Morphine stimulates cancer progression and mast cell activation and impairs survival in transgenic mice with breast cancer
Morphine stimulates cancer progression and mast cell activation and impairs survival in transgenic mice with breast cancer
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DOI：
10.1093/bja/aeu090
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发表时间：
2014-07-01
影响因子：
9.8
通讯作者：
Gupta, K.
中科院分区：
文献类型：
--
作者：
Nguyen, J.;Luk, K.;Gupta, K.
吗啡刺激小鼠血管生成和癌症进展。我们研究了吗啡是否影响肿瘤的发生、发展和动物模型的存活，以及Mu阿片受体(MOR)、淋巴管生成、肥大细胞激活和P物质(SP)是否与吗啡的促肿瘤作用有关。不同年龄的小鼠被给予临床相关剂量的吗啡或磷酸盐缓冲盐水，以确定对肿瘤发生和进展的影响，以及对小鼠存活的影响。用免疫荧光或激光扫描共聚焦显微镜分析肿瘤的MOR、血管生成、淋巴管生成、SP和肥大细胞的激活情况。细胞因子和SP水平通过酶联免疫吸附分析测定。在肿瘤出现之前给予吗啡不会影响肿瘤的发展，但显著促进已建立的肿瘤的进展，并降低生存率。在较大的肿瘤中观察到MOR免疫反应(Ir)，但在较小的肿瘤中未观察到。吗啡治疗可增加肿瘤血管生成、瘤周淋巴管生成、肥大细胞活化以及肿瘤中细胞因子和SP水平。SP-ir与肥大细胞和肿瘤中的其他细胞共定位。吗啡不影响肿瘤的发生，但它促进现有肿瘤的生长，并降低小鼠的总存活率。MOR可能与吗啡诱导的癌症进展有关，导致生存期缩短。吗啡激活肥大细胞可能导致细胞因子和SP水平升高，导致癌症进展和顽固性疼痛。
Morphine stimulates angiogenesis and cancer progression in mice. We investigated whether morphine influences tumour onset, development, and animal model survival, and whether A mu-opioid receptor (MOR), lymphangiogenesis, mast cell activation, and substance P (SP) are associated with the tumour-promoting effects of morphine.Transgenic mice with a rat C3(1) simian virus 40 large tumour antigen fusion gene which demonstrate the developmental spectrum of human infiltrating ductal breast carcinoma were used. Mice were treated at different ages with clinically relevant doses of morphine or phosphate-buffered saline to determine the effect on tumour development and progression, and on mouse survival. Tumours were analysed for MOR, angiogenesis, lymphangiogenesis, SP, and mast cell activation by immunofluorescent- or laser scanning confocal-microscopy. Cytokine and SP levels were determined by enzyme-linked immunosorbent assay.Morphine did not influence tumour development when given before the onset of tumour appearance, but significantly promoted progression of established tumours, and reduced survival. MOR-immunoreactivity (ir) was observed in larger but not in smaller tumours. Morphine treatment resulted in increased tumour angiogenesis, peri-tumoural lymphangiogenesis, mast cell activation, and higher levels of cytokines and SP in tumours. SP-ir co-localized with mast cells and elsewhere in the tumours.Morphine does not affect the onset of tumour development, but it promotes growth of existing tumours, and reduces overall survival in mice. MOR may be associated with morphine-induced cancer progression, resulting in shorter survival. Mast cell activation by morphine may contribute to increased cytokine and SP levels, leading to cancer progression and refractory pain.