慢性情绪应激在C3H/HeJ小鼠乳腺肿瘤发病中的作用
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摘要
目的：研究慢性情绪应激对C3H／HeJ小鼠乳腺肿瘤生长的影响，并进一步探讨应激影响乳腺肿瘤生长的神经内分泌机制与神经免疫学机制。
方法：C3H／HeJ小鼠110只，随机分为应激组与对照组，其中应激组接受饮水冲突应激与限制应激。两组小鼠分别于入组0月、3月、6月、9月分批处死，采集乳腺组织、血与脾脏，分别用于检测乳腺肿瘤，血浆皮质酮浓度，脾细胞产生的IL-2与脾NK细胞活性。
结果：(1)3月、6月时段应激组小鼠乳腺肿瘤发病率显著高于对照组(P＜0.05)；应激3月、6月、9月时段显著高于应激0月时段(P＜0.01)；对照组9月时段显著高于对照0月时段(P＜0.05)。(2)3月、6月、9月时段应激组小鼠血浆皮质酮显著高于对照组(P值分别为0.001、0.022、0.048)；在应激组，这三个时段小鼠的血浆皮质酮显著高于0月时段(P值分别为0.005、0.028、0.007)；对照组9月时段显著高于对照0月、3月时段(P＜0.05)。(3)3月与6月时段，应激组小鼠脾细胞产生的IL-2显著低于对照组(P值分别为0.012与0.005)。应激组0月时段、9月时段小鼠脾细胞产生的IL-2明显高6月时段(P＜0.05)。(4)6月时段与9月时段应激组小鼠NK细胞活性明显低于对照组(P＜0.01)。应激组3、6、9月时段显著低于0月时段(P＜0.01)，而3月时段又显著高于9月时段的小鼠(P值为0.025)。对照组0、3、6月时段显著高于9月时段(P值分别为0.013、0.043、0.037)。
结论：(1)慢性情绪应激可以促使C3H／HeJ小鼠乳腺肿瘤生长加快，缩短其发病潜伏期。(2)慢性情绪应激可以提高血浆皮质酮，抑制脾脏产生IL-2与NK细胞的活性，且这些变化同乳腺肿瘤的生长加快相伴随，提示它们可能参与介导应激对乳腺癌生长的促进作用。(3)皮质酮的增高同脾细胞产生的IL-2成负相关，与NK细胞活性则无关，提示皮质酮可能对IL-2的生成有抑制作用，而NK细胞活性的降低则可能是通过其他机制进行的。
Objectives:(l) To determine the effects of chronic emotional stress on the growth of mammary tumor of C3H/HeJ mice. (2) To investigate the potential neuroendocrinology and neuroimmunology mechanisms linking stress and the mammary tumor .
Methods: 110 C3H/HeJ female virgin mice were divided into chronic emotional stressed (CES) group which was exposed to drinking-conflict stress and restraint stress and non-treated control(C) group. Mice was decapitated in batches at the end of 0 month (before the exposure of stressors ), 3 months, 6 months or 9 months after being grouped . The parameters measured were the occurrence of mammary tumor , plasma corticosterone level, the production of IL-2 (interleukin-2) from splenocyte and activity of natural killer(NK) cell in spleen.
Results: (1) In months 3, 6, mammary tumor morbidity of CES group was significantly higher than that of C group (PO.05). In CES group, tumor morbidity of 3-month, 6-month and 9-month mice increased significantly compared to 0-month mice (P<0.01); In C group, tumor morbidity of 9-month mice was significantly higher than that of 0-month mice (P<0.05). (2) In months 3, 6, and 9, plasma corticosterone levels of CES group were significantly higher than that of C group (P =0.001, 0.022, 0.048 respectively). In CES group, corticosterone levels of 3-month, 6-month and 9-month mice increased significantly compared to 0-month mice (P =0.005, 0.028, 0.007 respectively); In C group, corticosterone levels of 9-month mice were significantly elevated compared to 0-month and 3-month mice (P<0.05). (3) In months 3, 6, the production of IL-2 of CES group was significantly higher than that of C group (P= 0.012 ,0.005 respectively) ; In CES group, the levels of IL-2 of 6-month mice were significantly lower than that of 0-month mice(P<0.05), but in month 9 ,we find they increased again compared to 6-month mice (PO.05); There was no significant difference in different
time courses of C group. (4) In months 6, 9, NK activity of CES group was lower than that of C group; In CES group, NK activity of 3-month, 6-month and 9-month mice was significantly lowered compared to 0-month mice (PO.01) and that of 3-month mice is higher than 9-month mice (P<0.05) . Interestingly, in C group, NK activity of 9-month unstressed mice is significantly lowered compared to the mice of other time courses.
