Sousa Sofia, Auriola Seppo, Mönkkönen Jukka, Määttä Jorma
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
Institute of Biomedicine, Department of Cell Biology and Anatomy, University of Turku, Turku, Finland.
BMC Cancer. 2015 Jan 15;15:4. doi: 10.1186/s12885-015-1005-7.
Tumour stromal macrophages differentiate to tumour-associated macrophages (TAMs) with characteristics of immunosuppressive M2-type macrophages, having a central role in promoting tumour vascularisation, cancer cell dissemination and in suppressing anti-cancer immune responses. Bisphosphonates (BPs) are a group of drugs commonly used as anti-resorptive agents. Further, nitrogen containing BPs like Zoledronate (ZOL), are known to cause unspecific inflammatory reactions hence the hypothesis that its use could modulate TAMs polarization toward a more inflammatory phenotype.
We studied the in vitro polarization of J774 murine macrophages upon culture in 4T1 breast cancer cell-conditioned medium (4T1CM) and stimulation with LPS and free and liposome-encapsulated bisphosphonates.
In this system, breast cancer soluble factors reduced the pro-inflammatory activation of macrophages but increased the secretion of matrix metalloproteinases (MMPs). In the presence of 4T1CM, a non-cytotoxic dose of liposome-encapsulated ZOL (ZOL-LIP) enhanced the expression of iNOS and TNF-α, markers of M1 activation, but did not diminish the expression of M2-type markers. In contrast, clodronate treatment either as a free drug (CLO) or liposome-encapsulated (CLO-LIP) decreased the expression of the M1-type markers and was highly cytotoxic to the macrophages.
Breast cancer cells soluble factors modulate macrophages toward M2 activation state. Bisphosphonates may be applied to counteract this modulation. We propose that ZOL-LIP may be suitable for favouring cytotoxic immune responses by TAMs in breast cancer, whereas CLO-LIP may be appropriate for TAM depletion.
肿瘤基质巨噬细胞分化为具有免疫抑制性M2型巨噬细胞特征的肿瘤相关巨噬细胞（TAM），在促进肿瘤血管生成、癌细胞播散及抑制抗癌免疫反应中起核心作用。双膦酸盐（BP）是一类常用的抗吸收药物。此外，含氮双膦酸盐如唑来膦酸（ZOL），已知会引起非特异性炎症反应，因此有假说认为其使用可调节TAM向更具炎症表型的极化。
我们研究了J774小鼠巨噬细胞在4T1乳腺癌细胞条件培养基（4T1CM）中培养并用脂多糖以及游离和脂质体包裹的双膦酸盐刺激后的体外极化情况。
在该系统中，乳腺癌可溶性因子降低了巨噬细胞的促炎激活，但增加了基质金属蛋白酶（MMP）的分泌。在存在4T1CM的情况下，非细胞毒性剂量的脂质体包裹的ZOL（ZOL-LIP）增强了M1激活标志物iNOS和TNF-α的表达，但并未降低M2型标志物的表达。相比之下，氯膦酸盐无论是作为游离药物（CLO）还是脂质体包裹（CLO-LIP）处理，均降低了M1型标志物的表达，且对巨噬细胞具有高度细胞毒性。
乳腺癌细胞可溶性因子将巨噬细胞调节至M2激活状态。双膦酸盐可用于抵消这种调节作用。我们提出，ZOL-LIP可能适用于促进乳腺癌中TAM的细胞毒性免疫反应，而CLO-LIP可能适用于TAM的清除。
