Shah Tariq, Wildes Flonne, Kakkad Samata, Artemov Dmitri, Bhujwalla Zaver M
JHU ICMIC Program, Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
NMR Biomed. 2016 Jul;29(7):904-11. doi: 10.1002/nbm.3543. Epub 2016 May 5.
Lymphatic vessels serve as the primary route for metastatic spread to lymph nodes. However, it is not clear how interactions between cancer cells and lymphatic endothelial cells (LECs), especially within hypoxic microenvironments, affect the invasion of cancer cells. Here, using an MR compatible cell perfusion assay, we investigated the role of LEC-prostate cancer (PCa) cell interaction in the invasion and degradation of the extracellular matrix (ECM) by two human PCa cell lines, PC-3 and DU-145, under normoxia and hypoxia, and determined the metabolic changes that occurred under these conditions. We observed a significant increase in the invasion of ECM by invasive PC-3 cells, but not poorly invasive DU-145 cells when human dermal lymphatic microvascular endothelial cells (HMVEC-dlys) were present. Enhanced degradation of ECM by PC-3 cells in the presence of HMVEC-dlys identified interactions between HMVEC-dlys and PCa cells influencing cancer cell invasion. The enhanced ECM degradation was partly attributed to increased MMP-9 enzymatic activity in PC-3 cells when HMVEC-dlys were in close proximity. Significantly higher uPAR and MMP-9 expression levels observed in PC-3 cells compared to DU-145 cells may be one mechanism for increased invasion and degradation of matrigel by these cells irrespective of the presence of HMVEC-dlys. Hypoxia significantly decreased invasion by PC-3 cells, but this decrease was significantly attenuated when HMVEC-dlys were present. Significantly higher phosphocholine was observed in invasive PC-3 cells, while higher glycerophosphocholine was observed in DU-145 cells. These metabolites were not altered in the presence of HMVEC-dlys. Significantly increased lipid levels and lipid droplets were observed in PC-3 and DU-145 cells under hypoxia reflecting an adaptive survival response to oxidative stress. These results suggest that in vivo, invasive cells in or near lymphatic endothelial cells are likely to be more invasive and degrade the ECM to influence the metastatic cascade. Copyright © 2016 John Wiley & Sons, Ltd.
淋巴管是癌细胞转移至淋巴结的主要途径。然而，尚不清楚癌细胞与淋巴管内皮细胞（LEC）之间的相互作用，尤其是在缺氧微环境中，如何影响癌细胞的侵袭。在此，我们使用一种与磁共振兼容的细胞灌注分析方法，研究了LEC与前列腺癌细胞（PCa）相互作用在常氧和缺氧条件下对两种人PCa细胞系PC-3和DU-145侵袭和降解细胞外基质（ECM）的作用，并确定了这些条件下发生的代谢变化。我们观察到，当存在人真皮淋巴管微血管内皮细胞（HMVEC-dlys）时，侵袭性PC-3细胞对ECM的侵袭显著增加，但侵袭性较差的DU-145细胞则不然。在HMVEC-dlys存在的情况下，PC-3细胞对ECM的降解增强，这表明HMVEC-dlys与PCa细胞之间的相互作用影响癌细胞侵袭。当HMVEC-dlys紧邻时，PC-3细胞中MMP-9酶活性增加，这部分归因于ECM降解增强。与DU-145细胞相比，PC-3细胞中观察到显著更高的uPAR和MMP-9表达水平，这可能是这些细胞无论HMVEC-dlys是否存在都能增加对基质胶侵袭和降解的一种机制。缺氧显著降低了PC-3细胞的侵袭，但当存在HMVEC-dlys时，这种降低显著减弱。在侵袭性PC-3细胞中观察到显著更高的磷酸胆碱，而在DU-145细胞中观察到更高的甘油磷酸胆碱。在HMVEC-dlys存在的情况下，这些代谢物没有改变。在缺氧条件下，PC-3和DU-145细胞中观察到脂质水平和脂滴显著增加，反映了对氧化应激的适应性存活反应。这些结果表明，在体内，淋巴管内皮细胞内或附近的侵袭性细胞可能更具侵袭性，并降解ECM以影响转移级联反应。版权所有© 2016约翰威立国际出版公司。
