乳腺癌癌前病变毒瘀互结大鼠模型的建立及解毒化瘀法干预研究
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摘要
乳腺癌是严重威胁女性健康的一类恶性肿瘤,乳腺癌的早期发现、早期诊断、早期治疗不仅可以大大提高患者治愈率,还能保障早期保乳治疗及乳房重建,提高患者生存质量。而对于乳腺癌癌前病变的治疗,不仅可以达到对乳腺癌的早期干预,还能预防肿瘤的发生。西医对于乳腺癌癌前病变的治疗仍以手术为主,如何有效干预乳腺癌非典型增生进而阻断乳腺癌癌前病变向乳腺癌发展,是目前中医药防治乳腺癌及其癌前状态研究的关键。
本研究在2010年北京市自然基金资助下,以乳腺癌癌前病变毒瘀互结理论为指导,拟建立大鼠乳腺癌癌前病变模型毒瘀互结模型,并通过本证、正证、佐证、反证等方法对模型进行全面评价,建立毒瘀互结模型的评价方法；反证法选用以解毒化瘀法组方的西黄丸为干预药物,进一步研究解毒化瘀法治疗乳腺癌非典型增生,干预乳腺癌癌前病变,阻断其向乳腺癌发展的作用机制。
目的：建立乳腺癌癌前病变毒瘀互结大鼠模型,从大鼠生物表征变化、病理变化、血液流变学等客观指标变化及解毒化瘀法代表方药治疗反证等方面对模型进行评价；进一步观察解毒化瘀法对毒瘀互结病证结合模型大鼠的调控作用：通过解毒化瘀法代表方药西黄丸干预乳腺癌癌前病变“毒瘀互结”模型,从大鼠的病理学变化观察其干预作用,并通过对雌激素受体ER、孕激素受体PR、抑制凋亡相关基因P53、Bcl-2和代表细胞侵袭性及转移性的相关指标(SDF-1/CXCR4轴、VEGF)的干预作用,探索其干预机制。
方法：75只SPF级SD雌性大鼠随机分为3组：空白组15只,单纯模型组(模型Ⅰ组)15只,病证结合模型组45只。空白组给予SPF级动物标准饮食喂养,持续至实验结束。模型Ⅰ组于试验第一天给予二甲基苯蒽(DMBA)100mg/kg灌胃制造乳腺癌癌前病变大鼠模型；病证结合模型组给予DMBA灌胃联合10周多重复合应激制造毒瘀互结病证结合模型。10周造模结束后,病证结合模型组45只大鼠随机分为：模型Ⅱ组15只,西黄丸15只,TAM组15只。空白组、模型Ⅰ、Ⅱ组大鼠分别给予蒸馏水10mL/kg灌胃,TAM组及西黄丸组大鼠分别给予相应药物灌胃1次/天,连续30天。于造模1天、造模10周、灌胃30天后分别观察并记录大鼠生物表征变化；实验结束后处死全部大鼠,腹腔取血检测血液流变学变化及SDF-1水平变化；无菌条件下取大鼠胸部左侧第2对乳腺及其周围皮肤分为两部分：一部分用于病理观察及免疫组化检测法检测组织ER.PR.P53. Bcl-2等表达水平,另一部分采用Real-time PCR及Western blot (?)去检测组织VEGF及CXCR4基因、蛋白表达。
结果：
(1)课题通过DMBA联合10周多重复合应激建立乳腺癌前病变毒瘀互结模型,该模型造模高度模拟了乳腺癌癌前病变的发病过程,并体现了“毒瘀互结”的形成过程,即符合造模之“因”(正证),证明造模方法可行；
(2)大鼠生物表征(本证)变化示：模型Ⅱ组大鼠肉眼可见肿瘤明显增多,肿瘤表面不光滑、大鼠精神萎靡、毛色灰暗、舌质暗等一系列“血瘀证”的生物表征变化；病理变化(佐证)发现模型Ⅱ组大鼠以中重度非典型增生为主,偶伴有导管内癌的存在；血液粘度(佐证)变化显示：模型Ⅱ组大鼠血液粘度增高(P<0.05)；模型Ⅱ组大鼠ER. PR. Bcl-2. p53. VEGF. CXCR4等指标均较模型Ⅰ组升高(P均<0.05)；解毒化瘀法代表方西黄丸治疗(反证)发现,西黄丸对该模型具有较好的干预作用。通过以上方面对模型进行了全面评价,证明造模成功；
(3)通过西黄丸干预乳腺癌癌前病变“毒瘀互结”模型大鼠的病理变化发现,西黄丸对乳腺癌癌前病变具有较好的干预作用。模型Ⅱ组以中-重度ADH为主,偶伴有导管内癌的出现,西黄丸组则以UDH伴轻度ADH为主,其干预作用与TAM相比,病理学无明显差异；
(4)西黄丸与TAM均能抑制ER. PR的表达,从而干预乳腺癌癌前病变,二者抑制作用差异无统计学意义(P>0.05)；西黄丸与TAM均对p53. Bcl-2有抑制作用,但是西黄丸干预作用更为明显,差异有统计学意义(P<0.05)；西黄丸与TAM均可以抑制VEGF表达并干预SDF-1/CXCR4信号通路被激活,二者干预作用差异无统计学意义(P>0.05),但是与正常组相比,VEGF, SDF-1, CXCR4表达仍较高,差异有统计学意义(P<0.05)。
结论：将疾病模型及中医病因致病模型结合制作乳腺癌癌前病变度毒瘀互结模型符合临床患者发病过程,经大鼠生物表征变化、组织病理学及血流动力学等客观指标变化、解毒化瘀法代表方西黄丸治疗反证等对模型进行综合评价,证明造模成功。
以解毒化瘀法组方的西黄丸可有效改善乳腺癌癌前病变大鼠的一般情况,逆转乳腺癌癌前病变非典型增生的病理变化,防止乳腺癌的发生发展。其干预的作用机制可能是：通过抑制ER, PR表达,逆转P53基因突变,促使P53发挥其正常抑制肿瘤的作用,抑制癌基因Bc1-2的过表达,二者协调使细胞凋亡可以正常进行,从而达到治疗乳腺非典型增生的作用。当乳腺癌癌前病变发现VEGF, SDF-1, CXCR4等高表达时,西黄丸还能降低VEGF蛋白的高表达及阻断SDF-1/CXCR4信号通路的异常激活,但是不能使其表达恢复正常,由此推测此类病变不能仅采取西黄丸单一的治疗方式,应该配合手术等其他治疗手段,以防止病情进一步发展。