Conclusions: (1) Chronic emotional stress can facilitate the growth of C3H/HeJ mammary tumor and shorten its latent period . (2) Chronic emotional stress can elevate plasma corticosterone level , inhibit the productivity of IL-2 and cause the suppression of NK activity. All these changes companied the accleration of mammary tumor growth, which indicated that these factors may take part in the mediation of the effect of stress on mammary tumor growth . (3) The levels of plasma corticosterone correlated negatively with the production of IL-2, which indicated corticosterone may inhibit the the production of IL-2. But there was no correlation between corticosterone and NK activity , which indicated that the change of NK activity caused by stress may mediated by other mechanisms.
方法：C3H／HeJ小鼠110只，随机分为应激组与对照组，其中应激组接受饮水冲突应激与限制应激。两组小鼠分别于入组0月、3月、6月、9月分批处死，采集乳腺组织、血与脾脏，分别用于检测乳腺肿瘤，血浆皮质酮浓度，脾细胞产生的IL-2与脾NK细胞活性。
结果：(1)3月、6月时段应激组小鼠乳腺肿瘤发病率显著高于对照组(P＜0.05)；应激3月、6月、9月时段显著高于应激0月时段(P＜0.01)；对照组9月时段显著高于对照0月时段(P＜0.05)。(2)3月、6月、9月时段应激组小鼠血浆皮质酮显著高于对照组(P值分别为0.001、0.022、0.048)；在应激组，这三个时段小鼠的血浆皮质酮显著高于0月时段(P值分别为0.005、0.028、0.007)；对照组9月时段显著高于对照0月、3月时段(P＜0.05)。(3)3月与6月时段，应激组小鼠脾细胞产生的IL-2显著低于对照组(P值分别为0.012与0.005)。应激组0月时段、9月时段小鼠脾细胞产生的IL-2明显高6月时段(P＜0.05)。(4)6月时段与9月时段应激组小鼠NK细胞活性明显低于对照组(P＜0.01)。应激组3、6、9月时段显著低于0月时段(P＜0.01)，而3月时段又显著高于9月时段的小鼠(P值为0.025)。对照组0、3、6月时段显著高于9月时段(P值分别为0.013、0.043、0.037)。
结论：(1)慢性情绪应激可以促使C3H／HeJ小鼠乳腺肿瘤生长加快，缩短其发病潜伏期。(2)慢性情绪应激可以提高血浆皮质酮，抑制脾脏产生IL-2与NK细胞的活性，且这些变化同乳腺肿瘤的生长加快相伴随，提示它们可能参与介导应激对乳腺癌生长的促进作用。(3)皮质酮的增高同脾细胞产生的IL-2成负相关，与NK细胞活性则无关，提示皮质酮可能对IL-2的生成有抑制作用，而NK细胞活性的降低则可能是通过其他机制进行的。
Objectives:(l) To determine the effects of chronic emotional stress on the growth of mammary tumor of C3H/HeJ mice. (2) To investigate the potential neuroendocrinology and neuroimmunology mechanisms linking stress and the mammary tumor .
Methods: 110 C3H/HeJ female virgin mice were divided into chronic emotional stressed (CES) group which was exposed to drinking-conflict stress and restraint stress and non-treated control(C) group. Mice was decapitated in batches at the end of 0 month (before the exposure of stressors ), 3 months, 6 months or 9 months after being grouped . The parameters measured were the occurrence of mammary tumor , plasma corticosterone level, the production of IL-2 (interleukin-2) from splenocyte and activity of natural killer(NK) cell in spleen.
Results: (1) In months 3, 6, mammary tumor morbidity of CES group was significantly higher than that of C group (PO.05). In CES group, tumor morbidity of 3-month, 6-month and 9-month mice increased significantly compared to 0-month mice (P<0.01); In C group, tumor morbidity of 9-month mice was significantly higher than that of 0-month mice (P<0.05). (2) In months 3, 6, and 9, plasma corticosterone levels of CES group were significantly higher than that of C group (P =0.001, 0.022, 0.048 respectively). In CES group, corticosterone levels of 3-month, 6-month and 9-month mice increased significantly compared to 0-month mice (P =0.005, 0.028, 0.007 respectively); In C group, corticosterone levels of 9-month mice were significantly elevated compared to 0-month and 3-month mice (P<0.05). (3) In months 3, 6, the production of IL-2 of CES group was significantly higher than that of C group (P= 0.012 ,0.005 respectively) ; In CES group, the levels of IL-2 of 6-month mice were significantly lower than that of 0-month mice(P<0.05), but in month 9 ,we find they increased again compared to 6-month mice (PO.05); There was no significant difference in different
time courses of C group. (4) In months 6, 9, NK activity of CES group was lower than that of C group; In CES group, NK activity of 3-month, 6-month and 9-month mice was significantly lowered compared to 0-month mice (PO.01) and that of 3-month mice is higher than 9-month mice (P<0.05) . Interestingly, in C group, NK activity of 9-month unstressed mice is significantly lowered compared to the mice of other time courses.
