Taran Katarzyna, Wnęk Aneta, Kobos Józef, Andrzejewska Ewa, Przewratil Przemysław
Department of Pathology, Medical University of Lodz, ul. Pomorska 251, 92-216 Lodz, Poland.
Department of Pediatric Surgery and Oncology, Central Clinical Hospital of Medical University of Lodz, Konopnicka Memorial Pediatric Center, ul. Sporna 36/50, 91-738 Lodz, Poland.
Immunobiology. 2017 Nov;222(11):1035-1042. doi: 10.1016/j.imbio.2017.05.014. Epub 2017 Jun 3.
Propranolol is a widely-known beta-blocker approved for treating infantile hemangiomas (IH). The mechanisms behind the spectacular IH involution after propranolol treatment remain unclear. Recently, there is strong evidence of overexpression of numerous angiogenic factors in IH tissues, and it is reported that propranolol influences their pathways. However, a number of MMPs studies is highly limited. Here, for the first time, we propose a comprehensive approach by analyzing the expression levels of metalloproteinases-2/9 (MMPs-2/9) and tissue metalloproteinase inhibitor-2 (TIMP-2) in vivo on both, molecular and immunohistochemical levels, and in both, IH tissues and in the serum of IH patients, and relates the obtained results to the tumor's biology and systemic propranolol treatment.
MMPs-2/9 and TIMP-2 were analyzed in 71 IH tissue samples using immunohistochemistry and real-time PCR, and in 50 serum samples of IH patients by ELISA.
Significantly lower MMPs-2/9 and higher TIMP-2 levels were observed in IH tissues on the mRNA level as well as lower serum MMP-2 concentration among the treated individuals.
MMPs-2/9 and TIMP-2 are both involved in the biology of IH and the propranolol pathways enabling their antiangiogenic properties. The most reliable method of IH examination appears to be direct MMPs-2/9 mRNA evaluation in tumor tissue; and MMP-2 evaluation in patients' serum is a valuable complement to it. Tissue and serum mRNA MMPs assessment may represent a suitable novel biomarker identifying tumor progression and involution processes with potential clinical impact in IH as well as in cancer disease.
普萘洛尔是一种广为人知的β受体阻滞剂,已被批准用于治疗婴儿血管瘤(IH)。普萘洛尔治疗后IH显著消退的背后机制仍不清楚。最近,有强有力的证据表明IH组织中多种血管生成因子过表达,并且有报道称普萘洛尔会影响它们的信号通路。然而,关于基质金属蛋白酶(MMPs)的研究数量非常有限。在此,我们首次提出一种综合方法,通过在分子和免疫组织化学水平上,对IH组织和IH患者血清中的基质金属蛋白酶-2/9(MMPs-2/9)和组织金属蛋白酶抑制剂-2(TIMP-2)的表达水平进行体内分析,并将所得结果与肿瘤生物学和普萘洛尔全身治疗相关联。
使用免疫组织化学和实时聚合酶链反应对71份IH组织样本中的MMPs-2/9和TIMP-2进行分析,并通过酶联免疫吸附测定法对50份IH患者的血清样本进行分析。
在mRNA水平上,IH组织中观察到MMPs-2/9水平显著降低,TIMP-2水平升高,并且在接受治疗的个体中血清MMP-2浓度也较低。
MMPs-2/9和TIMP-2均参与IH的生物学过程以及普萘洛尔发挥其抗血管生成特性的信号通路。IH检查最可靠的方法似乎是直接评估肿瘤组织中的MMPs-2/9 mRNA;而患者血清中的MMP-2评估是对其有价值的补充。组织和血清mRNA MMPs评估可能代表一种合适的新型生物标志物,可识别肿瘤进展和消退过程,对IH以及癌症疾病具有潜在的临床影响。