Melatonin interferes in the desmoplastic reaction in breast cancer by regulating cytokine production
Melatonin interferes in the desmoplastic reaction in breast cancer by regulating cytokine production
复制标题
DOI：
10.1111/j.1600-079x.2011.00940.x
复制
发表时间：
2012-04-01
影响因子：
10.3
通讯作者：
Cos, Samuel
中科院分区：
文献类型：
--
作者：
Alvarez-Garcia, Virginia;Gonzalez, Alicia;Cos, Samuel
褪黑激素通过干扰雌激素信号通路对乳腺癌发挥抑癌作用。褪黑激素抑制乳腺癌细胞和成纤维细胞中的芳香酶。此外，褪黑激素刺激成纤维细胞的脂肪形成分化。我们的目的是研究褪黑素是否通过调节恶性细胞分泌的一些因子，肿瘤坏死因子（TNF）-a，白细胞介素（IL）-11和白细胞介素（IL）-6来干扰促纤维增生反应。为了实现这一目标，我们将 3T3-L1 细胞与 MCF-7 细胞共培养。将乳腺癌细胞添加到共培养物中，通过减少细胞质内甘油三酯的积累（脂肪形成分化的指标）来抑制3T3-L1前脂肪细胞向成熟脂肪细胞的分化，并且还刺激它们的芳香酶活性。褪黑激素抵消了MCF-7细胞在3T3-L1细胞中诱导的脂肪细胞分化和芳香酶活性的抑制作用。共培养介质中细胞因子的水平是单独培养 3T3-L1 细胞时的 10 倍。褪黑激素降低了培养基中细胞因子的浓度，并抵消了 MCF-7 细胞对细胞因子水平的刺激作用。一毫摩尔褪黑激素可诱导 MCF-7 和 3T3-L1 细胞中 TNF-a、IL-6 和 IL-11 mRNA 表达的减少。研究结果表明，褪黑激素可能通过下调抗脂肪细胞因子的表达，从而降低这些细胞因子的水平，从而在乳腺癌的促纤维增生反应中发挥作用。较低水平的细胞因子刺激成纤维细胞的分化并降低芳香酶活性和表达，从而减少恶性细胞附近产生雌激素的细胞的数量。
Melatonin exerts oncostatic effects on breast cancer by interfering with the estrogen signaling pathways. Melatonin inhibits aromatase enzyme in breast cancer cells and fibroblasts. In addition, melatonin stimulates the adipogenic differentiation of fibroblasts. Our objective was to study whether melatonin interferes in the desmoplastic reaction by regulating some factors secreted by malignant cells, tumor necrosis factor (TNF)-a, interleukin (IL)-11, and interleukin (IL)-6. To accomplish this, we co-cultured 3T3-L1 cells with MCF-7 cells. The addition of breast cancer cells to the co-cultures inhibited the differentiation of 3T3-L1 preadipocytes to mature adipocytes, by reducing the intracytoplasmic triglyceride accumulation, an indicator of adipogenic differentiation, and also stimulated their aromatase activity. Melatonin counteracted the inhibitory effect on adipocyte differentiation and aromatase activity induced by MCF-7 cells in 3T3-L1 cells. The levels of cytokines in the co-culture media were 10 times those found in culture of 3T3-L1 cells alone. Melatonin decreased the concentrations of cytokines in the media and counteracted the stimulatory effect induced by MCF-7 cells on the cytokine levels. One millimolar melatonin induced a reduction in TNF-a, IL-6, and IL-11 mRNA expression in MCF-7 and 3T3-L1 cells. The findings suggest that melatonin may play a role in the desmoplastic reaction in breast cancer through a downregulatory action on the expression of antiadipogenic cytokines, which decrease the levels of these cytokines. Lower levels of cytokines stimulate the differentiation of fibroblasts and decrease both aromatase activity and expression, thereby reducing the number of estrogen-producing cells proximal to malignant cells.