Conclusions: (1) Chronic emotional stress can facilitate the growth of C3H/HeJ mammary tumor and shorten its latent period . (2) Chronic emotional stress can elevate plasma corticosterone level , inhibit the productivity of IL-2 and cause the suppression of NK activity. All these changes companied the accleration of mammary tumor growth, which indicated that these factors may take part in the mediation of the effect of stress on mammary tumor growth . (3) The levels of plasma corticosterone correlated negatively with the production of IL-2, which indicated corticosterone may inhibit the the production of IL-2. But there was no correlation between corticosterone and NK activity , which indicated that the change of NK activity caused by stress may mediated by other mechanisms.
引文
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[2] Lillberg K, Verkasalo PK, Kaprio J, et al. Stressful life events and risk of breast cancer in 10,808 women: a cohort study. Am J Epidemiol. 2003, 157(5):415-23
[3] Maunsell E, Brisson J, Mondor M, et al. Stressful life events and survival after breast cancer. Psychosom Med. 2001,63(2):306-15
[4] Chen CC, David AS, Nunneley H, et al. Adverse life events and breast cancer: case-control study BMJ 1995,311(7019):1527-30
[5] Price MA ,Christopher C.T, Phyllis N.B, et al. The role of psychosocial factors in the development of the carcinoma. Cancer 2001.91:686-97
[6] Butow PN, Hiller JE, Price MA, Thackway SV, et al. Epidemiological evidence for a relationship between life events, coping style, and personality factors in the development of breast cancer. J Psychosom Res, 2000,49(3):169-8
[7] Graham J, Ramirez A, Love S, et al. Stressful life experiences and risk of relapse of breast cancer: observational cohort study. BMJ, 2002, 324(7351):1420
[8] Barraclough J. Adverse life events and breast cancer. Other Studies have found no association. BM J, 1996, 312(7034):845.
[9] Protheroe D, Turvey K, Horgan K et al. Stressful life events and difficulties and onset of breast cancer: case-control study. BMJ, 1999, 319(7216):1027-30
[10] Freire-Garabal M, Nunez-Iglesias MJ, Balboa JL, et al. Effects of alprazolam on the development of Moloney sarcoma virus-induced tumors in stressed mice. Cancer Detect Prev 1996,20(2):160-5
[11] Yamamoto H, Fujii K, Hayakawa T.Inhibitory effect of cold stress on lung tumours induced by 7,12-dimethylbenz[a]anthracene in mice. J Cancer Res Clin Oncol 1995;121(7):393-6
[12] Kerr LR, Wilkinson DA, Emerman JT ,et al. Interactive effects of psychosocial stressors and gender on mouse mammary tumor growth .Physiol Behav, 1999,66(2):277-84
[13] Strange KS, Kerr LR, Andrews FIN, Emerman JT, et al.Psychosocial stressors and mammary tumor growth: an animal model. Neurotoxicol Teratol 2000;22(1):89-102
[14] Bauer ME, Vedhara K, Perks P, et al. Chronic stress in caregivers of dementia patients is associated with reduced lymphocyte sensitivity to glucocorticoids. J
Neuroimmunol 2000,103(1):84-92
[15] Kang DH, Fox C. Th1 and Th2 cytokine responses to academic stress. Res Nurs Health 2001.24(4):245-57
[16] Stefanski V. Social stress in laboratory rats: behavior, immune function, and rumor metastasis. Physiol Behav 2001,73(3):385-91
[17] Rowse GJ. et al: Role of natural killer cells in psychosocial stressors-induced changes in mouse mammary tumor growth. Cancer research. 1995;270:7420-7426
[18] http://jaxmice.jax.org/library/notes/430e.html
[19] Nusse, R.The int genes in mammary, tumorigenesis and nomal development. Trends Genet 1988, 4,291-295
[20] Nusse.R, H. Varmus. mammary, tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 1982,31:99-109
[21] Yamamoto, K. Steroid recepter regulated transcription of specific genes and gene networks. Annu Rev. Genet. 19:209-252.
[22] 蔡伟雄，杨德森，李凌江，等。慢性应激对大鼠海马CA3区长时程增强的影响。中华精神科杂志，2002，35(4)237-240
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