Breast cancer is a kind of malignant tumor which is a serious threat to women's health. Early detection, early diagnosis and early treatment of breast cancer, can not only greatly improve the cure rate in patients but also can practice breast conserving therapy and breast reconstruction, improve the quality of survival. So the treatment of precancerous lesions of breast cancer can achieve early intervention for breast cancer, and can prevent the happening of the tumor. At present the treatment of precancerous lesions of breast cancer is based on operation, how to intervence in the atypical hyperplasia rffectively, blocking its development to breast cancer, is the key to the traditional Chinese medicine in prevention and treatment of breast cancer research.
Based on the guidance of the theory of toxin-blood stasis syndrome, this study established the toxin-blood stasis model of precancerous lesions in the rat. Choose Xihuang pill as drug intervention to study the mechanism of blood detoxification method treating atypical hyperplasia of breast cancer.
Objective:Establish toxin-blood stasis model of precancerous breast lesions in rat and evaluate the model from the biological characterization changes, pathological changes, objective indicators such as the hemorheology changes and drugs counterevidence, etc. Then observe the regμLation and control function of blood detoxification method on the model:use Xihuang pill to intervent breast precancerous toxin-blood stasis model then explore the intervention mechanism from the pathological changes, the estrogen receptors, apoptosis related gene P53Bcl-2and index of the cell invasive and metastatic such as SDF-1/CXCR4axis and VEGF changes.
Methods:75SPF SD female rats were randomLy divided into3groups:blank group15, control group15, other45rats were randomLy divided into model group15, Xihuang pill group15and TAM group15.
Rats of blank group were given standard diet and lasts until the end of the ex per iment.
On the first day, control group were gavaged with100mg/kg DMBA manufacturing breast precancerous lesion rat model; others were given DMBA associated with m μ Lt iple compound stress for10weeks to manufac turing tox in-blood stasis model. After10weeks blank group, model group rats were gavaged with lOmL/kg distilled water for30days, TAM and west yellow pill group rats were given corresponding drugs.
To observe and recorde the biological characterization changes in rats on the first day, the end of10weeks and after the end of the gavage. All rats were killed after the end of the experiment, the abdominal cavity to take blood hemorheology change and SDF-1levels; the left side of the rats breast and surrounding skin is divided into two parts:one for pathological observation and immunohistochemical detection assay organizations such as ER, PR, P53, Bcl-2expression levels, another part of the Real-time PCR and Western blot assay tissue VEGF and CXCR4gene and protein expression.
