Sharma Sikander, Evans Andrew, Hemers Elaine
Biomolecular Sciences, School of Pharmacy and Bimolecular Sciences, Liverpool John Moores University, Liverpool, L3 3AF, UK.
Cell Tissue Res. 2016 Aug;365(2):357-66. doi: 10.1007/s00441-016-2389-7. Epub 2016 Mar 16.
Glucose deprivation, hypoxia and acidosis are characteristic features of the central core of most solid tumours. Myofibroblasts are stromal cells present in many such solid tumours, including those of the colon, and are known to be involved in all stages of tumour progression. HMGB1 is a nuclear protein with an important role in nucleosome stabilisation and gene transcription; it is also released from immune cells and is involved in the inflammatory process. We report that the microenvironmental condition of glucose deprivation is responsible for the active release of HMGB1 from various types of cancer cell lines (HT-29, MCF-7 and A549) under normoxic conditions. Recombinant HMGB1 (10 ng/ml) triggered proliferation in myofibroblast cells via activation of PI3K and MEK1/2. Conditioned medium collected from glucose-deprived HT-29 colon cancer cells stimulated the migration and invasion of colonic myofibroblasts, and these processes were significantly inhibited by immunoneutralising antibodies to HMGB1, RAGE and TLR4, together with specific inhibitors of PI3K and MEK1/2. Our data suggest that HMGB1 released from cancer cells under glucose deprivation is involved in stimulating colonic myofibroblast migration and invasion and that this occurs through the activation of RAGE and TLR4, resulting in the activation of the MAPK and PI3K signalling pathways. Thus, HMGB1 might be released by cancer cells in areas of low glucose in solid tumours with the resulting activation of myofibroblasts and is a potential therapeutic target to inhibit solid tumour growth.
葡萄糖剥夺、缺氧和酸中毒是大多数实体瘤中心区域的典型特征。肌成纤维细胞是存在于许多此类实体瘤（包括结肠癌）中的基质细胞，已知其参与肿瘤进展的各个阶段。高迁移率族蛋白B1（HMGB1）是一种核蛋白，在核小体稳定和基因转录中起重要作用；它也从免疫细胞中释放出来，并参与炎症过程。我们报告，在常氧条件下，葡萄糖剥夺的微环境状况导致各种癌细胞系（HT - 29、MCF - 7和A549）主动释放HMGB1。重组HMGB1（10 ng/ml）通过激活PI3K和MEK1/2触发肌成纤维细胞增殖。从葡萄糖剥夺的HT - 29结肠癌细胞收集的条件培养基刺激结肠肌成纤维细胞的迁移和侵袭，而针对HMGB1、RAGE和TLR4的免疫中和抗体以及PI3K和MEK1/2的特异性抑制剂可显著抑制这些过程。我们的数据表明，在葡萄糖剥夺条件下癌细胞释放的HMGB1参与刺激结肠肌成纤维细胞的迁移和侵袭，并且这是通过激活RAGE和TLR4发生的，导致MAPK和PI3K信号通路的激活。因此，HMGB1可能在实体瘤低葡萄糖区域由癌细胞释放，从而激活肌成纤维细胞，并且是抑制实体瘤生长的潜在治疗靶点。
