Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression
Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression
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DOI：
10.1073/pnas.1401799111
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发表时间：
2014-04-29
影响因子：
11.1
通讯作者：
Wink, David A.
中科院分区：
文献类型：
--
作者：
Heinecke, Julie L.;Ridnour, Lisa A.;Wink, David A.
炎症被广泛认为是癌症进展的诱导物。炎症相关酶，诱导型一氧化氮合酶（NOS 2），已成为雌激素受体（ER）阴性乳腺癌的候选癌基因，其表达增加与疾病的侵袭性和生存率低。尽管这些观察结果暗示NOS 2是一个有吸引力的治疗靶点，但肿瘤中NOS 2诱导和一氧化氮（NO）驱动的癌症进展的机制尚未完全了解。为了加强我们对NOS 2在肿瘤中的诱导机制及其在肿瘤生物学中的作用的理解，我们在ER-和ER+乳腺癌细胞中使用了NOS 2表达的刺激物，并检查了下游NO依赖性效应。在此，我们表明，NOS 2的上调发生在缺氧，血清戒断，IFN-γ，和外源性NO，在乳腺癌生物学中的肿瘤微环境的NO生产的前馈调节一致。此外，我们发现侵袭性癌症表型的关键指标，包括S100钙结合蛋白A8、IL-6、IL-8和组织抑制剂基质金属蛋白酶-1的增加，都受到这些NOS 2刺激剂的上调，而抑制MDA-MB-231乳腺癌细胞中的NOS 2则抑制了这些标志物。此外，NO还能改变MDA-MB-231细胞的迁移和对紫杉醇的耐药性。最值得注意的是，在裸鼠中通过抑制NOS 2显著抑制了MDA-MB 231肿瘤异种移植物和从脂肪垫到脑的细胞转移。总之，这些结果将升高的NOS 2与来自肿瘤微环境的信号联系起来，这些信号随着癌症进展而出现，并表明NO的产生调节乳腺癌细胞的化疗耐药性和转移。
Inflammation is widely recognized as an inducer of cancer progression. The inflammation-associated enzyme, inducible nitric oxide synthase (NOS2), has emerged as a candidate oncogene in estrogen receptor (ER)-negative breast cancer, and its increased expression is associated with disease aggressiveness and poor survival. Although these observations implicate NOS2 as an attractive therapeutic target, the mechanisms of both NOS2 induction in tumors and nitric oxide (NO)-driven cancer progression are not fully understood. To enhance ourmechanistic understanding of NOS2 induction in tumors and its role in tumor biology, we used stimulants of NOS2 expression in ER-and ER+ breast cancer cells and examined downstream NO-dependent effects. Herein, we show that up-regulation of NOS2 occurs in response to hypoxia, serum withdrawal, IFN-gamma, and exogenous NO, consistent with a feed-forward regulation of NO production by the tumor microenvironment in breast cancer biology. Moreover, we found that key indicators of an aggressive cancer phenotype including increased S100 calcium binding protein A8, IL-6, IL-8, and tissue inhibitor matrix metalloproteinase- 1 are up-regulated by these NOS2 stimulants, whereas inhibition of NOS2 in MDA-MB-231 breast cancer cells suppressed these markers. Moreover, NO altered cellular migration and chemoresistance of MDA-MB-231 cells to Taxol. Most notably, MDA-MB231 tumor xenographs and cell metastases from the fat pad to the brainwere significantly suppressed by NOS2 inhibition in nude mice. In summary, these results link elevated NOS2 to signals from the tumor microenvironment that arise with cancer progression and show that NO production regulates chemoresistance and metastasis of breast cancer cells.