ResμLts:(1)DMBA joint10weeks mμLtiple compound stress to establish toxin-blood stasis rat model of breast precancerous disease reflecting the formation process of toxin-blood stasis.Model group rats biological characterization changes show a series of changes reflects the biological characterization of blood stasis syndrome such as visible tumor increased significantly, unsmoothed tumor surface, grey dark fur colour, dark tongue and so on; Pathological changes show model group rats is mostly of moderately-severe atypical hyperplasia, occasionally accompanied by the existence of intra-ductal carcinoma; model group rats increased blood viscosity than control group {P<0.05); model group ER, PR, Bcl-2, p53, VEGF and CXCR4indicators increased than control group(P<0.05); Detoxification circμLation method treatment disprove West Pill has a good intervention to the model. All above prove successfμLly modeled.
(2)The pathological changes show, the model group based on severe ADH, occasionally accompanied by the emergence of intra-ductal carcinoma, Xihuang pill group is mostly of UDH with mild ADH and compared with TAM group no obvious difference.
(3)The Xihuang pill and TAM can inhibit the expression of ER, PR, there was no statistically significant difference of the inhibitory effect between them (P>0.05); Xihuang pill and TAM can both inhibi t the express ion of p53and Bcl-2, the Xihuang pill intervention effect is more apparent, the difference was statistically significant (P<0.O5), Xihuang pill and TAM can inhibit VEGF expression and the activation of SDF-1/CXCR4signaling pathways, there was no statist ically significant difference of the intervent ion (P>0.05), but compared with blank group, the VEGF SDF-1/CXCR4expression is higher, the difference was statistically significant (P<0.05).
Conclusion:combined the disease model with TCM etiology and pathogenesis modeling manufacturing breast precancerous lesion toxin-blood stasis model simμLating the pathogenesis, proved by the biological characterization of histopathological changes of rats, objective indicators such as the hemodynamic changes of blood and Xihuang pill treatment successfμL,.
Xihuang pill can effectively improve the general situation of breast precancerous lesions in rats, reverse breast precancerous pathological changes, the mechanism of action of the effective prevention of breast cancer development may be as follows:through the inhibition of ER, PR expression, reverse the p53gene mutations, inhibit the cancer gene expression of Be1-2, further reduce the high expression of VEGF protein and block the SDF-1/CXCR4signaling pathways of abnormal activation, so as to achieve treatment mammary atypical hyperplasia reverse precancerous breast cancer block the occurrence and development of breast cancer.
