Discipline of Pharmacy, The Graduate School of Health, University of Technology Sydney, PO Box 123, Broadway, Sydney, NSW, 2007, Australia.
iThree Institute, University of Technology Sydney, Sydney, NSW, 2007, Australia.
BMC Cancer. 2017 Feb 6;17(1):104. doi: 10.1186/s12885-017-3102-2.
Breast cancer is the most frequently diagnosed cancer in women. Resident macrophages at distant sites provide a highly responsive and immunologically dynamic innate immune response against foreign infiltrates. Despite extensive characterization of the role of macrophages and other immune cells in malignant tissues, there is very little known about the mechanisms which facilitate metastatic breast cancer spread to distant sites of immunological integrity. The mechanisms by which a key healthy defense mechanism fails to protect distant sites from infiltration by metastatic cells in cancer patients remain undefined. Breast tumors, typical of many tumor types, shed membrane vesicles called microparticles (MPs), ranging in size from 0.1-1 μm in diameter. MPs serve as vectors in the intercellular transfer of functional proteins and nucleic acids and in drug sequestration. In addition, MPs are also emerging to be important players in the evasion of cancer cell immune surveillance.
A comparative analysis of effects of MPs isolated from human breast cancer cells and non-malignant human brain endothelial cells were examined on THP-1 derived macrophages in vitro. MP-mediated effects on cell phenotype and functionality was assessed by cytokine analysis, cell chemotaxis and phagocytosis, immunolabelling, flow cytometry and confocal imaging. Student's t-test or a one-way analysis of variance (ANOVA) was used for comparison and statistical analysis.
In this paper we report on the discovery of a new cellular basis for immune evasion, which is mediated by breast cancer derived MPs. MPs shed from multidrug resistant (MDR) cells were shown to selectively polarize macrophage cells to a functionally incapacitated state and facilitate their engulfment by foreign cells.
We propose this mechanism may serve to physically disrupt the inherent immune response prior to cancer cell colonization whilst releasing mediators required for the recruitment of distant immune cells. These findings introduce a new paradigm in cancer cell biology with significant implications in understanding breast cancer colonization at distant sites. Most importantly, this is also the first demonstration that MPs serve as conduits in a parallel pathway supporting the cellular survival of MDR cancer cells through immune evasion.
乳腺癌是女性最常见的癌症。远处部位的驻留巨噬细胞提供了对外来浸润物的高度响应和免疫动态固有免疫反应。尽管已经广泛描述了巨噬细胞和其他免疫细胞在恶性组织中的作用，但对于促进转移性乳腺癌扩散到免疫完整的远处部位的机制知之甚少。在癌症患者中，一种关键的健康防御机制未能保护远处部位免受转移性细胞浸润的机制仍未确定。乳腺癌肿瘤与许多肿瘤类型一样，会脱落称为微泡（MPs）的膜囊泡，其直径范围为 0.1-1μm。 MPs 作为细胞间功能性蛋白质和核酸转移以及药物隔离的载体。此外，MPs 也正在成为逃避癌细胞免疫监测的重要参与者。
比较分析了从人乳腺癌细胞和非恶性人脑内皮细胞中分离的 MPs 对体外 THP-1 衍生巨噬细胞的影响。通过细胞因子分析、细胞趋化性和吞噬作用、免疫标记、流式细胞术和共聚焦成像评估 MPs 介导的细胞表型和功能变化。使用学生 t 检验或单向方差分析（ANOVA）进行比较和统计分析。
本文报道了一种新的免疫逃避的细胞基础的发现，该基础是由乳腺癌衍生的 MPs 介导的。从多药耐药（MDR）细胞中脱落的 MPs 被证明可以选择性地上调巨噬细胞功能，使其功能丧失，并促进其被异体细胞吞噬。
我们提出，这种机制可能在癌细胞定植之前物理破坏固有免疫反应，同时释放招募远处免疫细胞所需的介质。这些发现为癌细胞生物学引入了一个新的范例，对理解远处部位的乳腺癌定植具有重要意义。最重要的是，这也是首次证明 MPs 作为一种平行途径的导管，通过免疫逃避支持 MDR 癌细胞的细胞存活。
