Roy Ananya, Femel Julia, Huijbers Elisabeth J M, Spillmann Dorothe, Larsson Erik, Ringvall Maria, Olsson Anna-Karin, Åbrink Magnus
Swedish University of Agricultural Sciences, Department of Biomedical Sciences and Veterinary Public Health, Box 7028, 75007, Uppsala, Sweden.
Uppsala University, Department of Medical Biochemistry and Microbiology, Box 582, 75123, Uppsala, Sweden.
PLoS One. 2016 May 25;11(5):e0156151. doi: 10.1371/journal.pone.0156151. eCollection 2016.
In hematopoietic cells, serglycin proteoglycans mainly contribute to proper storage and secretion of inflammatory mediators via their negatively charged glycosaminoglycans. Serglycin proteoglycans are also expressed in cancer cells where increased expression has been linked to poor prognosis. However, the serglycin-dependent mediators promoting cancer progression remain to be determined. In the present study we report that genetic ablation of serglycin proteoglycan completely blocks lung metastasis in the MMTV-PyMT-driven mouse breast cancer model, while serglycin-deficiency did not affect primary tumour growth or number of mammary tumours. Although E-cadherin expression was higher in the serglycin-deficient primary tumour tissue, indicating reduced invasiveness, serglycin-deficient tumour cells were still detected in the circulation. These data suggest that serglycin proteoglycans play a role in extravasation as well as colonization and growth of metastatic cells. A microarray expression analysis and functional annotation of differentially expressed genes identified several biological pathways where serglycin may be important. Our results suggest that serglycin and serglycin-dependent mediators are potential drug targets to prevent metastatic disease/dissemination of cancer.
在造血细胞中，丝甘素蛋白聚糖主要通过其带负电荷的糖胺聚糖，对炎症介质的适当储存和分泌起作用。丝甘素蛋白聚糖也在癌细胞中表达，其表达增加与预后不良有关。然而，促进癌症进展的丝甘素依赖性介质仍有待确定。在本研究中，我们报告在MMTV-PyMT驱动的小鼠乳腺癌模型中，丝甘素蛋白聚糖的基因缺失完全阻断了肺转移，而丝甘素缺乏并不影响原发性肿瘤生长或乳腺肿瘤数量。虽然在丝甘素缺乏的原发性肿瘤组织中E-钙黏蛋白表达较高，表明侵袭性降低，但在循环中仍可检测到丝甘素缺乏的肿瘤细胞。这些数据表明，丝甘素蛋白聚糖在转移细胞的外渗以及定植和生长中发挥作用。对差异表达基因的微阵列表达分析和功能注释确定了几个丝甘素可能起重要作用的生物学途径。我们的结果表明，丝甘素和丝甘素依赖性介质是预防癌症转移性疾病/播散的潜在药物靶点。
