Timing within the oestrous cycle modulates adrenergic suppression of NK activity and resistance to metastasis: possible clinical implications
Timing within the oestrous cycle modulates adrenergic suppression of NK activity and resistance to metastasis: possible clinical implications
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DOI：
10.1054/bjoc.2000.1563
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发表时间：
2000-12-01
影响因子：
8.8
通讯作者：
Melamed, R
中科院分区：
文献类型：
--
作者：
Ben-Eliyahu, S;Shakhar, G;Melamed, R
临床观察表明，乳腺癌患者手术后的转移发展率和长期死亡率受到手术进行期间的月经期的影响。已知月经周期调节涉及肾上腺素能机制的各种生理反应和医学状况（例如，哮喘）。自然杀伤活性（NKA），一种控制转移的免疫功能，在手术后和体外被肾上腺素抑制。因此，我们假设临床观察结果可能部分归因于手术诱导的肾上腺素能抑制NK依赖性转移抵抗，这种抑制取决于手术期间的月经期。为了在大鼠中检验这一假设：140只处于发情周期不同阶段的F344雌性大鼠注射β-肾上腺素能激动剂--羟丙肾上腺素（MP）（0.4或0.8 mg/kg，s.c.），或在静脉接种MADB 106肿瘤细胞之前使用溶剂。该同基因乳腺腺癌细胞系仅转移至肺，并且对NKA高度敏感。在第二个实验中，在体外研究了MP对NKA的抑制作用，在发情周期的不同阶段抽取血液（n = 36）。最后，压力对NK细胞的数量和活性的影响进行了评估沿着发情周期（n = 71）。研究结果表明，MP对转移抗性和NKA的抑制作用在以高雌二醇水平为特征的发情期（D3/发情前期/发情期）显著更大。同样，NKA/细胞仅在此阶段受到应力抑制。在未处理的动物中，无意中的压力被最小化，发情周期对NKA或对转移的抵抗力没有明显的影响。这些发现表明，动情周期调节肾上腺素能抑制NKA和转移的阻力。这些发现的相关性，上述临床观察，以及我们的相关研究结果在妇女的平行研究，进行了讨论。(C)2000年癌症研究运动。
Clinical observations suggest that the rate of metastatic development and long-term mortality following surgery in breast cancer patients is influenced by the menstrual phase during which surgery is conducted. The menstrual cycle is known to modulate various physiological responses and medical conditions that involve adrenergic mechanisms (e.g., asthma). Natural killer activity (NKA), an immune function controlling metastasis, is suppressed following surgery, and in vitro by adrenaline. We therefore hypothesize that the clinical observation may be partly attributable to surgery-induced adrenergic suppression of NK-dependent resistance to metastasis, a suppression that depends on menstrual phase during surgery. To test this hypothesis in rats: 140 F344 females at different phases of their oestrous cycle were injected with a beta -adrenergic agonist, metaproterenol (MP) (0.4 or 0.8 mg kg(-1), s.c.), or with vehicle, before i.v. inoculation with MADB106 tumour cells. This syngeneic mammary adenocarcinoma line metastasizes only to the lungs, and is highly sensitive to NKA. In a second experiment, the suppression of NKA by MP was studied in vitro in blood drawn at different phases of the oestrous cycle (n = 36). Finally, the effects of stress on the number and activity of NK cells were assessed along the oestrous cycle (n = 71). The findings indicate that the suppressive effects of MP on resistance to metastasis and on NKA, are significantly greater during the oestrous phase characterized by high oestradiol levels (D3/proestrus/oestrus). Similarly, NKA per cell was suppressed by stress only during this phase. In untreated animals, in which inadvertent stress was minimized, no effects of the oestrous cycle on NKA or on resistance to metastasis were evident. These findings indicate that the oestrous cycle modulates adrenergic suppression of NKA and of resistance to metastasis. The relevance of these findings to the above clinical observation, as well as that of our related findings in women from a parallel study, is discussed. (C) 2000 Cancer Research Campaign.