Gao Darrin, Cazares Lisa H, Fish Eleanor N
Toronto General Hospital Research Institute, University Health Network, Toronto, Canada.
Department of Immunology, University of Toronto, Toronto, Canada.
BMC Cancer. 2017 Dec 8;17(1):834. doi: 10.1186/s12885-017-3817-0.
In earlier studies we have shown that CCL5 activation of CCR5 induces the proliferation and survival of breast cancer cells in a mechanistic target of rapamycin (mTOR)-dependent manner and that this is in part due to CCR5-mediated increases in glycolytic metabolism.
Using the MDA-MB-231 triple negative human breast cancer cell line and mouse mammary tumor virus - polyomavirus middle T-antigen (MMTV-PyMT) mouse primary breast cancer cells, we conducted in vivo tumor transplant experiments to examine the effects of CCL5-CCR5 interactions in the context of regulating tumor metabolism. Additionally, we employed Matrix-Assisted Laser Desorption/Ionization Fourier Transform Ion Cyclotron Resonance Mass Spectrometry imaging (MALDI-FTICR-MSI) to evaluate tumor utilization of cellular metabolites.
We provide evidence that, in the absence of CCR5, the early events associated with rapid tumor growth in the MMTV-PyMT mouse model of spontaneous breast cancer development, are diminished, as demonstrated by a delay in tumor onset. In tumor transplant studies into immunocompromised mice we identify a direct correlation between reduced tumor proliferation and decreased metabolic activity, specifically associated with tumor expression of CCR5. The reduction in tumorigenesis is accompanied by decreases in glucose uptake, glucose transporter-1 (GLUT-1) cell surface expression, intracellular ATP and lactate levels, as well as reduced CCL5 production. Using MALDI-FTICR-MS, we show that the rapid early tumor growth of CCR5 triple negative breast cancer cells in vivo is attributable to increased levels of glycolytic intermediates required for anabolic processes, in contrast to the slower growth rate of their corresponding CCR5 cells, that exhibit reduced glycolytic metabolism.
These findings suggest that CCL5-CCR5 interactions in the tumor microenvironment modulate metabolic events during tumor onset to promote tumorigenesis.
在早期研究中，我们已经表明，CCL5对CCR5的激活以雷帕霉素机制靶点（mTOR）依赖性方式诱导乳腺癌细胞的增殖和存活，部分原因是CCR5介导的糖酵解代谢增加。
使用MDA-MB-231三阴性人乳腺癌细胞系和小鼠乳腺肿瘤病毒-多瘤病毒中T抗原（MMTV-PyMT）小鼠原发性乳腺癌细胞，我们进行了体内肿瘤移植实验，以研究CCL5-CCR5相互作用在调节肿瘤代谢方面的作用。此外，我们采用基质辅助激光解吸/电离傅里叶变换离子回旋共振质谱成像（MALDI-FTICR-MSI）来评估肿瘤对细胞代谢物的利用情况。
我们提供的证据表明，在缺乏CCR5的情况下，MMTV-PyMT自发乳腺癌发展小鼠模型中与肿瘤快速生长相关的早期事件会减少，这表现为肿瘤发生延迟。在免疫缺陷小鼠的肿瘤移植研究中，我们发现肿瘤增殖减少与代谢活性降低之间存在直接相关性，这与肿瘤CCR5的表达特别相关。肿瘤发生的减少伴随着葡萄糖摄取、葡萄糖转运蛋白-1（GLUT-1）细胞表面表达、细胞内ATP和乳酸水平的降低，以及CCL5产生的减少。使用MALDI-FTICR-MS，我们表明CCR5三阴性乳腺癌细胞在体内的早期快速肿瘤生长归因于合成代谢过程所需的糖酵解中间体水平的增加，而其相应的CCR5细胞生长较慢，表现出糖酵解代谢降低。
这些发现表明，肿瘤微环境中的CCL5-CCR5相互作用在肿瘤发生过程中调节代谢事件以促进肿瘤发生。