本研究在2010年北京市自然基金资助下,以乳腺癌癌前病变毒瘀互结理论为指导,拟建立大鼠乳腺癌癌前病变模型毒瘀互结模型,并通过本证、正证、佐证、反证等方法对模型进行全面评价,建立毒瘀互结模型的评价方法；反证法选用以解毒化瘀法组方的西黄丸为干预药物,进一步研究解毒化瘀法治疗乳腺癌非典型增生,干预乳腺癌癌前病变,阻断其向乳腺癌发展的作用机制。
目的：建立乳腺癌癌前病变毒瘀互结大鼠模型,从大鼠生物表征变化、病理变化、血液流变学等客观指标变化及解毒化瘀法代表方药治疗反证等方面对模型进行评价；进一步观察解毒化瘀法对毒瘀互结病证结合模型大鼠的调控作用：通过解毒化瘀法代表方药西黄丸干预乳腺癌癌前病变“毒瘀互结”模型,从大鼠的病理学变化观察其干预作用,并通过对雌激素受体ER、孕激素受体PR、抑制凋亡相关基因P53、Bcl-2和代表细胞侵袭性及转移性的相关指标(SDF-1/CXCR4轴、VEGF)的干预作用,探索其干预机制。
方法：75只SPF级SD雌性大鼠随机分为3组：空白组15只,单纯模型组(模型Ⅰ组)15只,病证结合模型组45只。空白组给予SPF级动物标准饮食喂养,持续至实验结束。模型Ⅰ组于试验第一天给予二甲基苯蒽(DMBA)100mg/kg灌胃制造乳腺癌癌前病变大鼠模型；病证结合模型组给予DMBA灌胃联合10周多重复合应激制造毒瘀互结病证结合模型。10周造模结束后,病证结合模型组45只大鼠随机分为：模型Ⅱ组15只,西黄丸15只,TAM组15只。空白组、模型Ⅰ、Ⅱ组大鼠分别给予蒸馏水10mL/kg灌胃,TAM组及西黄丸组大鼠分别给予相应药物灌胃1次/天,连续30天。于造模1天、造模10周、灌胃30天后分别观察并记录大鼠生物表征变化；实验结束后处死全部大鼠,腹腔取血检测血液流变学变化及SDF-1水平变化；无菌条件下取大鼠胸部左侧第2对乳腺及其周围皮肤分为两部分：一部分用于病理观察及免疫组化检测法检测组织ER.PR.P53. Bcl-2等表达水平,另一部分采用Real-time PCR及Western blot (?)去检测组织VEGF及CXCR4基因、蛋白表达。
结果：
(1)课题通过DMBA联合10周多重复合应激建立乳腺癌前病变毒瘀互结模型,该模型造模高度模拟了乳腺癌癌前病变的发病过程,并体现了“毒瘀互结”的形成过程,即符合造模之“因”(正证),证明造模方法可行；
(2)大鼠生物表征(本证)变化示：模型Ⅱ组大鼠肉眼可见肿瘤明显增多,肿瘤表面不光滑、大鼠精神萎靡、毛色灰暗、舌质暗等一系列“血瘀证”的生物表征变化；病理变化(佐证)发现模型Ⅱ组大鼠以中重度非典型增生为主,偶伴有导管内癌的存在；血液粘度(佐证)变化显示：模型Ⅱ组大鼠血液粘度增高(P<0.05)；模型Ⅱ组大鼠ER. PR. Bcl-2. p53. VEGF. CXCR4等指标均较模型Ⅰ组升高(P均<0.05)；解毒化瘀法代表方西黄丸治疗(反证)发现,西黄丸对该模型具有较好的干预作用。通过以上方面对模型进行了全面评价,证明造模成功；
(3)通过西黄丸干预乳腺癌癌前病变“毒瘀互结”模型大鼠的病理变化发现,西黄丸对乳腺癌癌前病变具有较好的干预作用。模型Ⅱ组以中-重度ADH为主,偶伴有导管内癌的出现,西黄丸组则以UDH伴轻度ADH为主,其干预作用与TAM相比,病理学无明显差异；
(4)西黄丸与TAM均能抑制ER. PR的表达,从而干预乳腺癌癌前病变,二者抑制作用差异无统计学意义(P>0.05)；西黄丸与TAM均对p53. Bcl-2有抑制作用,但是西黄丸干预作用更为明显,差异有统计学意义(P<0.05)；西黄丸与TAM均可以抑制VEGF表达并干预SDF-1/CXCR4信号通路被激活,二者干预作用差异无统计学意义(P>0.05),但是与正常组相比,VEGF, SDF-1, CXCR4表达仍较高,差异有统计学意义(P<0.05)。
结论：将疾病模型及中医病因致病模型结合制作乳腺癌癌前病变度毒瘀互结模型符合临床患者发病过程,经大鼠生物表征变化、组织病理学及血流动力学等客观指标变化、解毒化瘀法代表方西黄丸治疗反证等对模型进行综合评价,证明造模成功。
以解毒化瘀法组方的西黄丸可有效改善乳腺癌癌前病变大鼠的一般情况,逆转乳腺癌癌前病变非典型增生的病理变化,防止乳腺癌的发生发展。其干预的作用机制可能是：通过抑制ER, PR表达,逆转P53基因突变,促使P53发挥其正常抑制肿瘤的作用,抑制癌基因Bc1-2的过表达,二者协调使细胞凋亡可以正常进行,从而达到治疗乳腺非典型增生的作用。当乳腺癌癌前病变发现VEGF, SDF-1, CXCR4等高表达时,西黄丸还能降低VEGF蛋白的高表达及阻断SDF-1/CXCR4信号通路的异常激活,但是不能使其表达恢复正常,由此推测此类病变不能仅采取西黄丸单一的治疗方式,应该配合手术等其他治疗手段,以防止病情进一步发展。
Breast cancer is a kind of malignant tumor which is a serious threat to women's health. Early detection, early diagnosis and early treatment of breast cancer, can not only greatly improve the cure rate in patients but also can practice breast conserving therapy and breast reconstruction, improve the quality of survival. So the treatment of precancerous lesions of breast cancer can achieve early intervention for breast cancer, and can prevent the happening of the tumor. At present the treatment of precancerous lesions of breast cancer is based on operation, how to intervence in the atypical hyperplasia rffectively, blocking its development to breast cancer, is the key to the traditional Chinese medicine in prevention and treatment of breast cancer research.
