Fibroblasts Isolated from Common Sites of Breast Cancer Metastasis Enhance Cancer Cell Growth Rates and Invasiveness in an Interleukin-6-Dependent Manner
Fibroblasts Isolated from Common Sites of Breast Cancer Metastasis Enhance Cancer Cell Growth Rates and Invasiveness in an Interleukin-6-Dependent Manner
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DOI：
10.1158/0008-5472.can-08-0400
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发表时间：
2008-11-01
期刊：
影响因子：
11.2
通讯作者：
Hall, Brett M.
中科院分区：
文献类型：
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作者：
Studebaker, Adam W.;Storci, Gianluca;Hall, Brett M.
乳腺癌转移的常见部位包括肺、肝和骨，在这些继发性转移部位中，雌激素受体α（EB α）阳性乳腺癌通常倾向于骨。在次级器官中，癌细胞将可预见地遇到组织特异性成纤维细胞或其可溶性因子，但我们对组织特异性成纤维细胞如何直接影响癌细胞生长速率和存活率的理解在很大程度上仍然未知。因此，我们检验了从乳腺癌转移的常见部位分离的间充质成纤维细胞提供关于肿瘤生长速率的更有利的微环境的假设。我们发现乳腺、肺和骨成纤维细胞增强ER α阳性乳腺癌细胞生长的能力与每个器官特异性成纤维细胞产生的可溶性白细胞介素-6（IL-6）水平之间存在直接相关性，并且成纤维细胞介导的生长增强作用可通过去除或抑制IL-6而受到抑制。有趣的是，共注射MCF-7乳腺肿瘤细胞和分泌IL-6的衰老皮肤成纤维细胞的小鼠发生了肿瘤，而共注射产生很少或不产生IL-6的衰老皮肤成纤维细胞的小鼠未能形成异种移植肿瘤。我们随后确定，IL-6通过信号转导和转录激活因子3依赖性上调Notch-3、Jagged-1和碳酸酐酶IX促进乳腺癌细胞的生长和侵袭。这些数据表明，组织特异性成纤维细胞及其产生的因子可以促进乳腺癌疾病的进展，并可能成为开发新疗法的有吸引力的靶点。[Cancer Res 2008;68（21）：9087-95]
Common sites of breast cancer metastasis include the lung, liver, and bone, and of these secondary metastatic sites, estrogen receptor alpha (EB alpha)-positive breast cancer often favors bone. Within secondary organs, cancer cells would predictably encounter tissue-specific fibroblasts or their soluble factors, yet our understanding of how tissue-specific fibroblasts directly affect cancer cell growth rates and survival remains largely unknown. Therefore, we tested the hypothesis that mesenchymal fibroblasts isolated from common sites of breast cancer metastasis provide a more favorable microenvironment with respect to tumor growth rates. We found a direct correlation between the ability of breast, lung, and bone fibroblasts to enhance ER alpha-positive breast cancer cell growth and the level of soluble interleukin-6 (IL-6) produced by each organ-specific fibroblast, and fibroblast-mediated growth enhancement was inhibited by the removal or inhibition of IL-6. Interestingly, mice coinjected with MCF-7 breast tumor cells and senescent skin fibroblasts, which secrete IL-6, developed tumors, whereas mice coinjected with presenescent skin fibroblasts that produce little to no IL-6 failed to form xenograft tumors. We subsequently determined that IL-6 promoted growth and invasion of breast cancer cells through signal transducer and activator of transcription 3-dependent up-regulation of Notch-3, Jagged-1, and carbonic anhydrase IX. These data suggest that tissue-specific fibroblasts and the factors they produce can promote breast cancer disease progression and may represent attractive targets for development of new therapeutics. [Cancer Res 2008;68(21):9087-95]