組胺由組氨酸在組氨酸脫羧酶的作用下產(chǎn)生，皮膚、肺、腸黏膜等許多組織的肥大細胞含有大量組胺。當(dāng)組織受到損傷或發(fā)生炎癥和過敏反應(yīng)時，都可釋放組胺。組胺受體包括4種類型：H1、H2、H3、H4。組胺受體H4主要表達于免疫細胞，還被發(fā)現(xiàn)于人類乳腺癌組織和細胞。不過，組胺、組胺受體H4、組氨酸脫羧酶對于三陰性乳腺癌的意義尚不明確。
2019年11月21日，英國癌癥研究基金會、英國《自然》旗下《英國癌癥雜志》在線發(fā)表阿根廷天主教大學(xué)、布宜諾斯艾利斯大學(xué)、巴塔哥尼亞圣胡安博斯科國立大學(xué)的研究報告，探討了組胺和組胺受體H4激動劑或拮抗劑對于免疫活性宿主三陰性乳腺癌模型的治療效果，并且利用公開發(fā)表的三陰性乳腺癌患者基因組大數(shù)據(jù)，進一步探討了組氨酸脫羧酶能否成為三陰性乳腺癌的生物標(biāo)志。
該研究首先向BALB/c小鼠乳腺注射4T1三陰性乳腺癌細胞建立腫瘤模型。隨后，分別用組胺（1或5 mg/kg）、組胺受體H4激動劑（1或5mg/kg）、組胺受體H4拮抗劑（10mg/kg）進行治療。最后，對TCGA、cBP、GEO基因組數(shù)據(jù)庫三陰性乳腺癌患者的組氨酸脫羧酶基因表達、無復(fù)發(fā)生存、總生存數(shù)據(jù)進行比較。
結(jié)果發(fā)現(xiàn)，4T1三陰性乳腺癌腫瘤小鼠接受組胺5mg/kg治療可以減少腫瘤生長并且增加細胞凋亡。雖然對于野生型小鼠，未見免疫調(diào)節(jié)作用，但是對于組胺受體H4基因剔除小鼠，可見腫瘤重量與細胞毒性T淋巴細胞浸潤數(shù)量之間成顯著正比關(guān)系。組胺受體H4激動劑、拮抗劑對于4T1三陰性乳腺癌小鼠腫瘤生長和免疫力具有相反的調(diào)節(jié)作用。此外，大數(shù)據(jù)分析表明，組氨酸脫羧酶基因表達水平，與乳腺癌患者的無復(fù)發(fā)生存和總生存之間成顯著正比關(guān)系。
因此，該研究結(jié)果表明，對于三陰性乳腺癌，組胺可以發(fā)揮復(fù)雜的調(diào)節(jié)作用，可能成為有前途的靶向治療藥物，值得進一步開展人類臨床研究。組氨酸脫羧酶基因表達水平與三陰性乳腺癌生存結(jié)局相關(guān)，具有一定的預(yù)后價值。
Br J Cancer. 2019 Nov 21. [Epub ahead of print]
Study of the antitumour effects and the modulation of immune response by histamine in breast cancer.
Melisa B. Nicoud, Helena A. Sterle, Noelia A. Massari, Mónica A. Táquez Delgado, Karina Formoso, María V. Herrero Ducloux, Diego Martinel Lamas, Graciela A. Cremaschi, Vanina A. Medina.
Pontifical Catholic University of Argentina, National Scientific and Technical Research Council, Buenos Aires, Argentina; University of Buenos Aires, Buenos Aires, Argentina; National University of Patagonia San Juan Bosco, Chubut, Argentina.
BACKGROUND: The aim of this work was to improve the knowledge of the role of histamine in breast cancer by assessing the therapeutic efficacy of histamine and histamine H4 receptor (H4R) ligands in a triple-negative breast cancer (TNBC) model developed in immunocompetent hosts. By using publicly available genomic data, we further investigated whether histidine decarboxylase (HDC) could be a potential biomarker.
METHODS: Tumours of 4T1 TNBC cells were orthotopically established in BALB/c mice. Treatments employed (mg/kg): histamine (1 and 5), JNJ28610244 (H4R agonist, 1 and 5) and JNJ7777120 (H4R antagonist, 10).
RESULTS: Increased HDC gene expression is associated with better relapse-free and overall survival in breast cancer patients. Histamine treatment (5 mg/kg) of 4T1 tumour-bearing mice reduced tumour growth and increased apoptosis. Although no immunomodulatory effects were observed in wild-type mice, significant correlations between tumour weight and cytotoxic lymphocyte infiltration were detected in H4R knockout mice. H4R agonist or antagonist differentially modulated tumour growth and immunity in 4T1 tumour-bearing mice.
CONCLUSIONS: Histamine plays a complex role and stands out as a promising drug for TNBC treatment, which deserves to be tested in clinical settings. HDC expression level is associated with clinicopathological characteristics, suggesting a prognostic value in breast cancer.
DOI: 10.1038/s41416-019-0636-x
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