Cell and Molecular Division, Department of Biology, University of North Carolina, Charlotte, 9201 University City Blvd., Charlotte, NC, 28223, USA.
Angiogenesis. 2014 Jul;17(3):573-85. doi: 10.1007/s10456-013-9405-2. Epub 2013 Nov 7.
Most deaths associated with breast cancer, the most common malignancy in women, are caused by metastasis. Tumor associated macrophages significantly contribute to breast cancer progression and development of metastasis through the promotion of angiogenesis which involves a central regulator of macrophage functions: nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Macrophages are activated by macrophage colony stimulating factor (MCSF) and chemokine (C-C motif) ligand 2 (CCL2) to secrete angiogenic factors including vascular endothelial growth factor (VEGF). The release of MCSF from tumor cells is mediated by ectodomain shedding through tumor necrosis factor alpha converting enzyme activation (TACE). Here we determined whether tumor cells TACE-shed MCSF promotes angiogenesis through activation of the NF-κB pathway in macrophages and the subsequent release of VEGF. These interactions were modeled in vitro using a panel of mammary cells mimicking the breast cancer progression from normal murine mammary gland cells to metastatic 4T1 cells along with J774 macrophages, all derived from BALB/c mice. TACE and MCSF expressions were higher in metastatic cells compared to epithelial cells (p < 0.05). Tumor conditioned medias activated the expression of VEGF by macrophages through stimulation of the NF-κB pathway and resulting macrophage secretions that promoted high levels of endothelial cell tubes. Furthermore, the combinations of CCL2, also highly expressed by tumor cells, and MCSF promoted pro-angiogenic macrophages. These results highlight the key role of tumor cell TACE-shed MCSF and secreted CCL2 in stimulating pro-angiogenic macrophages.
大多数与乳腺癌相关的死亡，乳腺癌是女性最常见的恶性肿瘤，是由转移引起的。肿瘤相关巨噬细胞通过促进血管生成显著促进乳腺癌的进展和转移的发展，血管生成涉及巨噬细胞功能的中央调节因子：核因子κ轻链增强子的激活 B 细胞（NF-κB）。巨噬细胞被巨噬细胞集落刺激因子（MCSF）和趋化因子（C-C 基序）配体 2（CCL2）激活，分泌血管生成因子，包括血管内皮生长因子（VEGF）。肿瘤细胞通过肿瘤坏死因子α转化酶激活（TACE）的外显子脱落来介导 MCSF 的释放。在这里，我们确定肿瘤细胞 TACE 脱落的 MCSF 是否通过激活巨噬细胞中的 NF-κB 途径以及随后释放 VEGF 来促进血管生成。这些相互作用在体外使用一系列模拟乳腺癌进展的乳腺细胞进行了建模，从正常的乳腺腺泡细胞到转移性 4T1 细胞，以及 J774 巨噬细胞，所有这些都来自 BALB/c 小鼠。与上皮细胞相比，转移性细胞中 TACE 和 MCSF 的表达更高（p < 0.05）。肿瘤条件培养基通过刺激 NF-κB 途径激活巨噬细胞表达 VEGF，并导致巨噬细胞分泌促进内皮细胞管高水平的物质。此外，肿瘤细胞也高表达的趋化因子 CCL2 与 MCSF 一起促进了促血管生成的巨噬细胞。这些结果强调了肿瘤细胞 TACE 脱落的 MCSF 和分泌的 CCL2 在刺激促血管生成的巨噬细胞中的关键作用。
