Department of Internal Medicine and Chronobiology Unit, Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", S. Giovanni Rotondo-FG, Italy.
Biomed Pharmacother. 2011 Oct;65(7):500-8. doi: 10.1016/j.biopha.2011.06.004. Epub 2011 Aug 27.
A customary temporal organization of physiological functions and biological processes is necessary to maintain body homeostasis and an altered body time structure may favour carcinogenesis. There is growing evidence that GH stimulates cancer growth, IGF1 may have a role in carcinogenesis and cancer promotion, GH-IGF1 axis, TRH, TSH, thyroxine, melatonin and cortisol modulate immune cell function and the immune system is often dysfunctional in patients with malignancies. The aim of our study was to evaluate GH-IGF1 axis, hypothalamus-pituitary-thyroid axis, melatonin, cortisol, lymphocyte subsets and IL2 in lung cancer patients. Peripheral blood samples were collected at 4-hour intervals in a 24-hour period from eleven healthy male subjects (age range 35-53 years) and nine male patients suffering from non-small cell lung cancer (age range 43-63 years). In each blood sample, lymphocyte subpopulations (CD3+, CD4+, CD8+, CD16+, CD20+, CD25+, HLA-DR+, γδTcR bearing cells) were analyzed and GH, IGF1, TRH, TSH, FT4, melatonin, cortisol and IL2 were measured. Circadian rhythmicity was evaluated and MESOR, amplitude and acrophase values were compared. In healthy subjects a significant circadian rhythm could be demonstrated with midday peaks for CD8+, CD16+, γδTCR expressing cells and cortisol, and peaks during the night for CD3+, CD4+, GH, TSH and melatonin. A borderline significant rhythm was also observed for CD20+, with a peak late in the evening. IGF1, TRH, FT4 and IL2 values did not show rhythmic variation. In cancer patients a significant circadian rhythm could be demonstrated with diurnal peak for CD16+ and peaks during the night for CD4+ and melatonin. GH, IGF1, TRH, TSH, FT4, cortisol and IL2 values did not show rhythmic variation. MESOR of CD8+ (P<0.0001), CD20+ (P=0.05), γδTCR expressing cells (P=0.01), IGF1 (P<0.001) and TSH (P=0.032) was higher in healthy subjects, whereas MESOR of CD16+ (P<0.0001), CD25+ (P=0.001), GH (P<0.001), TRH (P=0.002), FT4 (P=0.030), cortisol (P=0.01) and IL2 (P=0.02) was higher in cancer patients. Amplitude of circadian variation of γδTCR expressing cells (P=0.01), TSH (P<0.001) and cortisol (P=0.01) was higher in healthy subjects, whereas amplitude of circadian variation of CD4+ was higher in cancer patients (P=0.02). In conclusion, non-small cell lung cancer patients show severe alterations of periodic and quantitative characteristics of neuroendocrine and immune parameters with loss of circadian rhythmicity and internal desynchronization, leading to chronodisruption.
生理功能和生物过程的常规时间组织对于维持体内平衡是必要的，而改变身体的时间结构可能有利于致癌作用。越来越多的证据表明 GH 刺激癌症生长，IGF1 可能在致癌和癌症促进中发挥作用，GH-IGF1 轴、TRH、TSH、甲状腺素、褪黑素和皮质醇调节免疫细胞功能，而免疫系统在恶性肿瘤患者中常常功能失调。我们的研究目的是评估肺癌患者的 GH-IGF1 轴、下丘脑-垂体-甲状腺轴、褪黑素、皮质醇、淋巴细胞亚群和 IL2。从 11 名健康男性（年龄范围 35-53 岁）和 9 名患有非小细胞肺癌的男性患者（年龄范围 43-63 岁）中，在 24 小时内每 4 小时采集一次外周血样。在每个血液样本中，分析淋巴细胞亚群（CD3+、CD4+、CD8+、CD16+、CD20+、CD25+、HLA-DR+、γδTCR 阳性细胞），并测量 GH、IGF1、TRH、TSH、FT4、褪黑素、皮质醇和 IL2。评估昼夜节律性，并比较 MESOR、振幅和峰值时间值。在健康受试者中，可以证明存在明显的昼夜节律，CD8+、CD16+、γδTCR 阳性细胞和皮质醇的峰值出现在中午，CD3+、CD4+、GH、TSH 和褪黑素的峰值出现在夜间。也观察到 CD20+的边缘显著节律，峰值出现在晚上很晚。IGF1、TRH、FT4 和 IL2 值没有显示出节律变化。在癌症患者中，可以证明存在明显的昼夜节律，CD16+的峰值出现在白天，CD4+和褪黑素的峰值出现在夜间。GH、IGF1、TRH、TSH、FT4、皮质醇和 IL2 值没有显示出节律变化。CD8+（P<0.0001）、CD20+（P=0.05）、γδTCR 阳性细胞（P=0.01）、IGF1（P<0.001）和 TSH（P=0.032）的 MESOR 在健康受试者中更高，而 CD16+（P<0.0001）、CD25+（P=0.001）、GH（P<0.001）、TRH（P=0.002）、FT4（P=0.030）、皮质醇（P=0.01）和 IL2（P=0.02）的 MESOR 在癌症患者中更高。γδTCR 阳性细胞（P=0.01）、TSH（P<0.001）和皮质醇（P=0.01）的昼夜变化振幅在健康受试者中更高，而 CD4+的昼夜变化振幅在癌症患者中更高（P=0.02）。总之，非小细胞肺癌患者表现出神经内分泌和免疫参数的周期性和定量特征的严重改变，失去昼夜节律性和内部失同步性，导致生物钟紊乱。
