Canine mammary cancer cells direct macrophages toward an intermediate activation state between M1/M2.
Canine mammary cancer cells direct macrophages toward an intermediate activation state between M1/M2.
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DOI：
10.1186/s12917-015-0473-y
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发表时间：
2015-07-15
影响因子：
2.6
通讯作者：
Argyle DJ
中科院分区：
文献类型：
--
作者：
Beirão BC;Raposo T;Pang LY;Argyle DJ
犬乳腺癌是雌性犬中最常见的癌症，并且由于远距离转移的发展而常常是致命的。肿瘤的微环境通常含有大量的巨噬细胞浸润，称为肿瘤相关巨噬细胞（TAM）。TAM表达活化的表型，称为M2，其维持癌细胞的增殖，并且与人类癌症患者的不良临床结果相关。癌细胞本身已经涉及刺激巨噬细胞转化为具有M2表型的TAM。这一进程尚未得到充分阐明。在这里，我们调查癌细胞和巨噬细胞之间的相互作用，在犬乳腺癌的背景下。我们发现，癌细胞抑制脂多糖（LPS）诱导的巨噬细胞活化。此外，我们发现巨噬细胞相关蛋白，集落刺激因子（CSF）-1和C-C基序配体（CCL）-2，刺激巨噬细胞，并负责癌细胞对巨噬细胞的影响。我们认为巨噬细胞和癌细胞之间存在反馈回路;虽然癌细胞通过CSF-1和CCL 2影响TAM的表型，但巨噬细胞诱导犬乳腺癌细胞上调其自身CSF-1和CCL 2受体的表达，并增加癌细胞代谢活性。然而，这些细胞因子单独诱导巨噬细胞中的表型状态，其在M1和M2表型之间。总体而言，我们的研究结果表明犬乳腺癌细胞影响巨噬细胞表型的程度和这些细胞之间的反馈回路的相关性，涉及CSF-1和CCL 2作为重要的介质。本文的在线版本（doi：10.1186/s12917-015-0473-y）包含补充材料，可供授权用户使用。
Canine mammary carcinoma is the most common cancer in female dogs and is often fatal due to the development of distance metastasis. The microenvironment of a tumour often contains abundant infiltrates of macrophages called tumour-associated macrophages (TAMs). TAMs express an activated phenotype, termed M2, which sustains proliferation of cancer cells, and has been correlated with poor clinical outcomes in human cancer patients. Cancer cells themselves have been implicated in stimulating the conversion of macrophages to a TAM with an M2 phenotype. This process has yet to be fully elucidated. Here we investigate the interplay between cancer cells and macrophages in the context of canine mammary carcinoma. We show that cancer cells inhibit lipopolysaccharide (LPS)-induced macrophage activation. Further, we show that macrophage associated proteins, colony-stimulating factor (CSF)-1 and C-C motif ligand (CCL)-2, stimulate macrophages and are responsible for the effects of cancer cells on macrophages. We suggest the existence of a feedback loop between macrophages and cancer cells; while cancer cells influence the phenotype of the TAMs through CSF-1 and CCL2, the macrophages induce canine mammary cancer cells to upregulate their own expression of the receptors for CSF-1 and CCL2 and increase the cancer cellular metabolic activity. However, these cytokines in isolation induce a phenotypic state in macrophages that is between M1 and M2 phenotypes. Overall, our results demonstrate the extent to which canine mammary carcinoma cells influence the macrophage phenotype and the relevance of a feedback loop between these cells, involving CSF-1 and CCL2 as important mediators. The online version of this article (doi:10.1186/s12917-015-0473-y) contains supplementary material, which is available to authorized users.