rather than tumor as a significantly higher source of IL-6 expression. Mast cells (MCs) feature in inflammatory cancer-associated stroma, and activated MCs secrete IL-6. We observed a higher MC index (average number of mast cells per xenograft section/average tumor size) in MDA MB 468 compared to MDA MB 231 xenografts, where all MC were observed to be active (degranulating). This higher MC index correlated with greater mouse-specific IL-6 expression in the MDA MB 468 xenografts, implicating MC as an important source of stromal IL6. Furthermore, immunohistochemistry on these xenografts for pSTAT3, which lies downstream of the IL-6 receptor indicated frequent correlations between pSTAT3 and mast cell positive cells. Analysis of publically available databases for IL-6 expression in patient tissue revealed higher IL-6 in laser capture microdissected stroma compared to adjacent tissue epithelium from patients with inflammatory breast cancer (IBC) and invasive non-inflammatory breast cancer (non-IBC) and we show that IL-6 expression was significantly higher in Basal versus Luminal molecular/phenotypic groupings of breast cancer cell lines. Finally, we discuss how afferent and efferent IL-6 pathways may participate in a positive feedback cycle to dictate tumor progression.