Based on the guidance of the theory of toxin-blood stasis syndrome, this study established the toxin-blood stasis model of precancerous lesions in the rat. Choose Xihuang pill as drug intervention to study the mechanism of blood detoxification method treating atypical hyperplasia of breast cancer.
Objective:Establish toxin-blood stasis model of precancerous breast lesions in rat and evaluate the model from the biological characterization changes, pathological changes, objective indicators such as the hemorheology changes and drugs counterevidence, etc. Then observe the regμLation and control function of blood detoxification method on the model:use Xihuang pill to intervent breast precancerous toxin-blood stasis model then explore the intervention mechanism from the pathological changes, the estrogen receptors, apoptosis related gene P53Bcl-2and index of the cell invasive and metastatic such as SDF-1/CXCR4axis and VEGF changes.
Methods:75SPF SD female rats were randomLy divided into3groups:blank group15, control group15, other45rats were randomLy divided into model group15, Xihuang pill group15and TAM group15.
Rats of blank group were given standard diet and lasts until the end of the ex per iment.
On the first day, control group were gavaged with100mg/kg DMBA manufacturing breast precancerous lesion rat model; others were given DMBA associated with m μ Lt iple compound stress for10weeks to manufac turing tox in-blood stasis model. After10weeks blank group, model group rats were gavaged with lOmL/kg distilled water for30days, TAM and west yellow pill group rats were given corresponding drugs.
To observe and recorde the biological characterization changes in rats on the first day, the end of10weeks and after the end of the gavage. All rats were killed after the end of the experiment, the abdominal cavity to take blood hemorheology change and SDF-1levels; the left side of the rats breast and surrounding skin is divided into two parts:one for pathological observation and immunohistochemical detection assay organizations such as ER, PR, P53, Bcl-2expression levels, another part of the Real-time PCR and Western blot assay tissue VEGF and CXCR4gene and protein expression.
ResμLts:(1)DMBA joint10weeks mμLtiple compound stress to establish toxin-blood stasis rat model of breast precancerous disease reflecting the formation process of toxin-blood stasis.Model group rats biological characterization changes show a series of changes reflects the biological characterization of blood stasis syndrome such as visible tumor increased significantly, unsmoothed tumor surface, grey dark fur colour, dark tongue and so on; Pathological changes show model group rats is mostly of moderately-severe atypical hyperplasia, occasionally accompanied by the existence of intra-ductal carcinoma; model group rats increased blood viscosity than control group {P<0.05); model group ER, PR, Bcl-2, p53, VEGF and CXCR4indicators increased than control group(P<0.05); Detoxification circμLation method treatment disprove West Pill has a good intervention to the model. All above prove successfμLly modeled.
(2)The pathological changes show, the model group based on severe ADH, occasionally accompanied by the emergence of intra-ductal carcinoma, Xihuang pill group is mostly of UDH with mild ADH and compared with TAM group no obvious difference.
(3)The Xihuang pill and TAM can inhibit the expression of ER, PR, there was no statistically significant difference of the inhibitory effect between them (P>0.05); Xihuang pill and TAM can both inhibi t the express ion of p53and Bcl-2, the Xihuang pill intervention effect is more apparent, the difference was statistically significant (P<0.O5), Xihuang pill and TAM can inhibit VEGF expression and the activation of SDF-1/CXCR4signaling pathways, there was no statist ically significant difference of the intervent ion (P>0.05), but compared with blank group, the VEGF SDF-1/CXCR4expression is higher, the difference was statistically significant (P<0.05).
Conclusion:combined the disease model with TCM etiology and pathogenesis modeling manufacturing breast precancerous lesion toxin-blood stasis model simμLating the pathogenesis, proved by the biological characterization of histopathological changes of rats, objective indicators such as the hemodynamic changes of blood and Xihuang pill treatment successfμL,.
Xihuang pill can effectively improve the general situation of breast precancerous lesions in rats, reverse breast precancerous pathological changes, the mechanism of action of the effective prevention of breast cancer development may be as follows:through the inhibition of ER, PR expression, reverse the p53gene mutations, inhibit the cancer gene expression of Be1-2, further reduce the high expression of VEGF protein and block the SDF-1/CXCR4signaling pathways of abnormal activation, so as to achieve treatment mammary atypical hyperplasia reverse precancerous breast cancer block the occurrence and development of breast cancer.
引文
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