Scherer Sandra D, Bauer Jochen, Schmaus Anja, Neumaier Christian, Herskind Carsten, Veldwijk Marlon R, Wenz Frederik, Sleeman Jonathan P
Centre for Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany.
PLoS One. 2016 Sep 2;11(9):e0162221. doi: 10.1371/journal.pone.0162221. eCollection 2016.
In patients with low-risk breast cancer, intraoperative radiotherapy (IORT) during breast-conserving surgery is a novel and convenient treatment option for delivering a single high dose of irradiation directly to the tumour bed. However, edema and fibrosis can develop after surgery and radiotherapy, which can subsequently impair quality of life. TGF- β is a strong inducer of the extracellular matrix component hyaluronan (HA). TGF-β expression and HA metabolism can be modulated by irradiation experimentally, and are involved in edema and fibrosis. We therefore hypothesized that IORT may regulate these factors.Wound fluid (WF) draining from breast lumpectomy sites was collected and levels of TGF-β1 and HA were determined by ELISA. Proliferation and marker expression was analyzed in primary lymphatic endothelial cells (LECs) treated with recombinant TGF-β or WF. Our results show that IORT does not change TGF-β1 or HA levels in wound fluid draining from breast lumpectomy sites, and does not lead to accumulation of sHA oligosaccharides. Nevertheless, concentrations of TGF-β1 were high in WF from patients regardless of IORT, at concentrations well above those associated with fibrosis and the suppression of LEC identity. Consistently, we found that TGF-β in WF is active and inhibits LEC proliferation. Furthermore, all three TGF-β isoforms inhibited LEC proliferation and suppressed LEC marker expression at pathophysiologically relevant concentrations. Given that TGF-β contributes to edema and plays a role in the regulation of LEC identity, we suggest that inhibition of TGF-β directly after surgery might prevent the development of side effects such as edema and fibrosis.
在低风险乳腺癌患者中，保乳手术期间的术中放疗（IORT）是一种新颖且便捷的治疗选择，可将单次高剂量辐射直接送达肿瘤床。然而，手术和放疗后可能会出现水肿和纤维化，进而损害生活质量。转化生长因子-β（TGF-β）是细胞外基质成分透明质酸（HA）的强效诱导剂。实验表明，TGF-β的表达和HA代谢可受辐射调节，并与水肿和纤维化有关。因此，我们推测IORT可能会调节这些因素。收集了从乳房肿块切除部位引流的伤口渗出液（WF），并通过酶联免疫吸附测定法（ELISA）测定了TGF-β1和HA的水平。对用重组TGF-β或WF处理的原代淋巴管内皮细胞（LEC）进行了增殖和标志物表达分析。我们的结果表明，IORT不会改变从乳房肿块切除部位引流的伤口渗出液中TGF-β1或HA的水平，也不会导致sHA寡糖的积累。尽管如此，无论是否进行IORT，患者伤口渗出液中TGF-β1的浓度都很高，远高于与纤维化和LEC特性抑制相关的浓度。一致地，我们发现伤口渗出液中的TGF-β具有活性，并抑制LEC增殖。此外，在病理生理学相关浓度下，所有三种TGF-β亚型均抑制LEC增殖并抑制LEC标志物表达。鉴于TGF-β会导致水肿并在LEC特性调节中起作用，我们建议术后直接抑制TGF-β可能会预防水肿和纤维化等副作用的发生。
